Clinical trial NCT03664232
Conditions: Autism Spectrum Disorder
Sponsor: Janssen Research & Development, LLC
Start date: 2018-11-07; Completion date: 2022-10-28
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of JNJ-42165279 compared with placebo in the improvement of symptoms of Autism Spectrum Disorder (ASD) during 12 weeks of treatment using the Autism Behavior Inventory (ABI).

Detailed description:

Arms: arm 1: Participants will self-administer 25 milligram (mg) JNJ-42165279 tablets orally twice daily for 12 weeks. arm 2: Participants will self-administer matching placebo tablets orally twice daily for 12 weeks.
Interventions: intervention 1: JNJ-42165279 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 25 mg JNJ-42165279 orally twice daily for 12 weeks. intervention 2: Participants will receive a matching placebo orally twice daily for 12 weeks.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 29 September 2020
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study 
Investigating the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and 
Adult Subjects with Autism Spectrum Disorder
Protocol 42165279AUT2001; Phase 2a
JNJ-42165279
AMENDMENT 6
*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, 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 US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved
Date:
29 September 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-114678500, 11.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT03664232


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 33
TIME AND EVENTS SCHEDULE .............................................................................................................. 39
ABBREVIATIONS ...................................................................................................................................... 43
1.
INTRODUCTION................................................................................................................................ 46
1.1.
Background .................................................................................................................................... 47
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 60
2.1.
Objectives and Endpoints .............................................................................................................. 60
2.1.1.
Objectives ................................................................................................................................... 60
2.1.2.
Endpoints.................................................................................................................................... 62
2.2.
Hypothesis ..................................................................................................................................... 62
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 62
3.1.
Overview of Study Design.............................................................................................................. 62
3.2.
Study Design Rationale.................................................................................................................. 64
3.2.1.
Randomization, Blinding, and Control ........................................................................................ 64
3.2.2.
Study Population......................................................................................................................... 64
3.2.2.1.
Rationale for Including Adolescent Subjects, Aged 13 to 17 Years........................................ 64
3.2.3.
Rationale for Dose Selection ...................................................................................................... 66
3.2.4.
Rationale for Pharmacokinetic Evaluations................................................................................ 67
3.2.5.
Rationale for Pharmacogenomic and Biomarker Evaluations.................................................... 67
3.2.6.
JAKE System.............................................................................................................................. 67
3.2.6.1.
My JAKE /My JAKE MMApp.................................................................................................... 71
3.2.6.2.
JAKE Sense............................................................................................................................. 72
3.2.6.2.1.
Continuous Biosensor .......................................................................................................... 72
3.2.6.2.1.1.
Actigraphy/Accelerometry................................................................................................. 72
3.2.6.2.2.
Periodic Biosensors and JAKE Task Battery....................................................................... 73
3.2.6.2.2.1.
Periodic Biosensor of Interest: Electroencephalogram Portion ........................................ 74
3.2.6.2.2.2.
Periodic Biosensor of Interest: Eye Tracking Portion ....................................................... 75
3.2.6.2.2.3.
Affect Detection Portion .................................................................................................... 77
3.2.6.2.2.4.
HRV Portion ...................................................................................................................... 77
3.2.6.2.3.
JAKE Sense Workbench...................................................................................................... 78
3.2.7.
Standard Instruments and Rating Scales................................................................................... 78
3.2.7.1.
Diagnostic and Classification Instruments............................................................................... 78
3.2.7.2.
Instruments for Measuring Change ......................................................................................... 78
3.2.7.2.1.
Zarit Burden Interview.......................................................................................................... 79
3.2.8.
National Database for Autism Research/Global Unique ID........................................................ 80
4.
SUBJECT POPULATION.................................................................................................................. 80
4.1.
Inclusion Criteria ............................................................................................................................ 80
4.2.
Exclusion Criteria ........................................................................................................................... 84
4.3.
Prohibitions and Restrictions ......................................................................................................... 87
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 88


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6.
