Conditions: Schizophrenia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 178
Healthy volunteers: no

Brief summary:
The main purpose of this study is to assess the long-term safety and tolerability of paliperidone 6-month PP6M (Dose 1 or Dose 2 \[milligram\] mg eq.) and to provide access to PP6M in participants with schizophrenia completing the R092670PSY3015 study without relapse.

Detailed description:

Arms:
arm 1: Participants who enter the this open-label extension study immediately after completing Double-blind Phase Study R092670PSY3015 (previous study) will receive Paliperidone Palmitate 6 month (PP6M) intramuscular (IM) injections, dose will be selected based on the unblinded dose level ("moderate" or "higher") that the participant received during previous study. Participants in the "moderate" dose level will receive PP6M Dose 1 and "higher" dose level will receive PP6M Dose 2 during the open-label extension. The PP6M dose level may be adjusted (to Dose 1 or Dose 2) for every 6 month at Visits 3, 5, and 7, based on clinical judgment. Participants who enter this open-label extension study later (up to 3 months after they complete previous study) and were on a moderate or higher dose of PP3M (350 or 525 mg eq.) or PP1M (100 or 150 mg eq.) will receive initial dose of PP6M IM injection (Dose 1 or Dose 2) for every 6 months.

Interventions: intervention 1: PP6M injection Dose 1 intervention 2: PP6M injection Dose 2
Intervention descriptions: intervention 1: Participants will receive Dose 1 PP6M intramuscular (IM) injection at Visit 1 (Day) then once every 6 month up to 24 months. intervention 2: Participants will receive Dose 2 PP6M IM injection at Visit 1 (Day) then once every 6 month up to 24 months.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 15 December 2020
Janssen Research & Development *
Clinical Protocol
Single-arm, Open-label Extension to a Double-blind, Randomized, Active-controlled, 
Parallel-group Study of Paliperidone Palmitate 6-Month Formulation
Protocol R092670PSY3016; Phase 3
AMENDMENT 2
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: 2018-004532-30
Status:
Approved
Date:
15 December 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number: EDMS-ERI-177701234, 2.0
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.
NCT04072575


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
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Status: Approved,  Date: 15 December 2020
PROTOCOL AMENDMENTS
DOCUMENT HISTORY
Document
Date
Amendment 2
15-Dec-2020
Amendment 1 (COVID-19 Appendix)
23-Apr-2020
Original Protocol
14-Feb-2019
Amendment 2, 15 December 2020
Overall Rationale for the Amendment:  To remove text related to anticipated events and to increase the 
estimated number of subjects to be enrolled in the study.
Section Number
and Name
Description of Change
Brief Rationale
Section 12.3.1. All 
Adverse Events; 
Attachment 3
Text related to anticipated events has been deleted 
from Section 12.3.1.
Attachment 3 has been removed from the protocol.
Text related to anticipated events has 
been removed from the protocol to 
align with (1) the sponsor’s current 
Safety Assessment Committee 
policy, which does not require 
review of anticipated events in 
single-arm, open-label extension 
studies by a safety committee 
independent of the study team, and 
(2) current protocol template text, 
which does not require a list of 
anticipated events for single-arm, 
open-label studies.
Synopsis, Overview 
of Study Design; 
Section 3.1. 
Overview of Study 
Design
The estimated number of subjects to be enrolled in 
the study was increased from approximately 100 to 
approximately 180.
The estimated number of subjects 
was increased because (1) the 
number of subjects enrolled in Study 
R092670PSY3015 was higher than 
anticipated, (2) the relapse and early 
withdrawal rates during the double-
blind phase of Study 
R092670PSY3015 were lower than 
expected, resulting in a higher rate 
of enrollment in Study 
R092670PSY3016, and (3) 1 
country was added to the list of 
countries participating in Study 
R092670PSY3016.
Time and Events 
Schedule; 3.2. Study 
Design Rationale
Added the mental status examination to the list of 
assessments that may be performed at other 
scheduled or unscheduled visits, as deemed 
necessary by the investigator.
Text added to clarify that the mental 
status examination may be 
performed as needed per the 
investigator.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
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Status: Approved,  Date: 15 December 2020
Amendment 1, 23 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.


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Status: Approved,  Date: 15 December 2020
TABLE OF CONTENTS
PROTOCOL AMENDMENTS....................................................................................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF ATTACHMENTS............................................................................................................................ 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
SYNOPSIS.................................................................................................................................................... 7
TIME AND EVENTS SCHEDULE .............................................................................................................. 10
A.
Open-label Extension Study .......................................................................................................... 10
B.
Follow-up Phase (for Subjects Who Discontinue, Withdraw, or Relapse)..................................... 12
ABBREVIATIONS AND TERMS................................................................................................................ 13
1.
INTRODUCTION................................................................................................................................ 14
1.1.
Background .................................................................................................................................... 15
1.2.
Overall Rationale for the Study...................................................................................................... 18
1.3.
Benefit/Risk Assessment ............................................................................................................... 19
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 20
2.1.
Objectives and Endpoints .............................................................................................................. 20
2.2.
Hypothesis ..................................................................................................................................... 22
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 22
3.1.
Overview of Study Design.............................................................................................................. 22
3.2.
Study Design Rationale.................................................................................................................. 24
4.
SUBJECT POPULATION.................................................................................................................. 27
4.1.
Inclusion Criteria ............................................................................................................................ 27
4.2.
Exclusion Criteria ........................................................................................................................... 29
4.3.
Prohibitions, Restrictions, and Strong Recommendations............................................................. 29
5.
INTERVENTION ALLOCATION AND BLINDING ............................................................................ 30
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 30
7.
INTERVENTION COMPLIANCE....................................................................................................... 32
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 32
8.1.
Prestudy Medical Therapy and Psychotherapy ............................................................................. 32
8.2.
Concomitant Therapy..................................................................................................................... 32
8.3.
Prohibited Concomitant Medications ............................................................................................. 33
9.
STUDY EVALUATIONS .................................................................................................................... 34
9.1.
Study Procedures........................................................................................................................... 34
9.2.
Efficacy Evaluations....................................................................................................................... 35
9.2.1.
Clinical Global Impression - Severity.......................................................................................... 36
9.2.2.
Personal and Social Performance Scale.................................................................................... 36
9.2.3.
Positive and Negative Syndrome Scale ..................................................................................... 36
9.2.4.
Relapse Criteria .......................................................................................................................... 36
9.3.
Safety Evaluations ......................................................................................................................... 37
9.3.1.
Adverse Events........................................................................................................................... 37
9.3.2.
Mental Status Examination/Clinical Assessment ....................................................................... 37
9.3.3.
Clinical Laboratory Tests ............................................................................................................ 37


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9.3.4.
Vital Signs................................................................................................................................... 39
9.3.5.
Physical Examinations................................................................................................................ 40
9.3.6.
Extrapyramidal Symptom Rating Scales .................................................................................... 40
9.3.7.
Evaluations of the Injection Site ................................................................................................. 41
9.3.7.1.
Injection Site Evaluations by Subjects..................................................................................... 41
9.3.7.2.
Injection Site Evaluations and Follow-up by Investigators ...................................................... 41
9.3.8.
Columbia Suicide Severity Rating Scale .................................................................................... 42
9.3.9.
Electrocardiograms..................................................................................................................... 43
9.4.
Medical Resource Utilization.......................................................................................................... 43
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY INTERVENTION/ 
WITHDRAWAL FROM THE STUDY................................................................................................. 44
10.1.
Completion ..................................................................................................................................... 44
10.2.
Withdrawal From the Study............................................................................................................ 44
10.3.
Antipsychotic Therapy After the Study........................................................................................... 45
11.
STATISTICAL METHODS................................................................................................................. 46
11.1.
Subject Information ........................................................................................................................ 46
11.2.
Sample Size Determination ........................................................................................................... 46
11.3.
Efficacy Analyses ........................................................................................................................... 46
11.4.
Safety Analyses ............................................................................................................................. 47
11.5.
Medical Resource Utilization.......................................................................................................... 49
12.
ADVERSE EVENT REPORTING ...................................................................................................... 49
12.1.
Definitions ...................................................................................................................................... 49
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 49
12.1.2.
Attribution Definitions.................................................................................................................. 50
12.1.3.
Severity Criteria .......................................................................................................................... 51
12.2.
Special Reporting Situations.......................................................................................................... 51
12.3.
Procedures..................................................................................................................................... 51
12.3.1.
All Adverse Events...................................................................................................................... 51
12.3.2.
Serious Adverse Events ............................................................................................................. 52
12.3.3.
Pregnancy................................................................................................................................... 53
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 53
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 54
13.1.
Procedures..................................................................................................................................... 54
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 54
14.
STUDY INTERVENTION INFORMATION ........................................................................................ 54
14.1.
Physical Description of Study Intervention..................................................................................... 54
14.2.
Packaging ...................................................................................................................................... 54
14.3.
Labeling.......................................................................................................................................... 55
14.4.
Preparation, Handling, and Storage............................................................................................... 55
14.5.
Intervention Accountability ............................................................................................................. 55
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 55
16.
ETHICAL ASPECTS ......................................................................................................................... 56
16.1.
Study-specific Design Considerations ........................................................................................... 56
16.2.
Regulatory Ethics Compliance....................................................................................................... 56
16.2.1.
Investigator Responsibilities ....................................................................................................... 56
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 57
16.2.3.
Informed Consent ....................................................................................................................... 58
16.2.4.
Privacy of Personal Data ............................................................................................................ 59
16.2.5.
Country Selection ....................................................................................................................... 59
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 60
17.1.
Protocol Amendments.................................................................................................................... 60


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Status: Approved,  Date: 15 December 2020
17.2.
Regulatory Documentation ............................................................................................................ 60
17.2.1.
Regulatory Approval/Notification ................................................................................................ 60
17.2.2.
Required Prestudy Documentation............................................................................................. 60
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 61
17.4.
Source Documentation................................................................................................................... 61
17.5.
Electronic Case Report Form Completion ..................................................................................... 62
17.6.
Data Quality Assurance / Quality Control ...................................................................................... 62
17.7.
Record Retention ........................................................................................................................... 63
17.8.
Monitoring ...................................................................................................................................... 63
17.9.
Study Completion/Termination....................................................................................................... 64
17.9.1.
Study Completion (End of Study) ............................................................................................... 64
17.9.2.
Study Termination....................................................................................................................... 64
17.10.
On-Site Audits ................................................................................................................................ 65
17.11.
Use of Information and Publication................................................................................................ 65
REFERENCES............................................................................................................................................ 67
ATTACHMENTS......................................................................................................................................... 68
INVESTIGATOR AGREEMENT ................................................................................................................. 70
LIST OF ATTACHMENTS
Attachment 1:
Guidelines for the Intramuscular Injection of Paliperidone Palmitate 6-month 
Injection ...................................................................................................................... 68
Attachment 2:
Standard Placement of ECG Electrodes.................................................................... 69
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Conversions Between Doses and Injection Volumes for the 1-, 3-, and 6-Month 
Paliperidone Palmitate Products............................................................................................... 15
Table 2:
Supplemental Oral Antipsychotic Dosage Chart ...................................................................... 33
Table 3:
Switching Conversion Table (Oral and LAI Paliperidone) ........................................................ 46
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 23


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Status: Approved,  Date: 15 December 2020
SYNOPSIS
Single-arm, Open-label Extension to a Double-blind, Randomized, Active-controlled, 
Parallel-group Study of Paliperidone Palmitate 6-Month Formulation
Paliperidone, the active metabolite of risperidone, is a monoaminergic antagonist that exhibits the 
characteristic dopamine type 2 (D2) combined with predominant serotonin (5-hydroxytryptamine [5HT] 
type 2A [5HT2A]) antagonism of the newer, or second generation, antipsychotic drugs. Paliperidone is 
currently available for therapeutic use in 3 formulations: an oral extended-release (ER) tablet formulation 
and two long-acting injectable formulations (paliperidone palmitate 1-month injection [PP1M] and 
paliperidone palmitate 3-month injection [PP3M]). To support further improvement in adherence and 
convenience, the sponsor is now developing a third paliperidone palmitate product intended for 
administration once every 6 months (paliperidone palmitate 6-month injection [PP6M]).
The current study is an open-label extension designed to assess the long-term safety and tolerability of 
PP6M and to provide medication access to PP6M in subjects with schizophrenia who have previously 
been treated in a double-blind, randomized, active-controlled study (Study R092670PSY3015). Only a 
limited number of countries participating in Study R092670PSY3015 will take part in this open-label 
extension.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess
(in a limited number of 
countries)
the 
long-term 
safety 
and 
tolerability of PP6M (700 or 1000 mg eq.) 
and to provide access to PP6M in subjects 
with 
schizophrenia 
completing 
the 
R092670PSY3015 study without relapse.

Safety will be assessed through evaluation of 
adverse events, mental status examination, 
clinical laboratory values, vital signs, physical 
examinations, 
the 
Abnormal 
Involuntary 
Movement Scale (AIMS), and injection site 
evaluations. Mandatory assessments will occur 
at limited time points during the study with 
additional assessments to be added at the 
discretion of the investigator if considered 
necessary.

Proportion of subjects who receive 1, 2, 3, or 4 
PP6M injections. 
Secondary

To assess the long-term efficacy of PP6M 
based on:

Efficacy will be assessed based on the change 
from open-label extension baseline on:

Overall symptom improvement and 
global severity of the illness

The Clinical Global Impression-Severity
(CGI-S) scale.

Personal and social functioning

The Personal and Social Performance (PSP) 
scale.

Remission rates

The proportion of subjects in remission will 
be assessed based on the Positive and 
Negative 
Syndrome 
Scale 
(PANSS)
assessment 
at 
open-label 
extension 
baseline, Month 12, Month 24, and the


R092670 (paliperidone palmitate)
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Status: Approved,  Date: 15 December 2020
Objectives
Endpoints
End-of-Study/Early Withdrawal visit.

To continually assess the long-term 
effectiveness of PP6M on the prevention 
of relapse by evaluating the data from 
R092670PSY3015 and
R092670PSY3016.  

Effectiveness will be assessed based on relapse, 
where relapse in the open-label extension is 
defined as one or more of the following:

Psychiatric 
hospitalization 
for 
schizophrenia (involuntary or voluntary 
admission to a psychiatric hospital for 
decompensation 
of 
the 
subject’s 
schizophrenic symptoms);

Emergency Department/Room/Ward visit 
due to a worsening of the subject’s 
symptoms 
of 
schizophrenia, 
but 
a 
psychiatric hospitalization does not occur; 

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;

The subject has suicidal or homicidal 
ideation and aggressive behavior that is 
clinically significant (in frequency and 
severity) in the investigator’s judgment.

To evaluate the impact of PP6M on 
Medical Resource Utilization

Based on the Healthcare Resource Utilization 
Questionnaire (HRUQ).
Note: Data from this study may also be used in a future analysis and combined with results from other 
studies (R092670PSY3015 and R092670SCH4067). If performed, this analysis will be reported 
separately.
Hypothesis
The primary hypothesis is that long-term treatment with PP6M (700 or 1000 mg eq.) is safe and well 
tolerated in subjects with schizophrenia who have previously been treated with PP6M for 12 months, or 
are being switched to PP6M from corresponding doses of PP3M. 
OVERVIEW OF STUDY DESIGN
This study is a single-arm, 24-month open-label extension to Study R092670PSY3015, a double-blind, 
randomized, active-controlled, parallel-group study to evaluate whether the efficacy of PP6M is 
noninferior to that of PP3M in adults with schizophrenia. Subjects who complete the 12-month Double-
blind Phase of R092670PSY3015 in the selected countries without a relapse will be eligible to enter the 
open-label 
extension 
study 
(R092670PSY3016). 
Approximately 
180
subjects 
from 
Study 
R092670PSY3015 are estimated to be enrolled in the open-label extension.
All subjects will initially complete a screening assessment, during which eligibility will be assessed and 
informed consent obtained. Subjects who satisfy inclusion criteria will enter the 24-month open-label 
extension study. Subjects will attend site visits at a minimum of once every 3 months to complete safety, 
efficacy, and other assessments, with additional visits to be added at the discretion of the investigator as 
deemed necessary, per usual clinical practice. Subjects who meet criteria for relapse or other criteria for 
withdrawal during the study will be discontinued; these subjects will complete the End-of-Study 


R092670 (paliperidone palmitate)
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Status: Approved,  Date: 15 December 2020
procedures as soon as possible and return for a follow-up assessment 6 months (183 ± 14 days) after their 
last PP6M injection.
For subjects who do not relapse or withdraw, study participation will be continued for up to a maximum 
of 2 years, or until PP6M becomes commercially available in the subject’s local country, whichever 
occurs first. Subjects will get access to the medication for a maximum of 2 years. If PP6M becomes 
available locally before the 2-year endpoint, then subjects will be considered as having completed the 
open-label extension study and will be switched to a commercially available supply if they wish to 
continue the PP6M treatment.
SUBJECT POPULATION
The study will enroll adult men and women with Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) diagnosis of schizophrenia who completed the Double-blind Phase of Study 
R092670PSY3015 without a relapse and who continue to be willing to be treated with PP6M.
DOSAGE AND ADMINISTRATION
All subjects in the open-label extension study will receive treatment with PP6M (700 or 1000 mg eq.), 
with injections administered once every 6 months. The initial dose of PP6M will be determined based on 
the dose level (“moderate” or “higher”) that the subject was receiving during the Double-blind Phase of 
Study R092670PSY3015. Investigators will be allowed to change the PP6M dose during the study based 
on clinical judgment. All PP6M injections will be administered in the gluteal muscle, and will rotate 
across both sides (left or right) of the body.
EFFICACY EVALUATIONS
Efficacy evaluations include the CGI-S scale, the PSP scale, the PANSS (at limited timepoints, to allow 
assessment of remission), and relapse.
SAFETY EVALUATIONS
The study's safety evaluations will include assessment of adverse events, mental status examination, 
clinical laboratory assessments, vital signs, physical examinations, the AIMS, and injection site 
evaluations. In addition, the Columbia Suicide Severity Rating Scale (C-SSRS) will be performed if 
suicidal ideation is identified during the mental status examination. Other safety assessments (including 
but not limited to: 12-lead electrocardiogram [ECG], Barnes Akathisia Rating Scale [BARS], Simpson 
Angus Scale [SAS], and urine drug screen) may be conducted if deemed necessary by the investigator.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization will be evaluated using the HRUQ.
STATISTICAL METHODS
The sample size will be determined by the number of subjects who complete Double-blind Phase of Study 
R092670PSY3015 without relapse and are willing to participate in R092670PSY3016.
All subjects who receive at least one dose of study intervention (PP6M) during the open-label extension
study will be included in the evaluable analysis population. Descriptive statistics, summaries, tabulations, 
listings, etc. will be provided for each outcome as appropriate.




R092670 (paliperidone palmitate)
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Status: Approved,  Date: 15 December 2020
f.
The pregnancy test is applicable only to women of childbearing potential. It will be a urine test at all time points (via local 
testing) and must be confirmed negative before study intervention is administered at the marked visits.
g.
Results from the R092670PSY3015 End-of-Study visit may be used, unless the End-of Study visit of R092670PSY3015 and 
Visit 1 (Day 1) of R092670PSY3016 are more than 4 weeks apart.
h.
The mental status examination includes an assessment of suicidal ideation. If present, a C-SSRS is to be performed. 
i.
In addition to marked visits, assessments may also be performed at other visits, whether scheduled or unscheduled, as 
deemed necessary by the investigator. These include, but are not limited to: mental status examination, CGI-S, C-SSRS, 
AIMS, BARS, SAS, hematology labs, chemistry labs, urinalysis, urine drug screen, 12-lead ECG. 
j.
Physical examinations include body examination, weight, and waist circumference. Body mass index (BMI) will be 
calculated using the height measurement taken at the screening visit of Study R092670PSY3015.
k.
End-of-Study procedures must also be completed for subjects who relapse or meet other criteria for withdrawal from the 
study.  These procedures are to be completed on the day that withdrawal or relapse occurs, or as soon as possible thereafter.
Subjects who withdraw or relapse should return for an additional follow-up visit (please refer to the Time and Events 
Schedule for the Follow-up Phase on the next page).


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Status: Approved,  Date: 15 December 2020
B. Follow-up Phase (for Subjects Who Discontinue, Withdraw, or Relapse)
Phase
Follow-up Phase
Visit Number (of Study)
Variable
Day
183 days from last study drug injection
Visit Window (Days)
±14
Concomitant therapy
X
Adverse events
X
Note: The Follow-up Phase is applicable only to subjects who relapse or meet other relevant conditions for withdrawal or 
discontinuation, as described in Section 10.2 (Withdrawal From the Study). 


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Status: Approved,  Date: 15 December 2020
ABBREVIATIONS AND TERMS
Abbreviations
5HT2A
5-hydroxytryptamine type 2A
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
BMI
body mass index
CGI-S
Clinical Global Impression - Severity
C-SSRS
Columbia Suicide Severity Rating Scale
D2
dopamine type 2
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
F015
a formulation of paliperidone palmitate, used in PP3M and PP6M
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
G[x]
a general-psychopathology item of the PANSS scale, where x is the number of the item
GCP
Good Clinical Practice
HRUQ
Healthcare Resource Utilization Questionnaire
ICF
Informed Consent Form
ICH
International Conference on Harmonisation / International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
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
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)
SAS
Simpson Angus Scale
TEAE
treatment-emergent adverse event
VAS
Visual Analog Scale
Definitions
study 
“intervention”
PP6M (previously referred to as study “drug”)


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Clinical Protocol R092670PSY3016 Amendment 2
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Status: Approved,  Date: 15 December 2020
1.
INTRODUCTION
Paliperidone, the active metabolite of risperidone, is a monoaminergic antagonist that exhibits 
the 
characteristic 
dopamine 
type 
2 
(D2),
combined 
with 
predominant 
serotonin 
(5-hydroxytryptamine [5HT] type 2A [5HT2A]), antagonism of the newer, or second generation, 
antipsychotic drugs. Paliperidone is currently available for therapeutic use in 3 formulations: an 
oral extended-release (ER) tablet formulation (INVEGA®) and two long-acting injectable 
formulations (paliperidone palmitate 1-month injection [PP1M] and paliperidone palmitate 3-
month injection [PP3M]). To support further improvement in adherence and convenience, the 
sponsor is now developing a third paliperidone palmitate product intended for administration 
once every 6 months (paliperidone palmitate 6-month injection [PP6M]).
The PP6M product has been developed building upon the extensive knowledge collected during 
the development of the PP1M and PP3M formulations. The PP1M and PP3M formulations (F013 
and F015, respectively) contain the same drug substance and similar excipients and are 
manufactured using the same equipment and process. The main differences between PP3M and 
PP1M are the suspension strength, particle size, and the fill volume for injection. The PP6M 
product has the same formulation as the PP3M product (F015). The key differences between the 
PP3M and PP6M product are that PP6M will be provided as a larger injection volume (and hence 
larger dose), is administered once every 6 months (as opposed to once every 3 months for 
PP3M), and, due to the larger volume, it planned to only be delivered in the gluteal muscle. 
Based on population pharmacokinetic (PK) simulations, it is expected that these changes will 
enable sustained paliperidone exposures over a 6-month dosing interval. 
The current study is an open-label extension designed to evaluate the long-term safety and 
tolerability of PP6M and to provide medication access to PP6M for subjects with schizophrenia 
who have previously been treated in a double-blind, randomized, active-controlled study (Study 
R092670PSY3015). Subjects who complete 12 months of treatment with PP3M or PP6M during 
the Double-blind Phase of Study R092670PSY3015 without a relapse will be eligible, in a 
limited number of countries, to enter the current study and will receive PP6M (700 or 1000 mg 
eq.) during the 24-month open-label extension. 
Doses of paliperidone palmitate (PP1M, PP3M, and PP6M) can be expressed in milligrams (mg) 
of paliperidone palmitate or in milligrams equivalent (mg eq.) to paliperidone. Throughout this 
document, doses will be described in mg eq. Conversions between paliperidone palmitate 
products and between units are described in Table 1. 


R092670 (paliperidone palmitate)
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Status: Approved,  Date: 15 December 2020
Table 1:
Conversions Between Doses and Injection Volumes for the 1-, 3-, and 6-Month Paliperidone 
Palmitate Products
F013 Formulation
F015 Formulation
PP1M Dose
PP3M Dosea
PP6M Doseb
mg eq.
mg
Volume
mg eq.
mg
Volume
mg eq.
mg
Volume
25 mg eq.
39 mg
0.25 mL
--
--
--
--
--
--
50 mg eq.
78 mg
0.50 mL
175 mg eq.
273 mg
0.875 mL
--
--
--
75 mg eq.
117 mg
0.75 mL
263 mg eq.
410 mg
1.315 mL
--
--
--
Moderate dosec
100 mg eq.
156 mg
1.00 mL
350 mg eq.
546 mg
1.750 mL
700 mg eq.
1092 mg
3.50 mL
Higher dosec
150 mg eq.
234 mg
1.50 mL
525 mg eq.
819 mg
2.625 mL
1000 mg eq. 1560 mg
5.00 mL
a  PP3M dose = 3.5× the patient’s previous PP1M dose.
b  PP6M dose = ≈7× the patient’s previous PP1M dose or ≈2× the previous PP3M dose.
c Doses shown in Bold Italics represent the PP3M and PP6M doses evaluated during Double-blind Phase of Study 
R092670PSY3015.
Key: -- = No corresponding dose level available; 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.
For the most comprehensive nonclinical and clinical information regarding paliperidone and 
paliperidone palmitate products (including PP6M), refer to the latest version of the Investigator's 
Brochure for paliperidone/paliperidone palmitate.
The term “study intervention” throughout the protocol, refers to the 6-month paliperidone 
product (PP6M).
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.
1.1.
Background
Nonclinical Studies
Pharmacologic Profile
Paliperidone is a racemic mixture. Binding affinities are similar between risperidone and 
paliperidone for 5HT2A and D2 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 D2
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 conducted a 6-month local tolerability study in minipigs for PP6M up to a dose of 
1060 mg eq. in an injection volume of 5.3 mL, which is more than the highest dose and volume 


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2020
(1000 mg eq. in 5.0 mL) to be tested in the current clinical study. That 1060 mg eq. in 5.3 mL 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). Results of this 6-month local tolerability study in minipigs (described in the 
Investigator’s Brochure) adequately support the use of PP6M in clinical studies. 
Clinical Studies
Paliperidone Palmitate 6-month Product (PP6M)
The currently ongoing Phase 3 study (R092670PSY3015) is the first clinical study to evaluate 
the efficacy and safety of the PP6M product. Results of this study are not yet available; a brief 
overview of the study design is provided below. 

Study R092670PSY3015 is a randomized, double-blind, active-controlled, multicenter, 
interventional, parallel-group study in adults with schizophrenia. The study includes an 
initial open-label Transition and/or Maintenance Phase followed by a randomized Double-
blind Treatment Phase. During the open-label Transition and Maintenance Phases, subjects 
will be treated with PP1M or PP3M. Subjects who are clinically stable on a moderate or 
high dose of PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.) at the end of the 
Maintenance Phase will be eligible to enter the Double-blind Phase. At entry to the Double-
blind Phase, subjects will be randomized in a 1:2 ratio to receive either PP3M (350 or 525 
mg eq., every 3 months) or PP6M (700 or 1000 mg eq., every 6 months [with intervening 
placebo injections]). The dose of PP3M or PP6M for each subject during the Double-blind 
Phase will be calculated based on the last dose of PP1M or PP3M received during the 
Maintenance Phase (using the conversion factors as shown in Table 1). It is estimated 
approximately 549 subjects will be randomized in the Double-blind Phase. The Double-
blind Phase will be 12 months in duration. The primary endpoint is time to relapse during 
the Double-blind Phase, with noninferiority assessed based on the difference in Kaplan-
Meier 12-month estimate of survival (ie, percentage of subjects remaining relapse-free) 
between PP6M and PP3M. Secondary endpoints include evaluation of efficacy (based on 
changes from baseline in Positive and Negative Syndrome Scale [PANSS], Clinical Global 
Impression-Severity [CGI-S], and Personal and Social Performance [PSP] scales), safety 
and tolerability, and PK of PP6M versus PP3M.
Paliperidone Palmitate 1-month and 3-month Products (PP1M and PP3M)
While Study R092670PSY3015 is the first clinical study to evaluate the PP6M product, 
extensive clinical trial experience is available with the approved oral paliperidone formulation 
(paliperidone extended-release [ER] [or ‘prolonged-release’] tablets) and the approved 
paliperidone palmitate products (PP1M and PP3M). Up to the most recent clinical cut-off date of 
31 December 2017, over 15,000 subjects have received paliperidone ER, over 10,000 subjects 
have received PP1M, and approximately 1,500 subjects have received PP3M during cumulative 
clinical trial experience across all studied indications. 
Of note, the sponsor has completed 3 registrational clinical studies of PP3M, which has the same 
formulation as PP6M. A total of 1,191 subjects received at least 1 dose of PP3M (F015) in 


R092670 (paliperidone palmitate)
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Status: Approved,  Date: 15 December 2020
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.3 The combined exposure to PP3M was 567.6 
subject-years.3
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.
The sponsor developed a population 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 (see 
Section 3.2, Study Design Rationale), which has the same formulation.
Efficacy
Efficacy data are not yet available for the PP6M product. The efficacy of the PP1M product is 
well established. The efficacy of the PP3M product in the maintenance treatment in adults with 
schizophrenia was established in two 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 


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2020
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 clinical evaluation of PP6M, with a 
longer duration of efficacy expected to be provided by higher doses of the same formulation.
Safety
In addition to extensive studies of oral paliperidone and PP1M, the safety profile of PP3M 
(F015) was established in 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 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.
Overall, the previous safety and tolerability outcomes with PP3M support the clinical evaluation 
of PP6M, with acceptable safety and tolerability expected to be possible with higher doses of the 
same formulation for a longer duration.
1.2.
Overall Rationale for the Study
The main rationale for this study is to collect long-term safety and tolerability data with PP6M 
and to
provide access to the PP6M formulation for subjects who complete
Study 
R092670PSY3015 without relapse. This study will be continued for up to a maximum of 2 years
for each individual subject, or until PP6M becomes commercially available in a subject’s local 
country, whichever occurs first. In some countries, additional reimbursement negotiations and 
central formulary approvals will be needed before PP6M becomes available. In this case, 
subjects participating in the R092670PSY3016 study can continue to receive PP6M until the 
PP6M formulation is available in their local country, or for a maximum of 2 years. If PP6M 
becomes available locally before the 2-year endpoint, then subjects will be considered as having 
completed the open-label extension study at the end of the most recent 6-month injection cycle 
and will be switched to a commercially available supply if they wish to continue PP6M 


R092670 (paliperidone palmitate)
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2020
treatment. For these subjects, the End-of-Study visit will be conducted 6 months after the 
subject’s last dose of PP6M.
1.3.
Benefit/Risk Assessment
Schizophrenia is a severe and chronic mental disorder. Several oral and long-acting injectable 
(LAI) antipsychotic medications are available for the treatment of patients with schizophrenia, 
but the disorder is associated with high rates of nonadherence to oral medications and some 
patients are not willing or able to attend regular clinic visits to receive their medication, 
including available LAI injections. The PP6M product offers the potential for patients to receive 
just 2 antipsychotic injections per year. 
Having a LAI antipsychotic that requires injections only twice per year is unique; there is no 
other antipsychotic on the market with a comparable duration between injections. The 
combination of assured medication delivery, long-lasting antipsychotic coverage, and the 
reduced frequency of injections with the PP6M product may offer benefits in terms of improved 
patient convenience and reduced potential for nonadherence compared with currently available 
antipsychotics. If approved, PP6M therefore has the potential to improve serious outcomes (eg, 
hospitalization and/or relapse) associated with poor medication adherence in this population. 
There is extensive evidence that paliperidone (the active ingredient of PP6M) is a safe and 
effective molecule for the treatment of schizophrenia. The currently available data (see 
Section 1.1, Background) as well as the population PK modeling performed to select the PP6M 
dose levels (see Section 3.2, Study Design Rationale) provide support for the conduct of this 
long-term open-label study. 
The primary objective of this study is to evaluate the long-term safety and tolerability of the 
PP6M product (700 and 1000 mg eq., every 6 months) and provide medication access to PP6M 
in patients who have previously received PP6M or PP3M in Study R092670PSY3015. Only a 
limited number of countries that participated in Study R092670PSY3015 will take part in this 
open-label extension. Besides routine safety monitoring and subject management, this study 
includes several design features to minimize risk to subjects enrolled in this study. Firstly, only 
those subjects who have completed the Double-blind Phase and demonstrated adequate efficacy 
(ie, no relapses) and tolerability (ie, no significant adverse events) during 12 months of double-
blind treatment with PP3M or PP6M will be eligible to enter the open-label extension study. 
Therefore, subjects will have already demonstrated a good response and tolerability to 
paliperidone palmitate LAI prior to entering the open-label extension study. Subjects will either 
be continuing PP6M at the same dose as they received during the R092670PSY3015 Double-
blind Phase, or will be switching from PP3M to a corresponding dose of PP6M. Risks associated 
with switching from PP3M to PP6M are considered limited, given that both the PP3M and PP6M 
products have the same formulation (F015). Potential risks and risk mitigation strategies for 
subjects switching from PP3M are discussed further below:

Higher dose: The PP6M doses in this study (700 and 1000 mg eq.) are approximately 2-fold 
higher than the corresponding PP3M doses (350 and 525 mg eq., respectively) (see Table 1). 


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2020
The sponsor performed population PK simulations to select the chosen PP6M doses, and 
considered the 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 are predicted to stay within the range of exposures that were 
shown to be efficacious and tolerated during clinical trial experience with other 
paliperidone/risperidone products (see further details in Section 3.2, Study Design 
Rationale). The maximum exposures predicted with PP6M in this study are therefore 
expected to be adequately tolerated. In addition, medications commonly used to improve 
tolerability of antipsychotic medications (eg, anti-EPS medications, benzodiazepines) will 
be permitted during the study, as needed (see Section 8, Prestudy and Concomitant 
Medication).