DOSAGE AND ADMINISTRATION .................................................................................................. 89
7.
TREATMENT COMPLIANCE............................................................................................................ 90
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 90
9.
STUDY EVALUATIONS .................................................................................................................... 92
9.1.
Study Procedures........................................................................................................................... 92
9.1.1.
Overview..................................................................................................................................... 92
9.1.2.
Screening Phase ........................................................................................................................ 94
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 94
9.1.4.
Posttreatment Phase (Follow up) ............................................................................................... 95
9.2.
Efficacy........................................................................................................................................... 95
9.2.1.
Endpoints.................................................................................................................................... 95
9.2.2.
Evaluations ................................................................................................................................. 95
9.2.2.1.
Caregiver Reporting Tool: Modules and Components ............................................................ 96
9.2.2.1.1.
ABI........................................................................................................................................ 97
9.2.2.1.2.
Daily Tracker ........................................................................................................................ 98
9.2.2.1.3.
Journal and Event Trackers ................................................................................................. 98
9.2.2.1.4.
Therapy Tracker................................................................................................................... 99
9.2.2.1.5.
Medical/Developmental History............................................................................................ 99
9.2.2.2.
JAKE Sense............................................................................................................................. 99
9.2.2.2.1.
Continuous Biosensor .......................................................................................................... 99
9.2.2.2.2.
Periodic Biosensors ............................................................................................................. 99
9.2.2.2.2.1.
Electroencephalogram (Brain Products ActiCHamp 32)................................................. 100
9.2.2.2.2.2.
Actiwave Cardio Single-Channel ECG............................................................................ 100
9.2.2.2.2.3.
Eye Tracker (Tobii X2-30)............................................................................................... 100
9.2.2.2.2.4.
iMotions Biometric Research Platform: Emotient FACET Module.................................. 101
9.2.2.3.
JAKE Task Battery: Tasks and Stimuli for use With Periodic Biosensors ............................ 101
9.2.2.4.
Caregiver Reporting Tool: Data Processing.......................................................................... 103
9.2.2.5.
JAKE Sense Data Pipeline.................................................................................................... 104
9.2.2.6.
Standard Instruments and Scales ......................................................................................... 104
9.2.2.6.1.
Autism Diagnostic Observation Schedule™, Second Edition............................................ 104
9.2.2.6.2.
Kaufman Brief Intelligence Test, Second Edition............................................................... 104
9.2.2.6.3.
Zarit Burden Interview........................................................................................................ 104
9.2.2.6.4.
Social Responsiveness Scale 2™..................................................................................... 105
9.2.2.6.5.
Child Adolescent Symptom Inventory Anxiety ................................................................... 105
9.2.2.6.6.
Repetitive Behavior Scale-Revised (parent) ...................................................................... 105
9.2.2.6.7.
Aberrant Behavior Checklist-Community........................................................................... 105
9.2.2.6.8.
Clinical Global Impression-Severity and Improvement ...................................................... 105
9.2.2.6.9.
Caregiver Global Impression of Severity ........................................................................... 106
9.2.2.6.10.
Caregiver Assessment of Treatment ................................................................................. 106
9.2.2.6.11.
Self-Assessment of Improvement ...................................................................................... 106
9.2.2.6.12.
Evaluation of JAKE ............................................................................................................ 106
9.2.2.7.
JAKE Help/Manuals............................................................................................................... 106
9.2.2.8.
National Database for Autism Research/Global Unique ID................................................... 107
9.3.
Biomarker Evaluations ................................................................................................................. 107
9.4.
Pharmacokinetics......................................................................................................................... 108
9.4.1.
Evaluations ............................................................................................................................... 108
9.4.2.
Analytical Procedures............................................................................................................... 108
9.4.3.
Pharmacokinetic Parameters ................................................................................................... 109
9.5.
Pharmacogenomic (DNA) Evaluations ........................................................................................ 109
9.6.
Safety Evaluations ....................................................................................................................... 109
9.6.1.
Adverse Events......................................................................................................................... 110
9.6.2.
Suicidality Evaluation................................................................................................................ 110
9.6.2.1.
Columbia Suicide Severity Rating Scale............................................................................... 110
9.6.2.2.
Aberrant Behavior Checklist - Irritability Subscale ................................................................ 111
9.6.3.
Vital Signs................................................................................................................................. 111


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9.6.4.
Electrocardiogram..................................................................................................................... 111
9.6.5.
Physical and Neurological Examination ................................................................................... 111
9.6.6.
Clinical Laboratory Tests .......................................................................................................... 112
10.
SUBJECT COMPLETION / WITHDRAWAL FROM THE STUDY.................................................. 113
10.1.
Completion ................................................................................................................................... 113
10.2.
Discontinuation of Study Treatment and Withdrawal from Study ................................................ 113
11.
STATISTICAL METHODS............................................................................................................... 114
11.1.
Subject Information ...................................................................................................................... 114
11.2.
Sample Size Determination ......................................................................................................... 115
11.3.
Efficacy Analysis .......................................................................................................................... 115
11.3.1.
Primary Efficacy Endpoints....................................................................................................... 115
11.3.2.
Secondary Efficacy Endpoints.................................................................................................. 116
11.4.
Biomarker and Pharmacogenomic Analysis ................................................................................ 116
11.5.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis .......................................... 116
11.6.
Safety Analysis............................................................................................................................. 117
11.7.
Data Monitoring Committee ......................................................................................................... 118
12.
ADVERSE EVENT REPORTING .................................................................................................... 118
12.1.
Definitions .................................................................................................................................... 119
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 119
12.1.2.
Attribution Definitions................................................................................................................ 120
12.1.3.
Severity Criteria ........................................................................................................................ 121
12.2.
Special Reporting Situations........................................................................................................ 121
12.3.
Procedures................................................................................................................................... 122
12.3.1.
All Adverse Events.................................................................................................................... 122
12.3.2.
Serious Adverse Events ........................................................................................................... 123
12.3.3.
Pregnancy................................................................................................................................. 124
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 124
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 124
13.1.
Procedures................................................................................................................................... 124
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 124
14.
STUDY DRUG INFORMATION....................................................................................................... 125
14.1.
Physical Description of Study Drug(s) ......................................................................................... 125
14.2.
Labeling........................................................................................................................................ 125
14.3.
Preparation, Handling, and Storage............................................................................................. 125
14.4.
Drug Accountability ...................................................................................................................... 125
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 126
16.
ETHICAL ASPECTS ....................................................................................................................... 127
16.1.
Study-Specific Design Considerations......................................................................................... 127
16.2.
Regulatory Ethics Compliance..................................................................................................... 129
16.2.1.
Investigator Responsibilities ..................................................................................................... 129
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 129
16.2.3.
Informed Consent and Assent Form......................................................................................... 130
16.2.4.
Privacy of Personal Data .......................................................................................................... 132
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 132
16.2.6.
Country Selection ..................................................................................................................... 133
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 133
17.1.
Protocol Amendments.................................................................................................................. 133
17.2.
Regulatory Documentation .......................................................................................................... 133
17.2.1.
Regulatory Approval/Notification .............................................................................................. 133
17.2.2.
Required Prestudy Documentation........................................................................................... 133
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 134


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17.4.
Source Documentation................................................................................................................. 134
17.5.
Case Report Form Completion .................................................................................................... 135
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 136
17.7.
Record Retention ......................................................................................................................... 136
17.8.
Monitoring .................................................................................................................................... 137
17.9.
Study Completion/Termination..................................................................................................... 137
17.9.1.
Study Completion/End of Study................................................................................................ 137
17.9.2.
Study Termination..................................................................................................................... 138
17.10.
On-Site Audits .............................................................................................................................. 138
17.11.