Larger volume: The injection volumes for the PP6M doses (3.5 mL and 5 mL for the 700 
and 1000 mg eq. doses, respectively) are higher than injection volume for the PP3M product 
(Table 1). The sponsor has consulted nursing guidelines6 for the acceptability of the 
proposed PP6M volumes, and these guidelines indicate that volumes of up to 5 mL can be 
administered in the gluteus. The sponsor has accordingly restricted the administration of 
PP6M into the gluteal muscle in this study.

Longer-acting formulation: A concern may be associated with the longer-acting nature of 
PP6M vs. PP3M. 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.
Overall, the potential benefits associated with an LAI antipsychotic that only requires 
administration twice a year, in addition to the positive efficacy and safety profile of paliperidone 
demonstrated in previous clinical studies with the approved paliperidone/paliperidone palmitate 
formulations, support the evaluation of PP6M in the proposed study. The overall risk-benefit 
balance for conducting the proposed clinical study is considered favorable.
More detailed information about the known and expected benefits and risks of paliperidone and 
paliperidone palmitate, including PP6M, may be found in the Investigator’s Brochure.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess (in a limited number of 
countries) the long-term safety and 
tolerability of PP6M (700 or 1000 mg 
eq.) and to provide access to PP6M in 

Safety will be assessed through evaluation of 
adverse events, mental status examination, clinical 
laboratory 
values, 
vital 
signs, 
physical 
examinations, 
the 
Abnormal 
Involuntary 


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2020
Objectives
Endpoints
subjects with schizophrenia completing 
the R092670PSY3015 study
without 
relapse.
Movement Scale (AIMS), and injection site 
evaluations. Mandatory assessments will occur at 
limited time points during the study with 
additional assessments to be added at the 
discretion of the investigator if considered 
necessary.

Proportion of subjects who receive 1, 2, 3, or 4 
PP6M injections. 
Secondary

To assess the long-term efficacy of 
PP6M based on:

Efficacy will be assessed based on the change 
from open-label extension baseline on:

Overall symptom improvement and 
global severity of the illness

The Clinical Global Impression-Severity 
(CGI-S) scale.

Personal and social functioning

The Personal and Social Performance (PSP) 
scale.

Remission rates

The proportion of subjects in remission will 
be assessed based on PANSS assessment at 
open-label extension baseline, Month 12, 
Month 24, and the End-of-Study/Early 
Withdrawal visit.

To continually assess the long-term 
effectiveness of PP6M on the prevention 
of relapse by evaluating the data from 
R092670PSY3015 and 
R092670PSY3016.  

Effectiveness will be assessed based on relapse, 
where relapse in the open-label extension is 
defined as one or more of the following:

Psychiatric hospitalization for schizophrenia 
(involuntary or voluntary admission to a 
psychiatric hospital for decompensation of 
the subject’s schizophrenic symptoms);

Emergency Department/Room/Ward visit 
due to a worsening of the subject’s 
symptoms of schizophrenia, but a psychiatric 
hospitalization does not occur; 

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;

The subject has suicidal or homicidal 
ideation and aggressive behavior that is 
clinically significant (in frequency and 
severity) in the investigator’s judgment.

To evaluate the impact of PP6M on 
Medical Resource Utilization

Based on the Healthcare Resource Utilization 
Questionnaire (HRUQ).


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Status: Approved,  Date: 15 December 2020
Refer to Section 9 (Study Evaluations) for evaluations related to endpoints. 
Note: Data from this study may also be used in a future analysis and combined with results from 
other studies (R092670PSY3015 and R092670SCH4067). If performed, this analysis will be 
reported separately.
2.2.
Hypothesis
The primary hypothesis is that long-term treatment with PP6M (700 or 1000 mg eq.) is safe and 
well tolerated in subjects with schizophrenia who have previously been treated with PP6M for 
12 months, or are being switched to PP6M from corresponding doses of PP3M. 
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This study is a single-arm, 24-month open-label extension to Study R092670PSY3015, a double-
blind, randomized, active-controlled, parallel-group study to evaluate whether the efficacy of 
PP6M is noninferior to that of PP3M in adults with schizophrenia. Subjects who complete the 
12-month Double-blind Phase of R092670PSY3015 in the selected countries without a relapse 
will be eligible to enter the open-label extension study (R092670PSY3016). Approximately 
180 subjects from Study R092670PSY3015 are estimated to be enrolled in the open-label 
extension.
A diagram of the study design is provided in Figure 1.




R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2020
judgment.  However, given the slow rate of change in paliperidone blood levels expected over 
time with PP6M, it may take weeks or months for the desired effect of a dose change to occur.  
The duration of exposure to study drug and the duration of study participation in the open-label 
extension study are intended to be a maximum of 2 years (ie, four PP6M injection cycles). 
Subjects will attend site visits at a minimum of once every 3 months to complete safety, efficacy, 
and other assessments according to the Time and Events Schedule, with additional visits to be 
added at the discretion of the investigator as deemed necessary, per usual clinical practice. 
Subjects who meet criteria for relapse (as defined in Section 9.2.4, Relapse Criteria) or other 
criteria for withdrawal during the study will be discontinued (see Section 10.2, Withdrawal From 
the Study); these subjects will complete the End-of-Study procedures as soon as possible and 
return for a follow-up assessment 6 months (183 ± 14 days) after their last PP6M injection. 
For subjects who do not relapse or withdraw, study participation will be continued for up to a 
maximum of 2 years, or until PP6M becomes commercially available in the subject’s local 
country, whichever occurs first. In some countries, additional reimbursement negotiations and 
central formulary approvals will be needed before PP6M becomes available. In this case, 
subjects participating in the R092670PSY3016 study can continue to receive PP6M until the 
PP6M formulation is available in their local country, or for a maximum of 2 years. Subjects will 
get access to the medication for a maximum of 2 years. If PP6M becomes available locally 
before the 2-year endpoint, then subjects will be considered as having completed the open-label 
extension study at the end of the most recent 6-month injection cycle and will be switched to a 
commercially available supply if they wish to continue PP6M treatment. For these subjects, 
participation may continue as described in the Time and Events Schedule and the End-of-Study 
visit will be conducted 6 months after the subject’s last dose of PP6M.
3.2.
Study Design Rationale
Subject selection criteria
This study will recruit adult subjects (men and women) with schizophrenia who completed the 
Double-blind Phase of R092670PSY3015 without a relapse and who continue to be willing to 
receive PP6M during the open-label extension. Subjects will be required to meet selection 
criteria (see Section 4, Subject Population) and must voluntarily consent and be able and willing 
to fulfill all study requirements.
Study design
This is a single-arm, open-label study in which all subjects will receive PP6M. Open-label 
treatment design is considered suitable for the collection of long-term safety and tolerability data 
and is more consistent with real-world clinical practice. As such, this study will strive to be 
pragmatic, with minimal mandated assessments.
Subjects will be entering the open-label extension study after completing the 12-month Double-
blind Phase of Study R092670PSY3015. Therefore, subjects will either be continuing treatment 
with PP6M or will be switching from PP3M to PP6M. The inclusion of subjects switching from 


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PP3M to PP6M will allow for intrasubject comparison between PP3M and PP6M treatment and 
enable collection of additional data regarding the switch from stable PP3M treatment to PP6M, 
which is consistent with the proposed use of PP6M in clinical practice.
During this study, subjects will attend site visits at a minimum of once every 3 months according 
to the Time and Events Schedule. Additional study visits may be added at the discretion of the 
investigator, as deemed necessary, per usual practice. Concomitant psychotropic medications can 
be used during the study as required (eg, for concomitant conditions [eg, insomnia, anxiety], 
extrapyramidal symptoms), with some limitations (refer to Section 8, Prestudy and Concomitant 
Medications, for details). 
Selection of efficacy and safety evaluations
The full lists of efficacy and safety assessments for this study are described in Section 9, Study 
Evaluations.
The primary objective of this study is to collect long-term safety and tolerability information for 
PP6M and to provide access to PP6M for patients who successfully completed the Double-blind 
Phase of Study R092670PSY3015 without a relapse. At each study visit, adverse events will be 
assessed and investigators will evaluate the subject’s mental status (including an assessment of
suicidality). In addition, an assessment of the injection site will be performed after each PP6M 
injection. Clinical laboratory values, physical examinations (including body weight/body mass 
index [BMI]), vital signs, and the AIMS will be assessed at limited time points during the study, 
with additional assessments to be added at the discretion of the investigator. Paliperidone 
palmitate may cause increases in serum prolactin levels; therefore, prolactin levels will be 
measured as part of the clinical laboratory safety assessment. If clinically warranted, 
investigators may perform additional evaluations as needed during the study, including but not 
limited to: the mental status examination, Columbia Suicide Severity Rating Scale (C-SSRS), 
Barnes Akathisia Rating Scale (BARS), Simpson Angus Scale (SAS), 12-lead electrocardiogram 
(ECG), urine drug screen.
Efficacy and effectiveness of PP6M will be assessed as secondary objectives, and will be 
evaluated based on changes from baseline in CGI-S, PANSS, and PSP scales as well as 
assessment of relapse and remission. The CGI-S was chosen to assess efficacy as it is a well-
known and widely accepted scale to assess the severity of symptoms of schizophrenia. 
Additionally, the PSP will be utilized as a tool to assess the impact that treatment has on 
subjects’ personal and social functionality because of the vital importance of improvement in 
these domains. The relapse criteria used in this study (listed in Section 9.2.4) have been adapted 
from the criteria that were used in the R092670PSY3015 study and other registrational clinical 
studies that were conducted to support approval of PP1M and PP3M. The criteria selected for 
this open-label study more closely resemble typical indicators of relapse in real-world clinical 
practice.


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Dose selection rationale
The PP6M dose levels evaluated in this open-label extension study (and in the Double-blind 
Phase of Study R092670PSY3015), 700 and 1000 mg eq., were selected based on the results of 
population PK simulations. Both PP3M and PP6M are the F015 formulation; that is, PP3M and 
PP6M differ in the mass and volume of each dose, but not in the formulation of paliperidone 
palmitate. Therefore, the population PK model that was developed for PP3M is expected to be 
suitable for the dose selection of PP6M.
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).3 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.6 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.

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.
                                                
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 28 December 2018.
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 28 December 2018.


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Medical Resource Utilization Data Collection
The Healthcare Resource Use Questionnaire will be included in order to collect medical resource 
utilization data that will inform future schizophrenia treatment cost analyses. Data collected from 
this study will be analyzed together with results from other studies; the economic analyses may 
be conducted and reported separately from this study.
4.
SUBJECT POPULATION
Screening assessment for eligible subjects will be performed on Day 1 (Visit 1), prior to the first 
dose of study intervention administered in the open-label extension study.
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. 
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study: 
1.
Completed the Double-blind Phase of Study R092670PSY3015 without relapse and 
continue to be willing to be treated with PP6M. 
Note: There may be a small number of subjects who complete Study R092670PSY3015 
before the R092670PSY3016 protocol is approved and implemented in that local 
country. These subjects may be screened and can enter Study R092670PSY3016 later, 
provided that: Visit 1 (Day 1) of Study R092670PSY3016 (ie, first dose of PP6M) is 
scheduled to occur no later than 3 months after the End-of-Study visit of 
R092670PSY3015, that in the interim period the subject has been treated with PP1M 
(100 or 150 mg eq.) or PP3M (350 or 525 mg eq.) (PP3M is preferred) and has not 
experienced a relapse (per criteria in Section 9.2.4, Relapse Criteria), and the subject 
meets other criteria for study entry.
2.
Must, in the opinion of the investigator, be able to continue treatment at the same dose 
level (moderate or higher dose) as used during the Double-blind Phase of Study 
R092670PSY3015 at the time of screening for this study.
3.
A woman of childbearing potential must have a negative urine pregnancy test on Day 1.
4.
Use contraception consistent with local regulations for subjects participating in clinical 
studies. Before receiving study intervention, a woman must be either:
a. Not of childbearing potential, defined as being either postmenopausal or 
permanently sterile, as follows:
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 


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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 intervention; 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
Agree to remain on a highly effective method throughout the study and for 
at least 12 months after the last dose of study intervention. 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 begin a highly effective method of contraception, as described throughout 
this inclusion criterion. If reproductive status is questionable, additional evaluation 
should be considered.
5.
A man must agree that during the study and for a minimum of 12 months after receiving 
the last dose of study intervention, his female partner(s) will use a highly effective 
method of contraception as described above, and:
a)
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).
b)
He must, if being sexually active with a woman who is pregnant, use a condom.
c)
He must agree not to donate sperm.


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6.
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).
7.
In the opinion of the investigator, the patient would be able to participate for the 
duration of this study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study: 
1.
Has 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.
2.
Completed R092670PSY3015 while presenting adverse events deemed clinically 
relevant by the investigator, and which may interfere with safety and well-being of 
the patient.
3.
If a man, has plans to father a child while enrolled in this study or within 12 months 
after the last dose of study intervention. Must not, if a woman, have plans to become 
pregnant while enrolled in this study or within 12 months after the last dose of study 
intervention. 
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 intervention 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 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
4.3.
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.
Refer to Section 8, Prestudy and Concomitant Therapy, for details regarding prohibited 
and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).


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3.
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 intervention. (Women who 
have a positive pregnancy test during the study will be withdrawn from the study.)
4.
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 intervention.
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:
1.
Should not donate blood during the study and for at least 6 months after completion of 
the study.
2.
Should not participate in an investigational drug study during the study and 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, Prestudy and Concomitant Therapy).
4.
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.
INTERVENTION ALLOCATION AND BLINDING
Intervention Allocation
Randomization will not be used in this study. All subjects will receive PP6M during the open-
label extension; the PP6M starting dose will be allocated as described in Section 6, Dosage and 
Administration. 
Blinding
As this is an open study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
All subjects in the open-label extension study will receive treatment with PP6M. Two PP6M 
dose levels are available: 700 and 1000 mg eq. Subjects will receive up to 4 injections of PP6M 
during the 24-month treatment period.


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
For subjects who enter the open-label extension immediately after completing Study 
R092670PSY3015: Day 1 of Study R092670PSY3016 is intended to take place on the same 
day as the End-of-Study visit in R092670PSY3015, immediately after completion of the 
R092670PSY3015 End-of-Study procedures. This visit coincides with the timing of when 
PP6M may be administered relative to the subject’s last dose of PP6M (if randomized to 
PP6M treatment in Study R092670PSY3015) or PP3M (if randomized to PP3M treatment in 
Study R092670PSY3015). For these subjects, the initial dose of PP6M will be selected 
based on the unblinded dose level (“moderate” or “higher”) that the subject was receiving 
during the Double-blind Phase of Study R092670PSY3015; ie, subjects in the “moderate” 
dose level will receive PP6M 700 mg eq., and subjects in the “higher” dose level will 
receive PP6M 1000 mg eq. during the open-label extension. The blind in R092670PSY3015 
does not need to be broken for purposes of treatment assignment. 

For subjects who enter the open-label extension later (up to 3 months after they complete 
R092670PSY3015): In a small number of subjects, the Day 1 visit of R092670PSY3016 
may occur up to 3 months after the R092670PSY3015 End-of-Study visit, and these subjects 
may be receiving poststudy treatment with PP3M or PP1M (PP3M is preferred). For these 
subjects, the Day 1 visit of the open-label extension study will be scheduled to coincide with 
the subject’s next dose of PP3M or PP1M (ie, 90 ± 14 days after the last dose of PP3M, or 
30 ± 7 days after the last dose of PP1M). Only those subjects on a moderate or higher dose 
of PP3M (350 or 525 mg eq.) or PP1M (100 or 150 mg eq.) will be eligible to enter the 
open-label extension. For these subjects, the initial dose of PP6M (700 or 1000 mg eq.) in 
the open-label extension study will be calculated based on the subject’s previous dose of 
PP1M or PP3M, using the conversion factors summarized in Table 1.
For all subjects, study intervention (PP6M) during the open-label extension will be administered 
once every 6 months. Investigators will be allowed to change the dose at Visits 3, 5, and 7
(increase or decrease, to 700 or 1000 mg eq.) based on clinical judgment. However, given the 
slow rate of change in paliperidone blood levels expected over time with PP6M, it may take 
weeks or months for the desired effect of a dose change to occur.  
All PP6M injections will be administered in the gluteal muscle, and will rotate across both sides
(left or right) of the body. 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. See Attachment 1 for more details about administration.
Study intervention administration must be captured in the source documents and the electronic 
Case Report Form (eCRF).
Treatment After the Study 
See Section 10.3 (Antipsychotic Therapy After the Study) for further recommendations 
regarding poststudy treatments. Such treatments are nonstudy treatments and therefore are not 
described here.


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7.
INTERVENTION COMPLIANCE
The study intervention 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, gluteal muscle only) 
in the eCRF.
8.
PRESTUDY AND CONCOMITANT THERAPY
All medications (prescriptions, over-the-counter, herbal remedies) other than the study 
intervention that were either continued at the start, or begun during, the open-label extension 
study are to be documented in the eCRF. For subjects treated with PP1M or PP3M before 
entering this study (and after completion of study R092670PSY3015), all interim doses of PP1M 
or PP3M are to be documented in the eCRF as well. The sponsor is to be notified in advance (or 
as soon as possible thereafter) of any instances in which prohibited therapies are administered.
8.1.
Prestudy Medical Therapy and Psychotherapy
Except for the prohibited concomitant medications described in Section 8.3, Prohibited 
Concomitant Medications, any medications that are ongoing and stable at screening may be 
allowed to continue thereafter into the open-label extension study. Ongoing psychotherapy and 
other psychosocial interventions are allowed to continue. For psychiatric medications of special 
interest at study entry: 

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 
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study intervention. 
Except for the prohibited concomitant medications described below, concomitant medications 
may be initiated during the study for medical or psychiatric reasons. New psychotherapies and 
psychosocial treatments may be started. 