Use of Information and Publication.............................................................................................. 138
REFERENCES.......................................................................................................................................... 140
ATTACHMENTS....................................................................................................................................... 147
INVESTIGATOR AGREEMENT ............................................................................................................... 179
LIST OF ATTACHMENTS
Attachment 1:
Contraceptive and Barrier Guidance and Collection of Pregnancy Information....... 147
Attachment 2:
Examples of Prohibited Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers....... 149
Attachment 3:
Autism Behavior Inventory-Clinician Interview (ABI-C) ............................................ 150
Attachment 4:
Autism Diagnostic Observation Schedule, Second Edition (ADOS-2)..................... 152
Attachment 5:
Kaufman Brief Intelligence Test, Second Edition (KBIT-2) ...................................... 155
Attachment 6:
Zarit Burden Interview (ZBI) ..................................................................................... 156
Attachment 7:
Social Responsiveness Scale 2 (SRS-2) ................................................................. 158
Attachment 8:
Child Adolescent Symptom Inventory-Anx (CASI–Anx)........................................... 159
Attachment 9:
Repetitive Behavior Scale – Revised (RBS-R)......................................................... 160
Attachment 10:
Aberrant Behavior Checklist (ABC) .......................................................................... 161
Attachment 11:
Clinical Global Impression–Severity (CGI-S) and Clinical Global Impression-
Improvement (CGI-I)................................................................................................. 165
Attachment 12:
Columbia Suicide Severity Rating Scale – BASELINE/SCREENING...................... 167
Attachment 13:
Columbia Suicide Severity Rating Scale – Since Last Visit ..................................... 171
Attachment 14:
Caregiver-Assessment of Treatment........................................................................ 173
Attachment 15:
Anticipated Events.................................................................................................... 175
Attachment 16:
COVID-19 Appendix ................................................................................................. 176
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Volume of Blood to be Collected From Each Subject............................................................... 93
Table 2:
Caregiver Reporting Tool: Available Modules and Features.................................................... 96
FIGURES
Figure 1:
Subject-specific Trial Scheme .................................................................................................. 63
Figure 2: 
My JAKE System ...................................................................................................................... 69
Figure 3:
My JAKE MMApp...................................................................................................................... 70


JNJ-42165279
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Status: Approved, Date: 29 September 2020
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
14 September 2016
Amendment 1
9 March 2017
Amendment 2
17 July 2018
Amendment 3
26 September 2019
Amendment 4
9 December 2019
Amendment 5
13 April 2020
Amendment 6
29 September 2020
Amendments below are listed beginning with the most recent amendment.
Amendment 6 (29 September 2020)
The overall reason for the amendment: The overall reason for the amendment is to provide options for 
study-related participant management in the event of disruption to the conduct of the study due to the Coronavirus 
2019 (COVID-19) pandemic, remove alcohol breath test screening, extend the allowable time window for 
administration of the ADOS-2, change the version of the suicidality evaluation instrument used at screening, and 
modify the exclusion criterion regarding CYP3A4 inducers and inhibitors.
Applicable Section(s)
Description of Change(s)
Rationale:  Modifications to study conduct may be needed due to the COVID-19 pandemic.
9.1.1 Study Overview
Added reference to Attachment 16 for COVID-19 related guidance.
Attachments
Added Attachment 16 for guidance on study conduct during the COVID-19
pandemic.
Rationale: The risk of alcohol consumption on the day of a study visit is believed to be low in this patient 
population. Compliance with protocol-defined alcohol restrictions can be adequately assessed via verbal 
confirmation with subject and/or caregiver and general appraisal by site staff for signs of acute intoxication.
Time & Events;
9.1.2 Screening Phase
Removed alcohol breath test.
4.2. Exclusion Criteria
Removed positive tests for alcohol from Exclusion Criterion 9.
15.Materials
Removed breathalyzers.
Rationale: To broaden the allowable time window for ADOS-2 administration prior to the screening visit. ADOS-2 
scores are expected to be relatively stable within a 2-year period.
4.1 Inclusion Criteria;
9.2.2.6 Standard 
Instruments & Scales
Changed the allowable period for the ADOS-2 administration in Inclusion 
Criterion 2 from 12 months to 24 months prior to the screening visit.
Rationale: Removed requirement for investigators to consult with sponsor for all stable medical conditions given 
the burden and possible delay such a requirement poses and limited utility for well-managed, stable conditions. 
Investigators may continue to consult the sponsor should a subject’s concurrent medical diagnosis raise. 
4.2 Exclusion Criteria
Modified Exclusion Criterion 3 to indicate that the investigator, with consultation 
with the sponsor, if warranted, will determine whether patients with stable 
conditions can be enrolled in the study.


JNJ-42165279
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: To more precisely define length of time for which moderate/strong CYP3A4 inhibitors or inducers are 
prohibited during the study, call attention to non-drug supplements to which the prohibition also applies, and clarify
that Attachment 2 comprises a non-exhaustive list of CYP3A4 inhibitors and inducers.
4.2 Exclusion Criteria
Modified Exclusion Criterion 5 regarding moderate/strong CYP3A4 inhibitors or 
inducers: 1) included supplements, 2) removed ambiguous language from the 
intended prohibited period and added additional language to account for CYP3A4 
inhibitors or inducers with unusually long half-lives by changing the period for 
restriction from one month to 30 days or 5 half-lives (whichever is longer) prior to 
Day 1, and 3) indicated that the Attachment 2 list of medications includes some 
examples of CYP3A4 inhibitors or inducers.
Rationale: A different version of the C-SSRS is needed at screening to capture suicidal ideation and behavior 
during the periods defined in the exclusion criterion. The current version only captures lifetime suicidality.
9.6.2 Suicidality Evaluation
Changed the version of the C-SSRS to be used at screening from the Baseline 
version to the Baseline/Screening version.
Attachments
Replaced representative pages of the C-SSRS used at screening in Attachment 12.
Rationale:
To clarify the description of qualified study site personnel. 
16.1 Design Considerations
Modified the description of qualified personnel to indicate that safety assessments 
will be performed by experienced and medically-qualified study site personnel.
Amendment 5 (13 April 2020)
The overall reason for the amendment: The overall reason for the amendment is to update the JNJ-42165279 
clinical background information, change the dosing regimen/dose, increase the sample size, and remove the cap on 
the number of adult patients to be enrolled.
Applicable Section(s)
Description of Change(s)
Rationale: Recent analyses of Phase 2 data with JNJ-42165279 indicate that AEA levels are not sufficiently 
sustained in all patients over a 24-hour dosing interval with 25 mg once daily dosing. Subjects with higher trough 
AEA levels showed superior efficacy than those with lower AEA levels in measures of depression and anxiety.
PK/PD modeling predicts that higher trough drug exposure and AEA levels can be achieved with twice daily (BID) 
administration of JNJ-42165279 25 mg (50 mg total daily dose) while maintaining good safety margins.
Time & Events
Changed the dosing regimen from once daily to twice daily, and changed “bottle” to 
“bottles.”
Time & Events;
6. Dosage;
9.1.3 Treatment Phase
Added that dosing in the clinic should be the subject’s first dose of the day.
Synopsis;
Time & Events;
6. Dosage;
9.4.1. PK Evaluations
Modified the description of which study drug administrations should have the date 
and time recorded. 
Synopsis;
3.1 Overview of Design
Described that subjects enrolled prior to Protocol Amendment 5 were randomized to 
receive once daily dosing of placebo or 25 mg JNJ-42165279 and all other subjects 
will receive twice daily (BID) dosing of placebo or 25 mg JNJ-42165279 (total daily 
dose of 50 mg).


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Synopsis;
2.1 Objectives;
9.1.3. Treatment Phase
Removed the reference to once daily dosing.
1.1. Background
Added information on the estimated drug exposure and safety margins of 
adolescents compared to adults, as well as the estimated impact of the change to BID 
dosing on Cmax and AUC in adults.
1.1 Background;
3.2.2.1 Rationale for 
including adolescents
Replaced the safety margins associated with once daily dosing of JNJ-42165279 25 
mg to those associated with 25 mg BID.