Anti-EPS medications: 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. However, use of other benzodiazepines is permitted.   

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. Sleep aid medications should not be used in the 8 hours preceding any 
scheduled efficacy assessment or rating scale.


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
Oral Antipsychotic Supplementation:
Since this study attempts to be pragmatic, 
supplementation with oral antipsychotics during the study will be allowed. The duration and 
dose of antipsychotic supplementation should be linked to symptom exacerbation, per the 
investigator’s judgment. 
The maximum duration that oral antipsychotics can be co-administered with PP6M is 2 
weeks, at which point the subject must be assessed clinically for relapse criteria. Within a 
single 6-month injection cycle, if the subject does not meet relapse criteria (as defined in 
Section 9.2.4, Relapse Criteria), then an additional 2 weeks of oral antipsychotic can be 
administered continuously for a maximum of 4 weeks. During later injection cycles, oral 
supplementation can also be administered using this same approach. If oral risperidone or 
paliperidone ER/PR are used for supplementation, doses higher than those listed in Table 2
below are not recommended. If, in the investigator’s judgment, there is a clinical need for 
oral antipsychotic supplementation for more than 4 continuous weeks, the study intervention 
is to be discontinued and the subject is to be withdrawn (see Section 10.2, Withdrawal from 
the Study). The suggested antipsychotic medications and corresponding doses are provided 
in Table 2; use of oral antipsychotic medications other than those listed below is prohibited.
Table 2:
Supplemental Oral Antipsychotic Dosage Chart
Oral Risperidone
Oral Paliperidone ER/PR
Moderate Dose (700 mg eq. PP6M)
1-2 mg/day
1.5 – 3 mg/day
High Dose (1000 mg eq. PP6M)
1-3 mg/day
1.5 – 6 mg/day
8.3.
Prohibited Concomitant Medications
The concomitant medications described below may not be used during the study.

Concomitant oral and injectable antipsychotics are prohibited (other than as described in 
Section 8.2, Concomitant Therapy).

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); 
tricyclic 
antidepressants, and some antipsychotics (eg, chlorpromazine or ziprasidone) - are 
prohibited. 

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.

Dopamine agonists, including, but not limited to: ropinirole, pramipexole, pergolide, 
cabergoline, lisuride, and amantadine.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.


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9.
STUDY EVALUATIONS
9.1.
Study Procedures
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, safety, and 
other measurements applicable to this study. Actual dates and times of assessments will be 
recorded in the source documentation and eCRF.
Additional site visits may be performed at any time during the open-label extension study as 
determined necessary by the investigator. Additional urine pregnancy tests may be performed, as 
determined necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participation in the study. 
Efficacy and safety procedures are described in Section 9.2 and Section 9.3, respectively. 
Medical resource utilization data will also be collected (see Section 9.4).
The total blood volume to be collected from each subject is expected to be less than 400 mL, 
based on the clinical laboratory samples indicated in the Time and Events Schedule. Repeat or 
unscheduled samples may be taken at the discretion of the investigator (eg, for safety reasons or 
for technical issues with the samples). 
Screening/Day 1 (Visit 1)
Day 1 (Visit 1) of the open-label extension study is intended to coincide with the End-of-Study 
visit of R092670PSY3015, and will take place immediately after completion of the End-of-Study 
assessments. At this visit, subject eligibility will be assessed and informed consent obtained. 
Eligible subjects will then receive their first open-label injection of PP6M, as described in 
Section 6, Dosage and Administration.
There may be a small number of subjects who complete the End-of-Study visit for Study 
R092670PSY3015 before the R092670PSY3016 protocol is approved. These subjects may be 
screened and can enter Study R092670PSY3016 later, provided that: Day 1 (Visit 1) of 
Study R092670PSY3016 (ie, first dose of PP6M) occurs no later than 3 months after the End-of-
Study visit of R092670PSY3015, that in the interim period the subject has been treated with 
PP1M or PP3M (PP3M is preferred) and has not experienced a relapse (as defined in Section 
9.2.4, Relapse Criteria), and the subject meets other criteria for study entry. For these subjects, 
Day 1 (Visit 1) of Study R092670PSY3016 will take place at the time of the subject’s next 
scheduled dose of PP1M or PP3M (ie, 30 ±7 days after the last dose of PP1M; or 90 ±14 days 
after the last dose of PP3M).
For subjects who attend their first study visit of the open-label extension study (Day 1/Visit 1) 
more than 4 weeks after the R092670PSY3015 End-of-Study visit, a screening period of 2 weeks 
will apply during which the baseline procedures described in the Time and Events Schedule for 
Day 1/Visit 1 will need to be conducted. In addition, a baseline 12-lead ECG assessment should 
be performed and laboratory results will need to be available and reviewed prior to dosing.  


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For subjects who attend the first study visit the same day or within 4 weeks after the 
R092670PSY3015 End-of-Study visit, the assessments performed for the R092670PSY3015 
End-of-Study visit may be used as the baseline for the open-label extension study, where 
appropriate (see further details in the Time and Events Schedule).
Subsequent Study Visits
After the first study visit, subjects will attend site visits at a minimum of once every 3 months. 
Additional in-person or telephone visits may be added at the discretion of the investigator, if 
deemed necessary (eg, to monitor adverse events or symptom worsening, or if a relapse is 
suspected), per usual clinical practice. 
If a relapse is detected at a scheduled or unscheduled visit (as described in Section 9.2.4, Relapse 
Criteria), then the subject will be withdrawn from the study and the completion of End-of-Study 
procedures and arrangements for poststudy treatment are to occur as soon as possible (see 
Section 10, Subject Completion/Discontinuation of Study Intervention/ Withdrawal from the 
Study).
Subjects who do not relapse or meet other criteria for withdrawal during the study will 
participate in the study for up to 2 years. However, if PP6M becomes commercially available in 
the subject’s local country before the 2-year endpoint, then the subject will be considered as 
having completed the open-label extension study at the end of the most recent 6-month injection 
cycle and will be switched to a commercially available supply if they wish to continue PP6M 
treatment
(see Section 10, Subject Completion/Discontinuation of Study Intervention/ 
Withdrawal from the Study). For these subjects, the End-of-Study visit will be conducted 
6 months after the subject’s last dose of PP6M.
Follow-up Phase
Subjects who relapse or meet other relevant conditions for withdrawal will return for a follow-up 
visit 6 months (183 ± 14 days) after their last dose of PP6M. At this visit, information regarding 
post-study/concomitant medication as well as adverse event data will be collected. 
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 data.
9.2.
Efficacy Evaluations
The clinically assessed efficacy evaluations include the CGI-S, the PSP scale, the PANSS, and 
relapse criteria as described further in the sections below. 


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9.2.1.
Clinical Global Impression - Severity
The CGI-S rating scale7 is used to rate the severity of a subject’s overall clinical condition on a 
7-point scale ranging from 1 (not ill) to 7 (extremely severe). This scale permits a global 
evaluation of the subject’s condition at a given time.
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).7 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.4,5 This modified 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 Schedule, and at any 
clinic visit associated with a suspected or impending relapse.
9.2.2.
Personal and Social Performance Scale
The PSP scale assesses the degree of difficulty a subject exhibits over a 7-day period 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. Individual domain items of the PSP will be collected 
and recorded in the eCRF. 
9.2.3.
Positive and Negative Syndrome Scale
The neuropsychiatric symptoms of schizophrenia will be assessed using the 30-item PANSS 
scale,9 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 Schedule. The full PANSS may be administered using 
the Structured Clinical Interview (SCI-PANSS) format, or using an equivalent structured 
interview format to be provided by the sponsor, at the discretion of the investigator.
9.2.4.
Relapse Criteria
The criteria for relapse used in R092670PSY3015 were modified for this open-label extension 
study to reflect the change of the trial setting and a pragmatic approach. 
Relapse during the open-label extension study will be defined as 1 or more of the following:


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
Psychiatric hospitalization for schizophrenia (involuntary or voluntary admission to a 
psychiatric hospital for decompensation of the subject’s schizophrenic symptoms);

Emergency Department/Room/Ward visit due to a worsening of the subject’s symptoms of 
schizophrenia, but a psychiatric hospitalization does not occur;

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;

The subject has suicidal or homicidal ideation and aggressive behavior that is clinically 
significant (in frequency and severity) in the investigator’s judgment.
A relapse event will be recorded on the first date that a subject meets at least one of the above 
criteria. Unlike in the R092670PSY3015 study, an increase in PANSS score is not a criterion for 
relapse; therefore, if an increase in PANSS is noted, a second PANSS assessment to confirm the 
increase is not necessary.  
9.3.
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 Schedule.
9.3.1.
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).
9.3.2.
Mental Status Examination/Clinical Assessment
At each visit, the investigator will perform a mental status examination per usual care. Aspects of 
the examination are to be documented on the Mental Status Examination Form for 
R092670PSY3016, which was developed as a data collection tool for this study. At a minimum, 
the mental status examination performed must include the domains identified on the Mental 
Status Examination Form. These domains include: General Appearance and Behavior, Mood, 
Affect, Thought Process, Thought Content, Perceptions, and Insight. If suicidal ideation is 
present, a C-SSRS (see Section 9.3.8, Columbia Suicide Severity Rating Scale) must also be 
performed at the visit.
9.3.3.
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 


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any clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. The laboratory reports must be filed with the source documents.
The tests below will be performed by a local laboratory. The local laboratory should have local 
country approval and/or recognition for processing of human samples. For full panels, subjects 
should be in fasted state overnight or for at least 8 hours (and nonfasting exceptions should be 
noted). To permit standardization, reference and outlier ranges for each local lab will be 
collected. 

Hematology Panel
- hemoglobin
- red blood cell count
- hematocrit
- white blood cell count with differential
- platelet count
- hemoglobin A1c 

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
- lipid panel (total cholesterol, low-density lipoprotein, high-density lipoprotein, and 
triglycerides).
- prolactin
- thyroid stimulating hormone.


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
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.

Additional Tests

For women of childbearing potential, urine pregnancy tests (via local testing)
will be conducted at the timepoints indicated in the Time and Events Schedule.

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 (for illicit substances, including marijuana, even where legal) 
and alcohol breath tests may be performed at the discretion of the investigator. 
Alcohol and illicit substances are strongly discouraged but are not exclusionary 
and are not cause for withdrawal from the study.

For subjects who enter the open-label extension study more than 4 weeks after 
the R092670PSY3015 End-of-Study visit, blood samples for serum chemistry, 
hematology, and urine samples for analysis should be collected and results 
should be reviewed by the investigator before the first dose of PP6M. 
9.3.4.
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 
in the supine position (after at least 5 minutes rest) with a completely automated device. 
Pulse/heart rate will be measured 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-


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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.
Orthostatic vital signs may also be performed, at investigator’s discretion. If a subject is unable 
to stand up or is unable to remain standing for 2 minutes, 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.
9.3.5.
Physical Examinations
Physical examinations at the time points designated in the Time and Events Schedule include 
body examination, and measurements of weight and waist circumference. The height 
measurement taken at the screening visit of Study R092670PSY3015 will be used to calculate 
body mass index (BMI: weight/height² as kg/m²).
9.3.6.
Extrapyramidal Symptom Rating Scales
The Abnormal Involuntary Movement Scale (AIMS) will be performed at the timepoints 
indicated in the Time and Events schedule. Additional AIMS assessments may be performed at 
any time if deemed necessary by the investigator. 
Other scales to assess EPS (BARS for akathisia, and the SAS for parkinsonism), may be 
performed if deemed necessary by the investigator. These 2 scales can be performed at any time, 
at the discretion of the investigator. 
Abnormal Involuntary Movement Scale
The AIMS is included in the Early Clinical Development Evaluation Unit Assessment Manual 
from the US NIMH.7 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; 
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.
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.2 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.
Simpson Angus Scale
The SAS is led by signs (rather than by symptoms) to measure drug-induced parkinsonism.12
This study uses a version of the SAS that is slightly modified from the original (where the "head 


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dropping" item was changed to "head rotation," to avoid injury to the cervical spine), as was
done in the sponsor's other studies.4,5 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.
9.3.7.
Evaluations of the Injection Site
9.3.7.1.
Injection Site Evaluations by Subjects
The Visual Analog Scale (VAS) to measure pain has been widely used in diverse adult 
populations. 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). The instructions, time 
period for reporting, and verbal descriptor anchors have varied widely in the literature depending 
on the intended use of the scale. In some settings, test-retest reliability and ability to detect 
change have been demonstrated.8
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.4,5) The VAS-Acute will assess pain once within 
30 minutes after each injection; 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.
9.3.7.2.
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 after each PP6M injection, 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,4,5 and from a US FDA 


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guidance.d The results will be recorded on the eCRF. The investigator/subinvestigator should 
complete these assessments within 30 minutes after the injection; 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.
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.
9.3.8.
Columbia Suicide Severity Rating Scale 
The C-SSRS must be performed at any visit where suicidal ideation is detected during the mental 
status examination (see Section 9.3.2, Mental Status Examination/Clinical Assessment). 
Additional assessments may be performed at any time during the study, at the discretion of the 
investigator.
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.11 The C-SSRS is a clinical interview providing a summary of both ideation and 
                                                
d
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/GuidanceComplianceReg
ulatoryInformation/Guidances/Vaccines/ucm091977.pdf. Issued September 2007. Accessed 28 December 2018.


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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. 
An example of the C-SSRS is provided in the Manual of Assessments.
9.3.9.
Electrocardiograms
Since this study aims to approach real-world conditions, regular collection of 12-lead ECGs are 
not mandated. Instead ECGs can be collected at any time based on the judgment of the 
investigator. Electrocardiograms will be obtained locally. If possible, the same ECG machine 
and reader should be used at each collection. The ECG reader should be locally licensed and 
have approval to interpret ECGs. Relevant interval measurements (PR, QRS, QT, etc) will be 
collected, and an overall assessment of clinically relevant rhythm abnormalities will be recorded 
on the eCRF. The overall assessment of clinical relevance will be up to the judgment of the 
investigator.
A copy of the 12-lead ECG shall be printed and kept as part of the local source documentation. 
The paper speed should be set to 25 mm/second and the gain setting of (10 mm/1 mV). 
Suggested electrode placement is provided in Attachment 2.
For subjects who enter the open-label study more than 4 weeks after the R092670PSY3015 End-
of-Study visit, a baseline 12-lead ECG should be performed before the first dose of PP6M. 
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, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
9.4.
Medical Resource Utilization
Healthcare Resource Utilization Questionnaire
Medical resource utilization data will be collected using the HRUQ. This 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.10 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 questionnaire. An example of the HRUQ is provided in 
the Manual of Assessments.


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10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY INTERVENTION/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she completes the 24-month 
open-label treatment phase and completes the End-of-Study assessments at Day 729. 
A subject will also be considered as having completed the study if PP6M becomes commercially 
available locally during the study. For these subjects, the End-of-Study assessments should be 
performed 6 months (183 ± 14 days) after the subject’s last dose of PP6M, at which time he or 
she may be switched to a commercially available PP6M supply, if they wish to continue PP6M 
treatment.
Subjects who prematurely discontinue study intervention for any other reason before completion 
of the open-label extension will not be considered to have completed the study.
10.2.
Withdrawal From the Study
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Noncompliance (defined as a subject being more than 4 weeks late for their scheduled 
PP6M injection).

Discontinuation of study intervention for any reason. A subject's study intervention will be 
automatically discontinued if:

The investigator or sponsor believes (eg, that for safety or tolerability reasons 
(eg, adverse event) it is in the best interest of the subject to discontinue study 
intervention

The subject becomes pregnant

Supplemental oral antipsychotics are used for more than 4 continuous weeks 

Relapse
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. The study drug assigned to the withdrawn 
subject may not be assigned to another subject. If subjects withdraw from the study, additional 
subjects will not be entered. If a subject discontinues study intervention and withdraws from the 
study before the end of the open-label extension, End-of-Study assessments should be obtained. 


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If the reason for withdrawal from the study is withdrawal of consent then no additional 
assessments are allowed.
10.3.
Antipsychotic Therapy After the Study 
After discontinuation, withdrawal, or completion of the open-label extension study, investigators 
may choose to continue treatment with paliperidone palmitate, switch to treatment with a 
different LAI antipsychotic treatment, or switch to oral antipsychotic treatment. At the End-of-
Study Visit/Early Withdrawal visit and thereafter, the poststudy treatment is at the discretion of 
the subject's physician and is not a study intervention. 
By the end of the study, PP6M may be available commercially in most countries, if approved. 
Otherwise, subjects will have to option to receive PP3M since it is (or may be) approved in most 
of the participating countries by the end of R092670PSY3016.
Given the duration of activity expected from PP6M, recommendations (not requirements) for 
poststudy treatment schedules are summarized below.