3.2.3. Rationale for Dose 
Modified the rationale for dose selection to reflect the change from once daily to 
BID dosing.
6. Dosage;
9.1.3. Treatment Phase
Indicated that treatment phase visits should be scheduled for mornings.
6. Dosage
Added information regarding dosing, including recommended and required dosing 
intervals for BID dosing.
Changed the definition of noncompliance to be recorded on diaries from >1 pill to 
>2 pills.
9.1.1. Overview
Removed information regarding the time of day for scheduled visits.
11.1. Subject Information
Changed the primary analysis set from Intent-to-Treat (ITT) to ITT-BID, which 
includes only subjects who are enrolled under BID dosing.
Synopsis;
11.2. Sample Size
Indicated that the sample size is based on the number of subjects to receive BID 
dosing. 
11.3. Efficacy Analyses
Deleted statement that all efficacy analyses will be based on the ITT analysis set.
11.3.1. Primary efficacy 
endpoints
Added that primary efficacy analysis will be based on the ITT-BID analysis set.
Added that additional sensitivity analyses for the primary efficacy endpoints may be 
specified in the SAP.
Removed the subgroups to be included in the descriptive statistics and indicated that 
this will be specified in the SAP. 
11.6. Safety Analysis
Added “by dose level” to the summaries of adverse events and clinical laboratory 
tests.
16.1. Study-Specific Design 
Considerations
Changed the dose from 25 mg to 25 mg BID (total daily dose of 50 mg). 
Rationale: As some subjects have been enrolled under once daily dosing prior to Protocol Amendment 5, the total 
sample size needs to be increased to have adequate power for the comparison of placebo BID and JNJ-42165279 25 
mg BID.
Synopsis;
3.1. Overview of Design
The number of subjects to be randomized in the study was changed from 60 to 80.
Rationale: Data are now available from one Phase 1 study in healthy Japanese subjects and two Phase 2 studies 
with JNJ-42165279.
Synopsis;
Introduction
Updated the brief description of Phase 1 and Phase 2 studies.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
1.1. Background
Added a summary of results of the Phase 1 study in healthy Japanese subjects (Study 
42165279EDI1007), the Phase 2 study in patients with severe social anxiety disorder 
(Study 42165279SAX2001), and the Phase 2 study in patients with major depressive 
disorder with anxiety symptoms (42165279MDD2001).
Rationale: The restriction to enroll no more than 50% adult subjects is being removed due to low adolescent 
enrollment to date. There is no expected impact on evaluation of treatment efficacy in this Proof-Of-Concept study.
Synopsis;
3.1 Overview of Design;
4.1. Inclusion Criteria;
5. Treatment Allocation
Removed statement that at least 50% of subjects will be adolescents.
Rationale: Recent analyses of Phase 2 data indicate that assessing the relationship between plasma AEA levels and 
efficacy measures can aid in the understanding of treatment efficacy.
Synopsis;
2.1.1. Objectives
Added a secondary objective to evaluate the relationship between plasma 
concentrations of 
and efficacy.
Synopsis;
3.2.5. Rationale for 
Biomarker Evaluations
11.4. Biomarker Analysis
Modified the description to state that 
levels will be correlated with efficacy and 
other clinical evaluations.
Rationale: The length of contraception usage by female subjects, as well as the period in which eggs (ova, oocytes) 
should not be donated, is intended to reflect the period of time JNJ-42165279 may exert an effect on female
reproductive cells. The time frame has been shortened to be consistent with the average menstrual cycle length. 
Additionally, clarification was needed on the length of contraception usage for female partners of male subjects.
4.1 Inclusion Criteria
Added the duration for use of contraception by female partners of male subjects
(mirroring the male subject’s duration of contraception use) to Criterion 4. 
Changed the duration of contraception use for female subjects in Criterion 19 from 
90 to 30 days after the last dose.
Changed the duration for female subjects to avoid donation of eggs in Criterion 20 
from 90 to 30 days after the last dose.