It is recommended that poststudy LAI antipsychotic medication (paliperidone palmitate or 
other LAI antipsychotic) should not be started within 6 months after the last PP6M injection. 
This is to avoid the risk of accumulation of the overall antipsychotic concentration that 
could be caused by PP6M providing systemic concentrations of paliperidone over a period 
of 6 months. 

If, at any time within 6 months from the last injection, the investigator/treating physician 
feels it is necessary to prescribe oral antipsychotic treatment, medication selection should be 
based on clinical judgment, knowledge of each subject's ability to tolerate and respond to 
other antipsychotic medications, and the presumption of persisting exposure to PP6M (if 
supplementation within this 6-month time period will be with oral risperidone or oral 
paliperidone, Table 2 [Supplemental Oral Antipsychotic Dosage Chart] may be used to 
guide dose selection; for oral risperidone or oral paliperidone dose selection guidance after 
this 6-month time period, see Table 3).

Treatment with PP1M, PP3M, or PP6M may be resumed no earlier than 6 months from the 
last PP6M injection:

If resuming with PP1M, then a monthly regimen may be used immediately; the 
Day 1 and Day 8 initiation pair is not needed. The first PP1M injection should 
be administered in the deltoid muscle, and then subsequent injections may be 
administered in either the deltoid or gluteal muscles. The first PP1M dose should 
be 100 or 150 mg eq., based on whether the subject was on a PP6M dose of
700 or 1000 mg eq., respectively (see Table 3).

If resuming with PP3M, then the first PP3M injection may be administered in 
either the deltoid or gluteal muscles. The first PP3M dose should be 350 or 
525 mg eq., based on whether the subject was on a PP6M dose of 700 or 
1000 mg eq., respectively (see Table 3).


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
If resuming with PP6M, which may be possible if PP6M is commercially 
available, then dosing should be performed in accordance with the local 
prescribing information.  

Suggested starting doses for post-study oral or LAI paliperidone or oral risperidone are 
summarized in Table 3.
Table 3:
Switching Conversion Table (Oral and LAI Paliperidone)
Last dose during 
Open-label Extension:
Suggested Post-study Antipsychotic Medication Starting Dose:
PP6M 
(if commercially 
available)
PP1M
PP3M
Oral 
Risperidone
Oral 
Paliperidone
PP6M 700 mg eq.
700 mg eq
100 mg eq
350 mg eq
3-4 mg/day
9 mg/day
PP6M 1000 mg eq.
1000 mg eq
150 mg eq
525 mg eq
5-6 mg/day
12 mg/day
Note: 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. 
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 Statistical Analysis Plan. 
11.1.
Subject Information
Results will be summarized using the evaluable population, defined as all subjects who receive at 
least 1 dose of study intervention during the open-label extension study.
11.2.
Sample Size Determination
No formal sample size determination was performed for this study. The sample size will be 
determined by the number of subjects who complete Double-blind Phase of
Study 
R092670PSY3015 without relapse and are willing to participate in R092670PSY3016.
11.3.
Efficacy Analyses
All efficacy analyses will be carried out using the evaluable population. 
Descriptive statistics (mean, standard deviation, median, range [minimum and maximum]) will 
be provided for CGI-S, PSP, and PANSS over time, including all assessment time points from 
the baseline of the Double-blind Phase of Study R092670PSY3015 to the End-of-Study/Early 
Withdrawal visit of the open-label extension study. Descriptive statistics of the change from 
baseline (open-label extension baseline and the baseline of the Double-blind Phase of Study 
R092670PSY3015) will also be provided.

Relapse: The relapse rate at Month 12, Month 24, and at the End-of-Study/Early 
Withdrawal visit will be summarized.


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
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).1 The number and percentage 
of subjects achieving symptomatic remission at Month 12, Month 24, and at the End-of-
Study/Early Withdrawal visit will be presented. In addition, the number and percentage of 
subjects by remission status at each time point will be presented for those subjects who were 
in remission at Open-label baseline. 
11.4.
Safety Analyses
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). Intervention-emergent 
adverse events are adverse events with onset during the intervention 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.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue study intervention due to an adverse event, or who experience 
a severe or a serious adverse event. Analyses of the adverse events of special interest (including 
EPS-related TEAEs, potentially prolactin-related TEAEs, and suicidality-related TEAEs) will be 
described in the Statistical Analysis Plan.
Mental Status Examination 
The results of the mental status examination will be summarized descriptively at each time point.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. 
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.
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. 


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Extrapyramidal Symptom Rating Scales
The AIMS data will be summarized descriptively.
Other EPS scales (SAS and BARS) are not mandatory but may be performed at the investigator’s 
discretion. Any SAS and BARS data collected during the study will be summarized 
descriptively.   
Evaluations of the Injection Sites
The results of the evaluations by the subjects and by the investigators will be summarized 
descriptively.
Columbia Suicide Severity Rating Scale
The C-SSRS will only be performed if suicidal ideation is detected on the mental status 
examination. For those subjects who undergo C-SSRS assessment, suicide-related thoughts and 
behaviors based on the C-SSRS will be summarized descriptively.
Electrocardiograms
Electrocardiograms are not mandatory but may be performed at the investigator’s discretion. 
Any ECG data collected during the study will be summarized descriptively. Clinically relevant 
ECG abnormalities will be listed.
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.
The ECG variables that will be analyzed include heart rate, PR interval, QRS interval, QT 
interval, and corrected QT (QTc) interval.
Descriptive statistics of QTc intervals and changes from baseline will be summarized. The 
criteria for abnormal QTc interval values will be based on the classification from the relevant 
ICH guidelinee (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.
                                                
e
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 28 December 2018.


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11.5.
Medical Resource Utilization
The HRUQ data will be summarized. 
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product


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
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 PP6M, the expectedness of an adverse event 
will be determined by whether or not it is listed in the Investigator's Brochure. 
Adverse Event Associated With the Use of the Intervention
An adverse event is considered associated with the use of the intervention 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 intervention.
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 intervention. 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 intervention. 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).


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12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study intervention that may require expedited reporting or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention 

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study intervention, eg, name confusion)

Exposure to a sponsor study intervention from breastfeeding

Exposure to a sponsor study intervention 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 non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow-up of safety. Serious adverse 
events, including those spontaneously reported to the investigator within 6 months after the last 
dose of study intervention, 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. 


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All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, 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 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

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


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
The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
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 intervention, is considered a serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. 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 intervention. If a subject becomes pregnant during the study, a determination 
regarding study intervention discontinuation must be made by the investigator in consultation 
with the sponsor.
Because the effect of the study intervention 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.
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.


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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 INTERVENTION INFORMATION
14.1.
Physical Description of Study Intervention
The study intervention (previously referred to as “study drug”) (PP6M) will be supplied in 
prefilled syringes, as follows:

700 mg eq. (1092 mg) in 3.5 mL

1000 mg eq. (1560 mg) in 5.0 mL
The study intervention will be manufactured and provided under the responsibility of the 
sponsor. Refer to the Investigator's Brochure for a list of excipients.
Oral supplementation medication (risperidone and paliperidone) will not be supplied as part of 
study medications. Instead locally available commercial supply should be used and recorded.
14.2.
Packaging
The study intervention will be packaged in individual subject kits. Each kit will consist of a 
safety needle, instructions for use, and a foam insert containing a prefilled syringe assembled 
with a plunger rod.


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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 intervention is dispensed to a subject.
Study interventions labels will contain information to meet the applicable regulatory 
requirements.
14.4.
Preparation, Handling, and Storage
All study intervention must be stored at controlled temperatures as instructed by the clinical 
label.
14.5.
Intervention Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The study intervention administered to the 
subject must be documented on the intervention accountability form. All study intervention will 
be stored and disposed of according to the sponsor's instructions. Study-site personnel must not 
combine contents of the study intervention containers.
Study intervention 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 intervention 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 intervention will be documented on the intervention return form. When 
the study site is an authorized destruction unit and study intervention supplies are destroyed on-
site, this must also be documented on the intervention return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for intervention accountability purposes. 
Study intervention 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 intervention will be 
supplied only to subjects participating in the study. Returned study intervention must not be 
dispensed again, even to the same subject. Study intervention may not be relabeled or reassigned 
for use by other subjects. The investigator agrees neither to dispense the study intervention 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


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
Manuals:
o
For assessments (ie, questionnaires and scales)
o
For electronic data capture completion guidelines

Study-site investigational product binder
16.
ETHICAL ASPECTS
16.1.
Study-specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The current study will enroll subjects who have completed the Double-blind Phase of 
Study R092670PSY3015 and who continue to be willing to receive PP6M treatment. The 
primary ethical concern for this study is that subjects who were receiving PP3M during the 
Double-blind Phase of R092670PSY3015 will be switched to an investigational product, PP6M. 
This concern is considered limited given that the PP3M and PP6M products share the same 
formulation (F015). Therefore, a switch from PP3M to PP6M represents an increase in the 
dose/volume of study intervention, rather than a switch in active substance. As discussed further in 
Section 1.3, Benefit/Risk Assessment, and Section 3.2, Study Design Rationale, the increased dose 
of PP6M compared with PP3M is expected to result in sustained efficacy and acceptable 
tolerability during a 6-monthly dosing schedule. Because of the larger injection volume of 
PP6M, all injections will be administered in the gluteus. In addition, medications commonly used 
to improve tolerability of antipsychotic medications (eg, anti-EPS medications, benzodiazepines) 
and oral antispychotics (with some limitations) will be permitted during the study, as needed. 
The volume of blood to be collected in this study is not considered to pose an ethical concern or 
a special risk. The total blood volume to be collected will be limited and is considered to be an 
acceptable amount of blood to be collected over this time period from the population in this 
study, as it will be left to the clinical judgment of the investigator according to local standards.  
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 


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study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, 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 intervention


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
New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, 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 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.


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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.
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.
Exploratory research is not conducted under standards appropriate for the return of data to 
subjects. 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).


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17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
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 intervention 
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 


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obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

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 age at initial informed consent. In cases where the subject is not enrolled into the study, the 
date seen and age at initial informed consent 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; 
intervention receipt/dispensing/return records; study intervention administration information; and 


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date of study completion and reason for early discontinuation of study intervention 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 
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
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
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 an electronic CRF, 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 eDC tool. If corrections to a 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 eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC 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 


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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 eCRF 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.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
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 visit 
will be made as soon as possible after enrollment has begun. At these visits, the monitor will 
compare data entered into the eCRF with the source documents (eg, hospital/clinic/physician’s 
office medical records); a sample may be reviewed. The nature and location of all source 


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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 
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. 
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. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion, or 
earlier if PP6M is commercially available in the local country. 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 intervention development


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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 
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 PP6M or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including research data, generated as a result of this study, 
are considered confidential and remain the sole property of the sponsor. The investigator agrees 
to maintain this information in confidence and use this information only to accomplish this 
study, and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of PP6M, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of analyses 
performed after the Clinical Study Report has been issued will be reported in a separate report 
and will not require a revision of the Clinical Study Report. Study subject identifiers will not be 
used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 


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information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 18 months after study end date, 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 
International Medical Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which state 
that the named authors must have made a significant contribution to the conception or design of 
the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
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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REFERENCES
1.
Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in 
schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441-449.
2.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676.
3.
Clinical Overview. Paliperidone palmitate 3-month prolonged release suspension for injection for the treatment 
of schizophrenia. Janssen Research & Development, LLC (09 Jul 2015).
4.
Clinical Study Report R092670PSY3011. A randomized, multicenter, double-blind, non-inferiority study of 
paliperidone palmitate 3 month and 1 month formulations for the treatment of subjects with schizophrenia. 
Janssen Research & Development, LLC (10 Jun 2015).
5.
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).
6.
Cocoman A, Murray J. Intramuscular injections: a review of best practice for mental health nurses. J Psychiatr 
Ment Health Nurs. 2008;15:424-434.
7.
Guy W. ECDEU (Early Clinical Development Evaluation Unit) Assessment Manual for Psychopharmacology. 
Rockville, MD: US Department of Health and Human Services; 1976.
8.
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain. Arthritis Care Res. 
2011;63(Suppl 11):S240-S252. 
9.
Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. 
Schizophr Bull. 1987;13:261-276.
10.
Leal A, Rosillon D, Mehnert A, Jarema M, Remington G. Healthcare resource utilization during 1-year 
treatment with long-acting, injectable risperidone. Pharmacoepidemiol Drug Saf. 2004;13:811-816.
11.
Posner K, Brown GK, Stanley B, et al. The Columbia Suicide Severity Rating Scale: initial validity and 
internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168:1266-1277.
12.
Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl.
1970;212:11-19.


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ATTACHMENTS
Attachment 1: Guidelines for the Intramuscular Injection of Paliperidone Palmitate 6-month 
Injection
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.
Injections will rotate across sides of the body (left or right), 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: Standard Placement of ECG Electrodes
Limb Leads

Right Arm: right forearm proximal to wrist

Left Arm: left forearm proximal to wrist

Left leg: left lower leg proximal to ankle

Right leg: right leg proximal to ankle
Precordial Leads

V1 Fourth intercostal space at the right sternal edge

V2 Fourth intercostal space at the left sternal edge

V3 Midway between V2 and V4

V4 Fifth intercostal space in the mid-clavicular line

V5 Left anterio axillary line at the same horizontal level as V4

V6 Left mid-axillary line at the same horizontal level as V4 and V5
Source: Clinical Guidelines by Consensus: Recording a Standard 12-lead Electrocardiogram: An Approved 
Methodology. British Cardiovascular Society. Feb 2010. https://www.bcs.com/documents/consensus_guidelines.pdf




CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Approved, Date: 23 April 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Single-arm, Open-label Extension to a Double-blind, Randomized, Active-controlled, 
Parallel-group Study of Paliperidone Palmitate 6-Month Formulation
Protocol R092670PSY3016; Phase 3
AMENDMENT 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: 2018-004532-30
Status:
Approved
Date:
23 April 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number: EDMS-RIM-43675, 1.0
Local: EDMS-ERI-177701234, 1.0
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.
NCT04072575


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Approved, Date: 23 April 2020
PROTOCOL AMENDMENTS
DOCUMENT HISTORY
Document
Date
Amendment 1 (COVID-19 Appendix)
23-Apr-2020
Original Protocol
14-Feb-2019
Amendment 1, 23 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.


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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 judgment of the investigator to 
protect the health and well-being of participants and site staff. If, at any time, a participant’s safety 
is considered to be at risk, study intervention will be discontinued, and study follow-up will be 
conducted. In addition, the measures outlined in this Appendix are temporary, while access to sites 
is restricted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible in person at the subject’s home/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 R092670PSY3016 Amendment 1
COVID-19 Appendix
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Approved, Date: 23 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 such as the Mental Status 
Examination (including the Columbia Suicide Severity Rating Scale if suicidal ideation is 
identified during the Mental Status Examination), evaluation of relapse criteria, safety 
assessments deemed necessary by the investigator, and questionnaires. Please note, the visit 
windows included in the Time and Events Schedule are still applicable.

Administration of study intervention: If a subject cannot visit the research site in person 
for administration of study intervention (eg, for Visit 1, Visit 3), trained delegated staff 
may conduct the visit at the subject’s home in accordance with local regulations.
o
Study intervention transport and administration: 

The investigational product is injectable and will require qualified, trained 
delegated site staff to transport the product and administer it in the subject’s
home.

Depending on local regulations, the investigator must either administer the study 
intervention or supervise administration if PP6M is considered a controlled 
substance in that country.

It will be the investigator’s responsibility to ensure that the investigational 
product will be maintained at the appropriate allowed temperature (15-30°C) 
during transit to the subject’s home. 

If local regulations allow a home health service to deliver and/or administer the 
study intervention in the subject’s home, the sponsor may assist site staff with 
utilizing this option.

Efforts should be made to administer the study intervention within one hour after 
delivery by the pharmacy. 

The administration of study intervention at the subject’s home instead of at the 
study site will be documented in the subject’s file and in the CRF.

Study assessments:
o
Relapse assessment: A relapse assessment should be performed based on the criteria 
outlined in Section 9.2.4. If deemed necessary per the judgment of the investigator, 
a remote Positive and Negative Syndrome Scale for Schizophrenia (PANSS)
evaluation may be performed. 
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): Many of the 


R092670 (paliperidone palmitate)
Clinical Protocol R092670PSY3016 Amendment 1
COVID-19 Appendix
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Approved, Date: 23 April 2020
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. However, if permitted by local regulations, these assessments could 
be performed in the subject’s home by trained, delegated site staff or home health 
service staff. If blood samples are shipped to a laboratory other than the local 
laboratory typically used by the site, appropriate documentation of the reference and 
outlier ranges used by the laboratory would also be required.
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.
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 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 applicable visit.

Please notify the treating physician of the subject’s participation in Study 
R092670PSY3016 and details of the study treatment.

Source Data Verification/Monitoring: On-site monitoring visits may not be possible due to 
local regulations, restrictions and guidance. In these cases, the Site Manager will arrange to 
conduct site monitoring visits and activities remotely. 



SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 9 June 2022
Janssen Research & Development
Statistical Analysis Plan
Comparison of Single-arm, Open-label Extension Study of Paliperidone Palmitate 6-Month 
Formulation with Paliperidone Palmitate 1-Month and 3-Month Formulations Using Real 
World Data (IBM Medicaid Multistate Database) 
Protocol R092670SCH4067; Phase 4
R092670  (paliperidone palmitate)
Status:
Approved
Date:
9 June 2022
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-766970, 1.0
Compliance: The study described in this report is performed according to the principles of Good Clinical Practice (GCP). 
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.
NCT04072575


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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2
Status: Approved, Date: 9 June 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
1.
INTRODUCTION ................................................................................................................................ 3
1.1.
Objectives and Endpoints ................................................................................................................ 3
1.2.
Study Design.................................................................................................................................... 4
1.2.1.
Medication Exposure .................................................................................................................... 4
1.2.2.
Data Collection Period.................................................................................................................. 6
1.2.3.
Baseline Period and Study Start (Index) Dates............................................................................ 6
1.3.
Inclusion/Exclusion........................................................................................................................... 7
1.3.1.
PP6M Cohort ................................................................................................................................ 7
1.3.2.
PP3M and PP1M Cohorts............................................................................................................. 7
2.
STATISTICAL HYPOTHESIS .......................................................................................................... 12
3.
POPULATIONS (ANALYSIS SET) FOR ANALYSIS........................................................................ 12
3.1.
PP6M Population ........................................................................................................................... 12
3.2.
PP3M and PP1M (ECA) Populations............................................................................................. 12
3.3.
Propensity Score Matching ............................................................................................................ 13
4.
STATISTICAL ANALYSES............................................................................................................... 14
4.1.
Inferential Analysis......................................................................................................................... 14
4.1.1.
Cox Regression .......................................................................................................................... 15
4.2.
Sensitivity Analysis......................................................................................................................... 15
4.2.1.
Assessment of the Covariate Balance........................................................................................ 15
4.2.2.
Assessment of Primary Endpoints.............................................................................................. 15
5.
LIMITATIONS .................................................................................................................................. 16
6.
REFERENCES................................................................................................................................... 17
7.
SUPPORTING DOCUMENTATION ................................................................................................. 18
          Appendix 1: List of Abbreviations...................................................................................................... 18
          Appendix 2: SAP Version History ..................................................................................................... 19
          Appendix 3: Appendix 3 Diagnosis Codes for Inclusion, Exclusion and Propensity Score 
Matching....................................................................................................................... 20
          Appendix 4: Relapse Definition in RWD by Diagnosis Codes .......................................................... 21
          Appendix 5: Listing of Antipsychotic Medications ............................................................................. 22
          Appendix 6: List of Antipsychotics by CPT and HCPCS Drug Codes .............................................. 23
          Appendix 7: List of Mental Health Related Medical and Data Specific Codes ................................. 24
          Appendix 8: List of Chronic Conditions Included in Exclusion List and Their ICD-9-CM /
ICD-10-CM/Rx Listings .................................................................................................. 27
          Appendix 9: List of Other Criteria Included in Inclusion/Exclusion List and Their 
ICD-9-CM/ICD-10-CM/Rx Listings................................................................................. 28


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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Status: Approved, Date: 9 June 2022
1. INTRODUCTION
Schizophrenia is a severe and chronic behavioral health disorder with debilitating long-term
outcomes associated with cognitive and functional impairment. The prevalence rate of
schizophrenia is estimated to be approximately 1% worldwide (Lehman 2010). Patients with 
schizophrenia experience multiple relapses throughout the course of their illness and this comes at 
a cost to the patient and society. During these episodes, patients can lose a significant number of 
workdays to the illness and in the event of severe symptoms, will require substantial healthcare 
resources.
Treatment adherence and reducing treatment discontinuation are therefore key factors in 
minimizing recurrent relapses.
Paliperidone palmitate (Invega®, Janssen Pharmaceuticals) is a long acting injectable (LAI)
atypical antipsychotic approved by the US Food and Drug Administration for treatment of 
schizophrenia. The 1-month paliperidone palmitate extended-release injectable suspension (PP1M 
injectable formulation, Invega® Sustenna) was approved by the FDA for the acute and 
maintenance treatment of schizophrenia in adults in July 2009, and for the treatment of 
schizoaffective disorder in November 2014. A 3-month paliperidone palmitate extended-release 
injectable suspension was approved by the FDA in May 2015 for preventing relapse among 
patients with schizophrenia (PP3M injectable formulation, Invega® Trinza). 
Invega® Hafyera®, a 6-month paliperidone palmitate extended-release injectable suspension 
(LAI) also known as PP6M, is the latest in this series of LAIs that includes the PP1M, and PP3M, 
approved in 2021. Real-world data has shown that PP1M and PP3M are superior to oral
antipsychotics in delaying the time to relapse or treatment failure (Alphs 2015; Segarra 2021)3,
and PP6M is expected to further improve these outcomes. To evaluate this hypothesis, an External 
Comparator Arm (ECA) study will be conducted to compare relapse rates among PP6M 
(R092670PSY3016) patients separately against PP1M and PP3M patients in IBM® Medicaid 
Multistate® Database (IBM MDCD). The patients from the IBM MDCD comparator cohorts will 
be selected
and matched
closely with those patients from
the open-label study
(R092670PSY3016).
1.1.
Objectives and Endpoints
The primary objective of this study is to compare effectiveness of PP6M (R092670PSY3016) 
versus PP3M and PP1M (IBM MDCD) in delaying time to first relapse.
The overall primary hypothesis to be tested in this study is that 24 months treatment with PP6M is 
superior to 24 months’ treatment with PP3M or PP1M in delaying time to first relapse in subjects 
with schizophrenia disorder. The primary effectiveness null hypothesis is that there is no difference 
in the distribution of time to first relapse among 3 treatment groups.


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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Status: Approved, Date: 9 June 2022
The primary endpoint for the study is the delay/prevention of relapse. A relapse event represented
one or a combination of following events as listed in the open-label study for PP6M:

Psychiatric hospitalization for schizophrenia (involuntary or voluntary admission to a 
psychiatric hospital for decompensation of the subject’s schizophrenic symptoms);

Emergency Department/Room/Ward visit due to a worsening of the subject’s symptoms of 
schizophrenia, but a psychiatric hospitalization does not occur;

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; 

The subject has suicidal or homicidal ideation and aggressive behavior that is clinically 
significant (in frequency and severity) in the investigator’s judgment.
A relapse event will be recorded on the first date during study period that a subject meets at least 
one of the above criteria in Real-world data (RWD, IBM MDCD) for PP1M and PP3M.
The secondary objectives included examination of reasons for relapse and to characterize 
schizophrenia patients on paliperidone palmitate therapies.
1.2.
Study Design
Schematic display of Study Design is shown in Figure 1. Medication exposure, data collection 
period, baseline period and study start (index) date determination are explained in details below.
1.2.1.
Medication Exposure
Two dosing schemes will be considered: Moderate-dose and High-dose. PP6M, PP3M, and PP1M 
patients will be assigned into one of these 2 drug dose categories based on their PP injection dose 
at study entry. Details regarding patient categorization in moderate and higher doses are presented 
in Table 1.


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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5
Status: Approved, Date: 9 June 2022
Table 1:
Conversion Between Doses and Injection Volumes for the 1-, 3-, and 6-Month Paliperidone Palmitate Products
Dose
F013 Formulation
F015 Formulation
PP1M Dose
PP3M Dosea
PP6M Doseb
mg eq.
mg
Volume
mg eq.
mg
Volume
mg eq.
mg
Volume
N/A
25 mg eq.
39 mg
0.25 mL
…
…
…
…
…
…
50 mg eq.
78 mg
0.50 mL
175 mg eq.
273 mg
0.875 mL
…
…
…
75 mg eq.
117 mg
0.75 mL
263 mg eq.
410 mg
1.315 mL
…
…
…
Moderate dosec
100 mg eq.
156 mg
1.00 mL
350 mg eq.
546 mg
1.750 mL
700 mg eq.
1092 mg
3.50 mL
High dosec
150 mg eq.
234 mg
1.50 mL
525 mg eq.
819 mg
2.625 mL
1000 mg 
eq.
1560 mg
5.00 mL
a
PP3M dose = 3.5x the patient's previous PP1M dose
b
PP6M dose = 7x the patient's previous PP1M dose or approximately 2x the previous PP3M dose
c
Doses shown in bold italics represents the PP3M and PP6M doses evaluated during Double-blind Phase of Study R092670PSY3015
Key: N/A = Not applicable; PP1M=paliperidone palmitate 1-month product; PP3M=paliperidone palmitate 3-month product; PP6M=paliperidone palmitate 6-
month product


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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6
Status: Approved, Date: 9 June 2022
1.2.2.
Data Collection Period
PP6M cohort patients included in PSY3016-ECA study will be same as PSY3016 Open Label 
Extension (OLE) study. PP6M cohort consists of patients that are transitioned from Clinical Trial 
PSY3015 and already met the PSY3016-ECA study inclusion/exclusion criteria adapted from 
Clinical Trial PSY3015 (see 1.3 Inclusion/Exclusions). In addition to inclusion/exclusion criteria, 
these PP6M patients also met the “no relapse” requirement during 12-month double-blind phase 
in PSY3015 to be eligible for PSY3016 OLE study.
PP3M and PP1M cohorts will be extracted from the IBM MDCD RWD insurance claims database 
and will include patients that meet inclusion/exclusion criteria adapted from Study PSY3015. 
Patients with PP3M and PP1M injection dates starting from 2017 will be included in this 
PSY3016-ECA study to minimize biases are associated with differences in calendar times. 
PSY3016-ECA study period will be from 2017 until the end of available data (last patient out is 
listed as 06/2021).
1.2.3.
Baseline Period and Study Start (Index) Dates
Baseline period and study start-date (Index date) for the PP6M, PP3M, and PP1M cohorts will be 
determined as described below.

Baseline Period: Baseline period for PP3M and PP1M cohorts will be a period between index 
PP injection date and up to 12-month prior to this date. All RWD (PP3M and PP1M) patients 
must have continuous medical and prescription coverage based on their insurance enrollment 
records during this period. For PP6M cohort, baseline period will be listed as 12-month double 
blinded PSY3015 study period and inclusion and exclusion criteria will be applied at 
PSY3015 study screening.

Index date (PP6M): Index date for the PP6M cohort will be the start date of the open-label 
extension (OLE) phase in PSY3016 study. PP6M cohort includes patients with Moderate/High 
dose PP6M injections in PSY3016 OLE phase and are relapse free and PP adherent during 
their 12-month double blinded PSY3015 study period.

Index date (PP3M) : Among the schizophrenia patients with both PP3M and PP1M injections 
in IBM MDCD, PP3M patients will be evaluated first for the index date determination. In 
PP3M cohort, patients receiving Moderate/High dose PP3M injections (see Table 1) starting 
from January 1st, 2017, will be identified first and their PP3M injections will be evaluated for 
inclusion/exclusion criteria (see Section 1.3 Inclusion/ Exclusion). In addition to their pre-
index/baseline inclusion/exclusion criteria listed below, a PP3M patient will also meet the 
stability criteria. PP3M patients must be on PP1M/PP3M injections and adherent to their 
medication for at least 6-month prior to their index PP3M injection date. Based on the stability 
requirement, the last two doses of PP1M, or 1 dose of PP3M needs to be same, and/or
equivalent. Days between injections will be evaluated backwards starting from index date of 
PP3M. Up to 45 days of gap between injections will be allowed to consider these patients 
adherent. If a patient had two or more eligible PP3M injection dates, inclusion/exclusion 
criteria will be applied for each PP3M injection date and the first eligible PP3M injection date 
will be used for selection purposes. While calculating number of stable days during baseline 
period, except for injectable Risperidone, oral and/or injectable antipsychotic drugs other than 
LAI paliperidone palmitate (see Appendix for the list of all antipsychotic drugs) will not be


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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Status: Approved, Date: 9 June 2022
allowed during stabilization period. If this condition is violated during baseline period, PP3M 
patient will not be considered as stable up to this time point and any PP1M/PP3M injections 
prior to this violation will not be counted towards 6-month stability period and considered 
ineligible. Duration of stable period will then be calculated based on the difference between 
index PP3M injection date and the earliest eligible PP injection date during baseline period. 
These PP3M patients must have at least 12-month pre- and post-index continuous enrollment 
records and have at least 2 PP3M injection on or after index date. Once all potential PP3M 
injection dates are evaluated for eligibility, the first PP3M injection date that meets all 
eligibility criteria will be selected in case patient have multiple potential entry dates. Eligible 
PP3M patients will be considered as “final” PP3M cohort. This patient cohort will be removed 
from the IBM MDCD PP1M pool.

Index date (PP1M) : After removing eligible PP3M patients from PP1M patient pool, 
remaining PP1M patients will be evaluated first for their index date determination. In PP1M 
cohort, patients receiving Moderate/High dose of PP1M injections (see Table 1) starting from 
January 1st, 2017, will be identified and their PP1M injection dates will be evaluated for 
inclusion/exclusion. Similar to PP3M, PP1M injection dates starting from January 2017 will 
be considered as “potential” index dates and will be evaluated up to 12-month before this date 
(baseline period) for inclusion/exclusion criteria and up to 6-month for stability. PP1M 
patients may not have PP3M injections during baseline period. For PP1M cohort, except for 
injectable Risperidone, other injectable antipsychotic drugs (see Appendix for the list of 
antipsychotic drugs) will not be allowed between PP1M index date and 6-month stabilization
period. If this condition is violated, earlier PP1M injections prior to this event will be ineligible 
and will not be counted towards stability period and number of days and duration of 
stabilization period will be calculated based on the first eligible PP1M injection date during 
baseline period and PP1M index date. Up to 45 days of gap between injections will be allowed 
to consider these patients’ adherence. Patients with PP1M injections will be included in the 
study if these index dates meet both 6-month stability and 12-month baseline 
inclusion/exclusion. If a patient had more than 1 eligible PP1M injection dates, the first 
eligible PP1M injection date will be used. These PP1M patients also required to have at least 
12-month pre- and post-index continuous enrollment records and must have at least 5 PP1M 
injections on or after index date. Once all potential index dates are evaluated for PP1M 
patients, the first index date that meets all eligibility criteria will be selected in case patient 
have multiple potential entry dates.  
1.3.
Inclusion/Exclusion
1.3.1.
PP6M Cohort
All PP6M cohort patients from PSY3016 OLE will be eligible for this study. 
1.3.2.
PP3M and PP1M Cohorts
Patients from PP3M and PP1M cohorts will be selected from the IBM MDCD data source. First,
PP3M cohort patients will be evaluated for inclusion based on the study start date and baseline 
period as described above. The inclusion/exclusion criteria adapted from double-blind PSY3015 
study will be applied to identify eligible patients. Once eligible PP3M patients are identified, they 


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
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Status: Approved, Date: 9 June 2022
will be removed from the PP1M pool, and the remaining patients will be evaluated for their 
eligibility based on their study start and baseline period inclusion/exclusion criteria for PP1M 
cohort. 
Applicable Inclusion/Exclusion criteria in IBM MDCD based on Clinical Protocol 
R092670PSY3016 are listed below:
Inclusion Criteria
-
PSY3016 OLE study and IBM MDCD patients must have medium/high dose paliperidone 
palmitate injections
-
Age ≥ 18 at index PP injection
-
Schizophrenia diagnosis at or prior to PP index date
-
At least 12 months continuous medical and prescription (Rx) enrollment records before and 
after index PP injection dates for PP3M and PP1M cohorts. Enrollment records with “medical 
insurance only” or indicating dual eligibility (ie. Medicaid and Medicare) will not be 
considered as “continuous” enrollment period since some of the medical and/or prescription 
claims might be captured by Medicare and may not appear in Medicaid. 
-
PP3M and PP1M patient cohorts must have at least 6-month stable period as described in 
section “Baseline Period and Study Start (Index) Dates” and PP3M cohort patients must have 
at least 2 PP3M injections and PP1M patients must have at least 5 PP1M injections during 
study period.
Exclusion Criteria
-
Relapse record during the 12-month baseline period including
o
Mental health related inpatient hospitalization,
o
Emergency room visits due to Schizophrenia,
o
Self-injury or Violent/Aggressive behavior results in suicide, or
o
Suicidal or Homicidal ideation,
-
Patients with injectable antipsychotic Rx administration other than long acting injectable 
paliperidone palmitate within 6-month pre-index date for PP3M or PP1M injections except for 
injectable Risperidone,
-
Patients with “Autism” prior to index date,
-
Patients with “Dementia” prior to index date,
-
Patients with “Manic episode” or “Bipolar disorder” prior to index date,
-
BMI >40 (Morbidly obese patients) and/or patients with abnormal weight loss /underweight 
diagnosis during baseline period 
-
Female patients with pregnancy / delivery records during baseline or study period 
(1 January 2016, forward)


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Status: Approved, Date: 9 June 2022
-
Patients with following severe chronic conditions 
-
Diabetes (DM patients with complications and/or DM patients on Insulin)
-
Heart conditions (Patients with Prolonged QT Syndrome, Arrythmia, Sick sinus 
-
syndrome, Complete atrioventricular block / Congestive heart failure, or
-
Polymorphic ventricular tachycardia)
o
Chronic renal diseases (Hepatic insufficiency etc.)
o
Thyroid diseases
o
Chronic liver diseases
o
Hematologic diseases
o
Coagulation disorders
-
Patients with cancer (By Diagnosis and Antineoplastic and/or Chemotherapy Rx)
-
Clozapine use within 2 months index date for PP injection
-
Inducers of proteins involved in the metabolism of paliperidone
-
Systemic antifungals
-
Dopamine agonists
ICD-9-CM, ICD-10-CM, CPT, and Rx codes will be applied to inclusion/exclusion criteria 
adapted from double-blind PSY3015 study. These codes are listed in Appendix 3 through
Appendix 7.
To ensure that data follow-up periods between the PP6M and PP1M/PP3M (RWD) pairs will be
comparable, the RWD cohort study periods will be censored so that the maximum study period
duration for real-world endpoint evaluation will be same as the maximum study period duration in 
the open label clinical trial, which is 24-months. Clinicians and their patients may want to know 
the potential effect on relapse when patients fully adhering to the treatment, ie, the extent of the 
pharmacological effect. Likewise, it is useful to estimate differences in relapse rates in a population 
that might not have been fully adherent due to various reasons, including adverse events and 
treatment discontinuation, ie, an average population effect. Treatment policy types of estimand 
strategy provides a population-level effect of the tested therapy, which may be of primary interest 
to policy makers. There is a need for greater transparency and alignment in how external control 
arm patient cohort selection maps to PSY3016 to minimize measurement error in terms of 
adherence to medications post index date. PP3M cohort will include those patients with at least 
2 injections of PP3M and PP1M cohort will include those patients with at least 5 injections of 
PP1M after the corresponding index dates.


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Status: Approved, Date: 9 June 2022
Time to relapse for all 3 cohorts will be derived as the first occurrence of any of the events listed 
in the Relapse Criteria. If a patient relapses, days to relapse will be calculated based on the 
difference between the event date minus the index date +1. Patients who do not experience a 
relapse will be censored. The time of censoring will be calculated as earliest of the following 
conditions minus the index date +1.:  

Patient reaches maximum study period (2-year)

Early termination (PP6M only)

End of RWD availability prior to 2-year study period (RWD cohorts only),

Patient leaving the insurance plan (RWD cohorts only).


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Status: Approved, Date: 9 June 2022
Figure 1:
Schematic Display of Study Design
PP6M Cohort
PP3M Cohort
PP1M Cohort
Index Date
(Start date of Open-label phase)
Baseline Period
(12-month Pre-Index)
Study period 
(Up to 24-month post-Index)
Patient is censored if one of the conditions met:
     - End of 2 Year Study Period or
    - Early Termination
Study Starts
(2017)
Study Ends
(2022)
Index Date
(First Eligible PP3M Injection Date)
Baseline Period
(12-month Pre-Index)
Study period 
(Up to 24- month post-Index)
Patient is censored if one of the conditions met:
     - End of 2 Year Study Period or
     - End of Last RWD or
     - End of Enrollment
≥6-month stability before index PP3M injection
No other inj./oral antipsychotic Rx between PP1M inj.
Last 2 PP1M or 1 PP3M injections are moderate/high 
No relapse records during baseline period
12-month pre-index and post-index enrollment and ≥ 2 PP3M 
injections on or after index PP3M injection
Study Starts
01/01/2017
Study Ends
06/30/2021
≥ 6-month stability before index PP1M injection
No other inj. antipsychotic Rx between PP1M inj.
Last 2 PP1M injection dose is moderate/high 
No relapse records during baseline period
12-month pre-index and post-index enrollment and ≥ 5 PP1M 
injections on or after index PP1M injection
Index Date
(First Eligible PP1M Injection Date)
Baseline Period
(12-month Pre-Index)
Study period
(Up to 24- month post-Index)
Patient is censored if one of the conditions met:
     - End of 2 Year Study Period or
     - End of Last RWD or
    - End of Enrollment
No relapse records during baseline period
12-month pre-index and post-index enrollment
Study Starts
01/01/2017
Study Ends
06/30/2021


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2. STATISTICAL HYPOTHESIS
The primary effectiveness endpoint for this study will be the time to first relapse event. The overall 
primary hypothesis to be tested in this study will be that 24 months’ treatment with PP6M is 
superior to 24 months’ PP1M or PP3M treatments in delaying time to first relapse in subjects with 
schizophrenia disorder. The primary null hypothesis is that there is no difference in distribution of 
time to first relapse among PP6M and PP3M or PP1M.
3. POPULATIONS (ANALYSIS SET) FOR ANALYSIS
The full analysis set will include all patients who received PP6M during PSY3016 open-label 
extension study population. Analysis set will also include PP6M matched patients that were in 
PP3M and PP1M cohorts and corresponds to “ITT” population in PSY3016 open-label extension 
study and from IBM MDCD. 
3.1.
PP6M Population
PP6M population will include all PSY3016 Open-label extension (OLE) study patient 
population. 
3.2.
PP3M and PP1M (ECA) Populations
External PP3M and PP1M comparison groups will resemble the open-label extension study 
population with respect to key inclusion/exclusion criteria and baseline demographic and disease 
characteristics. Important covariates to be considered for selection of external cohorts include:

Covariates that mimic the inclusion/exclusion criteria for the PSY3016 trial (please see
Appendix 3, 7, 8, and 9) in the external comparator group

Covariates that will be utilized to minimize selection bias (i.e., to build the propensity score 
model)
Patients will be selected from IBM MDCD database will be aligned to PP6M trial cohort with 
respect to study eligibility (inclusion/exclusion) criteria. These external cohort of patients will be
selected based on baseline demographic and disease characteristics to ensure comparability of 
treatment groups and carry out propensity score matching with open label PP6M cohort patients.
The open-label extension study analysis dataset had “Planned Treatment for Period 01 (TRT01P)” 
and “Planned Treatment for Period 01 (N) (TRT01PN)” variables set to “PP6M” and “1” 
respectively. These 2 variables will be added to IBM MDCD analysis datasets and set to “PP3M” 
and “2” for PP3M cohort and “PP1M” and “3” for PP1M cohort respectively. PP6M patients will 
be matched with PP1M and PP3M patients. To identify these 3 “matched” patients, “Matched ID” 
variables for PP6M, PP3M, and PP1M cohorts will be included in analysis datasets. 


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3.3.
Propensity Score Matching
Propensity Scoring matching will be performed in the following order:
PP3M-PP1M: All eligible PP3M and PP1M patients from IBM MDCD database will be included 
in the matching process. First, 2 RWD cohorts will be combined into a single dataset and then 
TRT01PN variable will be used as exposure indicator to determine whether the patient came from 
PP3M cohort (TRT01PN =2) or PP1M (TRT01PN =3) in SAS PSMATCH procedure. Baseline 
demographic and disease characteristics including index drug dose (moderate/higher dose), age 
categories (18-25, 26-50, 51-65, and >65), gender, race, and other treatment related factors 
including presence of baseline depressive disorder, Charlson Comorbidity Index Score, and 
Elixhauser Comorbidity Index Score will be included in matching process. Propensity scores will 
be calculated using the following factors; Exact match categories (Index drug dose, Age category, 
gender) and Others (Race, Presence of baseline depressive disorder, Charlson Comorbidity Index 
Score, and Elixhauser Comorbidity Index Score). Charlson Comorbidity and Elixhauser 
Comorbidity Index Scores will be calculated using medical coding algorithm described by Quan 
et al. (Quan 2005). Patients will be matched at 1:1 ratio using the nearest neighbor matching 
algorithm with a caliper of 0.2 SD without replacement such that index drug dose, age category, 
and gender will be an exact match5,6. Once these patients are matched, their patient IDs and Match 
IDs will be saved. This data set will be the base for PP6M related matching process.
PP6M-PP3M: All PP6M cohort patients and PP3M cohort patients that previously matched with 
eligible PP1M cohort patients from IBM MDCD database will be matched. First, PP6M and PP3M 
cohorts will be combined into a single dataset. This dataset will contain variables for baseline 
characteristics including index drug dose (moderate/higher-dose), patient demographics (age 
categories [18-25, 26-50, 51-65, and > 65] and gender), and an exposure indicator of whether the 
patient came from PP6M cohort (TRT01PN=1) or PP3M (TRT01PN=2). Propensity scores will 
be calculated using the following factors: Exact match categories (PP dose, gender) and age 
categories. Factors are chosen based on previous clinical findings that supported their relevance. 
Patients will be matched at 1:1 ratio using the nearest neighbor matching algorithm with a caliper 
of 0.2 SD without replacement such that index PP3M dose, and gender will be an exact match
(Austin 2021; Chesnaye 2021). Once these patients are matched, their patient IDs and Match IDs 
will be saved.
PP6M-PP1M: All PP6M cohort patients and PP1M cohort patients that previously matched with 
eligible PP3M cohort patients from IBM MDCD database will be paired using PP3M Match IDs 
that are created during PP6M-PP3M matching process. First, PP3M patients that matched with 
PP6M cohort will be identified and using their PP6M-PP3M and PP3M-PP1M Match IDs, PP1M 
patients will be mapped with PP6M patients.
Common support (ie, comparable distribution of scores between the groups) will be determined 
based on PP6M PS distribution. PP3M and PP1M patients will be considered for matching only 
when their PS score are within the common support. 


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The quality of matching will be assessed using the absolute standardized mean difference (SMD) 
for each baseline factor. Standardized differences in covariate means before and after matching 
will be computed and compared. The absolute standardized differences between cohorts <0.107
considered to be a good match
Overall attrition summary will be listed for PP3M and PP1M to show size of database for IBM 
MDCD.
Once the PS matching is completed, patient demographics (age, age category, gender [from ADaM 
“adsl” and RWD “enrollment” tables]), Rx (Total duration of exposure and exposure categories, 
mean and mode dose, and last dose from ADaM “adex/adexsum” and RWD “drug claims” tables), 
disposition (Completed and censored [“Discontinued/Withdrawn” patients from ADaM “addisp”, 
and Enrollment discontinuation due to RWD study period limitation or lack of individual’s 
insurance enrollment]), and time to event (relapse information from ADaM “adtte” and RWD 
“medical claims” tables) records from matched samples will be combined to create proper analyses 
data sets including time to event analysis dataset.
Baseline demographic characteristics will be summarized with descriptive statistics for the PP6M, 
PP3M and PP1M cohorts before and after matching.
Study Outcomes
The outcomes of the single-arm open-label PP6M clinical trial (time to first relapse and individual 
time to relapse components) will be reproduced in the ECA. Pairwise comparisons will be carried 
out. The reasons for Relapse will be summarized. Time to event endpoints of interest included:
-
Time to 1st Psychiatric hospitalization.
-
Time to 1st Emergency room visit due to Schizophrenia
-
Time to 1st Deliberate self-injury, violent/Aggressive behavior potentially results in suicide 
-
Time to 1st Suicidal or Homicidal ideation
If any of the relapse conditions are within seven-day period, then they will be considered as part 
of a single relapse episode. Any subsequent relapse record that is greater than seven days after 
previous relapse will be considered as a new relapse event. Number of relapses during 24-month 
study period will also be summarized.
4. STATISTICAL ANALYSES
4.1.
Inferential Analysis
Comparative effective analyses will be carried out for time to first relapse among the matched 
groups. Kaplan-Meier survival curves will be used to assess time to first relapse in three matched 
cohorts. Hazard ratio and 95% CI will be used to describe reduction in risk of relapses. The overall 
Type I error rate for testing PP6M vs PP3M and PP6N vs PP1M will be controlled at the 2-sided 
0.05 significance level using a Holm’s step-down procedure. In Holm’s procedure, p-values from 


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analyses of PP6M vs PP3M and PP1M will be ordered from lowest to highest. Let p(1) < p(2) to 
be ordered p-values corresponding null hypotheses H(1) and H(2). In Step 1, if p(1) < 0.05/2 then 
corresponding null hypothesis will be rejected and testing will move to the second step; otherwise, 
none of the hypotheses will be rejected and we will stop testing. In Step 2, p(2) will be tested at 
0.05 level.
Kaplan-Meier survival analysis will be conducted to estimate time to relapse. The median time to 
first relapse will be reported for all matched cohorts. Due to paired nature of the data, the 
dependence between paired survival time will be taken into consideration when performing 
survival analysis. Therefore, stratified log-rank test will be conducted to assess the equality of 
survival curves in matched samples5. Treatment differences will be compared using a log-rank 
test. The cumulative distribution function of the time to treatment failure will be estimated by the 
Kaplan-Meier method. The 95% CIs for the median treatment failure rates, as well as the failure 
rates at 6 months, 12 months, 18 months, and at 24 months will be provided. The reasons for 
relapses will be summarized.
4.1.1.
Cox Regression
In the matched samples, a Cox model will be used to regress time to first relapse on treatment 
status, with a robust variance estimator used to account for the clustering within matched sets
(Austin 2021). Hazard ratio and 95% CI will be used to describe reduction in risk of relapses. 
4.2.
Sensitivity Analysis
To assess robustness of our results, sensitivity analysis will be performed using propensity score 
matching at 1:2 ratio using the nearest neighbor matching algorithm with a caliper set at 0.2 SD 
and without replacement such that index drug dose, age category, and sex will be in exact match
(Austin 2021; Chesnaye 2021).
4.2.1.
Assessment of the Covariate Balance
Baseline characteristics in the RWD (PP1M and PP3M) and trial (PP6M) cohorts will be assessed 
for balance both before and after propensity score matching. Standardized mean difference of 
<10% will be considered negligible imbalance between groups (Chesnaye 2021). If the 
standardized differences remain too large after matching, the propensity score model will be
revisited. Besides having similar means, continuous variables will be examined to ascertain that 
the distribution and variance are similar between groups. 
4.2.2.
Assessment of Primary Endpoints
Unadjusted hazard ratios will be calculated using Cox proportional hazard model to regress time 
to first relapse, with a variance estimator used to account for the clustering within matched sets
(Austin 2015). The data will be assessed for meeting the proportional hazards assumption and the 
global p-value will be reported. Unadjusted hazards ratios will be reported for PP3M vs. PP1M, 
PP6M vs PP3M, PP6M vs PP1M. 


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5. LIMITATIONS
This study is subject to the following limitations:

Unlike randomized controlled trials, ECAs derived from RWD cannot control for unmeasured 
or unknown confounders; they are restricted to known confounders that are available in both
the trial data and the claims database. RWDs also reflect real-world patterns of care and vary
in data quality and completeness. As with any Real-world database, where data are collected 
for clinical care and insurance claims, misclassification and incomplete or delayed data entry 
might have been inherent in the used databases. In some cases, the relevant information 
recorded in the trial may not be collected in the RWD, such as with lab values and mental 
health related scales. 

Not all inclusion and exclusion criteria from R092670PSY3016 study could be applied to the 
IBM MDCD patients.

All clinical trial outcomes could not be wholly reproduced in the ECA due to a lack of similar
outcomes in the claims database.

The generalizability of findings from this study will be for the US Medicaid eligible 
population and this warrants further analysis on Commercial, and Medicare insured 
populations.


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6. REFERENCES
Lehman, A. F., Lieberman, J. A., Dixon, L. B., McGlashan, T. H., Miller, A. L., Perkins, D. O., et al. 
(2010). “Practice guideline for the treatment of patients with schizophrenia”, 2nd ed. American 
Psychiatric Association. Available at: 
https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia.pdf
Alphs L, Benson C, Cheshire-Kinney K, Lindenmayer JP, Mao L, Rodriguez SC, Starr HL. Real-world 
outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a 
randomized, open-label, review board-blinded 15-month study. J Clin Psychiatry. 2015 May;76(5):554-
61. doi: 10.4088/JCP.14m09584. PMID: 25938474.
Segarra R, Recio-Barbero M, Sáenz-Herrero M, Mentxaka O, Cabezas-Garduño J, J I Eguíluz, et al, Oral 
and palmitate paliperidone long-acting injectable formulations’ use in schizophrenia spectrum disorders: 
A retrospective Cohort Study from the First Episode Psychosis Intervention Program 
(CRUPEP), International Journal of Neuropsychopharmacology, Volume 24, Issue 9, September 2021, 
Pages 694–702, https://doi.org/10.1093/ijnp/pyab021
Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and 
ICD-10 administrative data. Med Care 2005 Nov;43(11):1130-1139.
Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting 
measures of effect similar to those used in randomized experiments. Stat Med [Internet]. 2014 Mar 30 
[cited 2021 Oct 22];33(7):1242–58. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285179
Chesnaye N, Stel V, Tripepi2 G, Dekker F, Fu EL, Zoccali C, et al. An introduction to inverse probability 
of treatment weighting in observational research. CKJ Clin Kidney J. 2021 Sep 3.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment 
weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. 
Stat Med [Internet]. 2015 Dec 10 [cited 2021 Sep 2];34(28):3661–79. Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626409/


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7. SUPPORTING DOCUMENTATION
Appendix 1 List of Abbreviations
ANOVA
analysis of variance
ANCOVA
ECA
analysis of covariance
external Control Arm
LAI
long-acting injectables
PP
paliperidone palmitate
PP1M
paliperidone palmitate 1-month injectable formula
PP3M
paliperidone palmitate 3-month injectable formula
PP6M
paliperidone palmitate 6-month injectable formula
RWD
Real World Data
RWE
Real World Evidence
SAP
Statistical Analysis Plan
SD
standard deviation


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Appendix 2 SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
Not Applicable
Initial release


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Appendix 3: Mental Health-related Diagnosis Codes for Inclusion, Exclusions
Criteria
Code type
Codes
ICD-9-CM
295.70-295.75, 295.80-295.85, 295.90-295.95, 297, 297.0-297.3,  297.8-
297.9
ICD-10-CM
F20, F250, F251, F258, F259
ICD-9-CM
296.0,  296.00-296.06,  296.1,  296.10-296.16,  296.4,  296.40-296.46,  
296.5,  296.50-296.56,  296.6,  296.60-296.66,  2967,  296.8,  296.80-296.81, 
296.89
ICD-10-CM
F30, F31
ICD-9-CM
046.0, 046.1, 046.11, 046.19, 094.1, 290, 290.0, 290.1, 290.10, 290.11, 
290.12, 290.13, 290.2, 290.20, 29021, 290.3, 290.4, 290.40, 290.41, 290.42, 
290.43, 290.8, 290.9, 291.1, 291.2, 292.82, 294, 294.1, 294.10, 294.11, 
294.2, 294.20, 294.21, 294.8, 294.9, 310, 310.2, 330, 330.1, 330.2, 330.3, 
330.8, 330.9, 331, 331.1, 331.11, 331.19, 331.2, 331.3, 331.4, 331.5, 331.7, 
331.8, 331.82, 333.4, 780.93, 797
ICD-10-CM
F01, F02, F03
ICD-9-CM
299.9
ICD-10-CM
Z9183, F840
ICD-9-CM
296.2, 296.20, 296.21, 296.22, 296.23, 296.24, 296.3, 296.30, 296.31, 
296.32, 296.33, 296.34, 300.4, 300.40, 309.0, 309.00, 309.1, 309.10, 311, 
311.0, 311.00
ICD-10-CM
F32, F33, F34
Schizophrenia Dx
Manic episode / Bipolar disorder
Dementia
Autism
Depressive disorder


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Appendix 4: Relapse Definition in RWD by Diagnosis Codes
Criteria
Code type
Codes
ICD-9-CM
V62.84
ICD-10-CM
R45.851
ICD-9-CM
V62.85
ICD-10-CM
R45.850
ICD-9-CM
312, 312.89, 312.10
ICD-10-CM
F03.91, F91.8, R45.5, R45.6
ICD-9-CM
E950 - E958
ICD-10-CM
T1491, X71, X72, X73, X74, X75, X76, X77, X78, X79, X80, X81, X82, X83, 
T36, T37, T38, T39, T40, T41, T42, T43, T44, T45, T46, T47, T48, T49, T50, 
T51, T52, T53, T54, T55, T56, T57, T58, T59, T60, T61, T62, T63, T64, T65, 
T66, T67, T68, T69, T70, T71
* Only "initial encounter" diagnosis codes will be included
Homicidal Ideation
Deliberate Self-injury, Violent 
Behavior
Violent behavior resulting in 
suicide *
Suicidal Ideation


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Appendix 5: Listing of Antipsychotic Medications
Typical
Chlorpromazine 
Zuclopenthixol 
Periciazine 
Pipamperone 
Thioridazine 
Prochlorperazine 
Chlorprothixene 
Piperacetazine
Loxapine 
Pimozide 
Benperidol 
Pipotiazine
Molindone 
Lenperone 
Clopenthixol 
Promazine
Perphenazine 
Chlorpromazine 
Cyamemazine 
Spiperone
Thiothixene 
Thioridazine 
Dixyrazine 
Sulforidazine
Trifluoperazine 
Loxapine 
Fluspirilene 
Thiopropazate
Haloperidol 
Oxyprotepine 
Levomepromazine 
Thioproperazine 
Fluphenazine 
Penfluridol 
Periciazine 
Droperidol
Perazine
Oxypertine
Atypical
Amisulpride 
Paliperidone
Sulpiride 
Nemonapride
Aripiprazole 
Paliperidone Palmitate 
Ziprasidone 
Reserpine
Asenapine 
Perospirone 
Zotepine 
Sultopride
Blonanserin 
Quetiapine 
Amoxapine
Tiapride
Clotiapine 
Remoxipride 
Amisulpride
Veralipride
Clozapine 
Risperidone 
Brexpiprazole
Sertindole 
Iloperidone 
Amisulpride 
Cariprazine
Sulpiride 
Lurasidone 
Aripiprazole 
Carpipramine
Ziprasidone 
Mosapramine 
Asenapine 
Clocapramine
Zotepine 
Olanzapine 
Blonanserin 
Clorotepine
Olanzapine/Fluoxetine 
Sertindole 
Melperone


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Appendix 6: List of Antipsychotics by CPT and HCPCS Drug Codes
CPT-4
80159 - Clozapine
80173 - Haloperidol
HCPCS
C9125 - Risperidone inj
C9255 - Injection, paliperidone palmitate, 1 mg
C9497 - Loxapine, inhalation powder, 10 mg
J0400 - Injection, aripiprazole, intramuscular, 0.25 mg
J0401 - Injection, aripiprazole, extended release, 1 mg
J0780 - Injection, prochlorperazine, up to 10 mg
J1630 - Injection, haloperidol, up to 5 mg
J1631 - Injection, haloperidol decanoate, per 50 mg
J1790 - Injection, droperidol, up to 5 mg
J1810 - Injection, droperidol and fentanyl citrate, up to 2 ml ampule
J2358 - Injection, olanzapine, long-acting, 1 mg
J2426 - Injection, paliperidone palmitate extended release, 1 mg
J2680 - Injection, fluphenazine decanoate, up to 25 mg
J2794 - Injection, risperidone, long acting, 0.5 mg
J2950 - Injection, promazine hcl, up to 25 mg
J3230 - Injection, chlorpromazine hcl, up to 50 mg
J3280 - Injection, thiethylperazine maleate, up to 10 mg
J3310 - Injection, perphenazine, up to 5 mg
J3400 - Injection, triflupromazine hcl, up to 20 mg
J3486 - Injection, ziprasidone mesylate, 10 mg
Q0161 - Chlorpromazine hydrochloride, 5 mg, oral
Q0164 - Prochlorperazine maleate, 5  mg, oral
Q0165 - Prochlorperazine maleate, 10  mg, oral
Q0171 - Chlorpromazine hydrochloride, 10  mg
Q0172 - Chlorpromazine hydrochloride, 25 mg
Q0174 - Thiethylperazine maleate, 10 mg, oral
Q0175 - Perphenazine, 4 mg, oral
Q0176 - Perphenazine, 8mg, oral
S0136 - Clozapine, 25 mg
S0163 - Risperidone inj
S0166 - Injection, olanzapine, 2.5 mg
S0183 - Prochlorperazine maleate, oral, 5mg


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Appendix 7: List of Mental Health Related Medical and Data Specific Codes 
Code Type
Description
ICD-9-CM
230 - 319 Mental, Behavioral and Neurodevelopmental Disorders 
ICD-10-CM
F01 - F99 Mental, Behavioral and Neurodevelopmental Disorders 
MS DRG
876 - 887 Mental Diseases & Disorders
CPT-4
90785 - Interactive complexity add-on (for psychotherapy codes)
90791 - Psychiatric/psychological diagnostic interview without medical services (intake 
interview)
90792 - Psychiatric diagnostic interview (for prescribers / medical services)
90832 - Individual psychotherapy, 30 minutes
90833 - Use add-on code for Individual psychotherapy, 30 minutes with the patient 
and/or family member (time range 16-37 minutes), when performed with an 
evaluation and management service.
90834 - Individual psychotherapy, 45 minutes
90836 - When performed with an evaluation & management service
90837 - Individual psychotherapy, 60 minutes
90838 - When performed with an evaluation & management service
90839 - Psychotherapy for crisis, first 60 minutes
90840 - Add-On service code - describes billing an additional 30 minutes of crisis 
therapy services rendered after the first 90 minutes of treatment.
90845 - Psychoanalysis 
90847 - Family psychotherapy (conjoint psychotherapy) (with patient present), 50 
minutes
90849 - Multiple-family group psychotherapy
90853 - Group psychotherapy
90875 - Individual psychophysiological therapy incorporating biofeedback training by 
any modality (face-to-face with the patient), with psychotherapy (eg, insight 
oriented, behavior modifying or supportive psychotherapy); 30 minutes
90876 - 45 minutes
96101 - Psychological testing, interpretation and reporting per hour by a psychologist 
(per hour)
96102 - Psychological testing per hour by a technician (per hour)
96103 - Psychological testing by a computer, including time for the psychologist’s 
interpretation and reporting (per hour)
96105 - Assessment of Aphasia
96111 - Developmental Testing, Extended
96116 - Neurobehavioral Status Exam (per hour)
96118 - Neuropsychological testing, interpretation and reporting by a psychologist (per 
hour)
96119 - Neuropsychological testing per hour by a technician
96120 - Neuropsychological testing by a computer, including time for the 
psychologist’s interpretation and reporting
96150 - Health & Behavioral Assessment – Initial (each 15 mins)
96151 - Reassessment (each 15 mins)


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Code Type
Description
96152 - Health & Behavior Intervention – Individual (each 15 mins)
96153 - Health & Behavior Intervention – Group (each 15 mins)
96154 - Health & Behavior Intervention – Family with Patient (each 15 mins)
96155 - Health & Behavior Intervention – Family without Patient (each 15 mins)
Standard services
Psychiatric and/or Substance Abuse
Revenue codes
0114 - Private medical or general-psychiatric
0513 - Clinic-psychiatric
0900 - Psychiatric/psychological treatments-general class
0901 - Psychiatric/psychological treatments-electroshock treat
0902 - Psychiatric/psychological treatments-milieu therapy
0903 - Psychiatric/psychological treatments-play therapy
0904 - Psychiatric/psychological treatments-activity therapy
0909 - Psychiatric/psychological treatments-other
0910 - Psychiatric/psychological services-general classification
0911 - Psychiatric/psychological svcs-rehabilitation
0912 - Psychiatric/psychological svcs-day care or less intense
0913 - Psychiatric/psychological svcs-night care or intense
0914 - Psychiatric/psychological svcs-individual therapy
0915 - Psychiatric/psychological svcs-group therapy
0916 - Psychiatric/psychological svcs-family therapy
0917 - Psychiatric/psychological svcs-biofeedback
0918 - Psychiatric/psychological svcs-testing
0919 - Psychiatric/psychological svcs-other
0961 - Professional fees-psychiatric
1001 - BH R & B Residential - Psych
Standard place
Inpatient Psychiatric Facility
Psych Facility Partial Hosp
Community Mental Health Center
Intermed Care/Mental Retarded
Residential Subst Abuse Facil
Psych Residential Treatmnt Ctr
Non-resident Subst Abuse Facil


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 9 June 2022
Code Type
Description
Standard provider
Mental Health/Chemical Dep NEC
Mental Health Facilities
Chemical Depend Treatment Ctr
Mental Hlth/Chem Dep Day Care
Procedure groups
Psychotherapy, individual
Psychotherapy, family
Psychotherapy, group
Psych advice
Other psychiatric services


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
27
Status: Approved, Date: 9 June 2022
Appendix 8: List of Chronic Conditions Included in Exclusion List and Their ICD-9-
CM/ICD-10-CM/Rx Listings
Criteria
Code type
Codes
ICD-9-CM
410, 412, 428, 4254, 4255, 425.7, 425.8, 425.9, 398.91, 402.01, 402.11, 
402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 426.0, 426.7, 426.9, 
427.0, 427.1, 427.2, 427.3, 427.4, 427.6, 427.8, 427.9, 785.0, V45.0, V53.3, 
426.13, 426.10, 426.12, 996.01, 996.04
ICD-10-CM
I21, I22, I252, I43, I495, I50, I099, I110, I130, I132, I255, I420, I425, I426, I427, 
I428, I429, I442, P290, I47, I48, I49, I441, I442, I443, I456, I459, R000, R001, 
R008, T821, Z450, Z950
ICD-9-CM
427.81, 426.0
ICD-10-CM
I495, I442
ICD-9-CM
427.1
ICD-10-CM
I472
ICD-9-CM
426.82
ICD-10-CM
I45.81
Rx
Type IA antiarrhythmics (Quinidine,Procainamide,Disopyramide), Type IC 
antiarrhythmics (Flecainide, Encainide), Class III antiarrhythmics (Sotalol, 
Amiodarone), Antipsychotics (Chlorpromazine, Haloperidol, Droperidol, 
Quetiapine, Olanzapine, Amisulpride, Thioridazine), Tricyclic 
antidepressants (Amitriptyline, Doxepin, Imipramine, Nortriptyline, 
Desipramine), Other antidepressants (Mianserin, Citalopram, Escitalopram, 
Venlafaxine, Bupropion, Moclobemide), Antihistamines (Diphenhydramine, 
Astemizole, Loratidine, Terfanadine), Other Rx (Chloroquine, 
Hydroxychloroquine, Quinine), Macrolides (Erythromycin, Clarithromycin) 
ICD-9-CM
250.4, 250.5, 250.6, 250.7, 250.8, 250.9
ICD-10-CM
E102, E103, E104, E105, E106, E107, E108, E112, E113, E114, E115, 
E116, E117, E118, E122, E123, E124, E125, E126, E127, E128, E132, 
E133, E134, E135, E136, E137, E138, E142, E143, E144, E145, E146, 
E147, E148
Rx
Insulin
ICD-9-CM
582, 585, 586, V56, 583.0, 583.1, 583.2, 583.4, 583.6, 583.7, 588.0, V42.0, 
V45.1, 403.01, 403.11, 403.91, 404.02, 404.03, 404.12, 404.13, 404.92, 
404.93, V56, 
ICD-10-CM
I120, I131, N18, N19, N032, N033, N034, N035, N036, N037, N052, N053, 
N054, N055, N056, N057, N250, Z490, Z491, Z492, Z940, Z992
ICD-9-CM
239.7;240.0-240.9;241.0-241.9;242.00-242.91;243;244.0-244.9;245.0-
245.9;246.0-246.9
ICD-10-CM
E00, E01, E02, E03, E04, E05, E06, E07, E89.0
ICD-9-CM
456.0, 456.1, 456.2, 572.2, 572.3, 572.4, 572.8, 570, 571, 070.6, 070.9, 
456.0, 456.1, 456.2, 572.2, 572.3, 572.4, 572.8, 573.3, 573.4, 573.8, 573.9, 
V42.7, 0702.2, 070.23, 070.32, 070.33, 070.44, 070.54
ICD-10-CM
B18, I85, K70, K72, K73, K74, I864, I982, K711, K765, K766, K767, I864, 
I982, K713, K714, K715, K717, K760, K762, K763, K764, K768, K769, Z944
Patients with Cancer 
ICD-9-CM
140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 
155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 170, 171, 172, 174, 
175, 176, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 
192, 193, 194, 195, 200, 201, 202, 203, 204, 205, 206, 207, 208, 196, 197, 
198, 199
ICD-10-CM
C00-C26, C30-C34, C37-C41, C43, C45-C58, C60-C85, C88, C90-C97
Rx
Antineoplastic and Chemotherapy Drugs
ICD-9-CM
286, 287.1, 287.3, 287.4, 287.5
ICD-10-CM
D65, D66, D67, D68, D69
ICD-9-CM
280-285, 288-289
ICD-10-CM
D55, D56, D57, D60, D61
Coagulation disorders
Prolonged QT Syndrome
Ventricular tachycardia
Renal diseases
Thyroid diseases
Chronic liver diseases
Hematologic disease
Patients with DM with 
complications and/or on Insulin
Congestive heart failure, 
arrythmia
Sick sinus syndrome, Complete 
atrioventricular block


R092670  (paliperidone palmitate)
Statistical Analysis Plan R092670SCH4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
28
Status: Approved, Date: 9 June 2022
Appendix 9: List of Other Criteria Included in Inclusion/Exclusion List and Their 
ICD-9-CM/ICD-10-CM/Rx Listings
Criteria
Code type
Codes
ICD-9-CM
640-677, 760-763, V22-V24, V27-V28, V30-V39
ICD-10-CM
Oxx, Oxxx, Oxxxx, Oxxxxx, Z33-Z39, P00-P03, Z3201, Z34, Z36, Z37, Z38, 
Z39, Z3A
CPT
59000-59899
ICD-9-CM
278.01, 278.03, 783.21, 783.22, V85.41-V85.45
ICD-10-CM
E6601, E662, R634, R636, Z684, Z6841-Z6845
Rx
Clozapine, Clozaril, Fazaclo, Versacloz
HCPCS
S0136
Inducers of protein involved in 
paliperidone metabolism
Rx
Rifampicin, Carbamazepine, Oxcarbazepine, Barbiturates, Phenytoin, 
Troglitazone
Systemic antifungals
Rx
Ketoconazole, Itraconazole, Fluconazole, Fosfluconazole, Voriconazole, 
Posaconazole, Isavuconazole, Griseofulvin, Terbinafine
Dopamine agonists
Rx
Ropinirole, Pramipexole, Pergolide, Cabergoline, Lisuride, Amantadine etc..
Pregnancy / Delivery records 
during baseline
Patients with >=40 and/or < 18 
BMI
Clozapine use within 2 months 
index PP injection