Rationale: To allow for revisions to the Evaluation of JAKE questionnaire during the study, the representative 
pages of this questionnaire were removed.
9.2.2.6.12. Evaluation of 
JAKE
Removed “4-item” from description of the Evaluation of JAKE questionnaire and 
removed cross-reference to the corresponding attachment of representative pages.
12.3.1. All Adverse Events;
Attachments
Renumbered the Attachment of Anticipated Events
Attachments
Removed representative pages of the Evaluation of JAKE questionnaire.
Rationale: Minor changes were made to improve clarity or readability, correct errors and inconsistencies, repeat 
text in other applicable sections, and remove unnecessary information.
Synopsis
Removed text considered unnecessary for a study synopsis.
Synopsis;
2.1.2. Endpoints
Indicated that the endpoints lists are efficacy endpoints.
Synopsis;
3.1 Overview of Design;
5. Treatment Allocation
Added information regarding the timing of the interim PK analysis that was included 
in Section 11.5. 
CCI
CCI


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Synopsis;
3.1. Overview of Design
Indicated that the continuous biosensor is a wristband that measures activity.
3.2.2.1. Rationale for 
Inclusion of Adolescents
Corrected the percent reduction in sperm motility observed in the 3-mos GLP rat 
study to 25%.
3.2.5. Rationale for 
Pharmacogenetic;
11.5. Pharmacokinetic
Removed 
9.1.3. Treatment Phase
Modified section to be more concise.
9.2.2.7. JAKE 
Help/Manuals
Deleted information regarding the format and timing of training on the JAKE 
system.
11.6. Safety Analysis
Changed the QTcF intervals to be used for reporting to be consistent with the 
exclusion criterion (>450 msec for males and >470 msec for females).
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made. 
Amendment 4 (9 December 2019)
The overall reason for the amendment: The overall reason for the amendment is to modify the list of examples of 
prohibited cytochrome P450 (CYP) 3A4 inhibitors and inducers.
Applicable Section(s)
Description of Change(s)
Rationale: Errors and omissions were identified in the list of examples of prohibited CYP3A4 inhibitors and 
inducers.
8. Concomitant Therapies
Added description of Attachment 2, and that the investigator should evaluate all 
prestudy and concomitant medications to assess whether they are moderate or strong 
inducers or inhibitors of CYP3A4 and consult with the Sponsor if unsure.
Attachment 2
Modified attachment title to specify CYP3A4, and added statement that this is not a 
comprehensive list of all moderate and strong CYP3A4 inhibitors and inducers.
Modified the list of inducers and inhibitors.
Amendment 3 (26 September 2019)
The overall reason for the amendment: The overall reason for the amendment is to add a description of a new 
application containing the caregiver reporting tool, My JAKE MMApp, modify eligibility criteria considered 
unnecessarily restrictive, modify the blood sampling schedule to enhance exposure/response analyses, and include a 
clinician rating of disease improvement.
Applicable Section(s)
Description of Change(s)
Rationale: A new caregiver reporting application (App) is needed due to a decision by Microsoft to discontinue 
Microsoft Health Vault, which stores the data collected in the current application, My JAKE. Some components 
of My JAKE will not be available in the new application, and there may be periods when neither application is 
available.
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Abbreviations;
Definitions
Added abbreviation and definition of the new application containing the caregiver 
reporting tool, My JAKE Mobile Medical Application v 1.0, and updated the 
definition of My JAKE.
Throughout the protocol 
Replaced term “My JAKE” with “caregiver reporting tool” in statements that are 
applicable to both applications (My JAKE and My JAKE MMApp).
Added “My JAKE Mobile Medical App v 1.0” and/or the abbreviation “My JAKE 
MMApp” where applicable  
T&E
Modified the description of the caregiver reporting tool account set up in 
footnote e.
Synopsis;
T&E;
3.2.6.1 My JAKE;
9.2.2 Evaluations;
9.2.2.1 Caregiver Reporting 
Tool
Indicated which components of the caregiver reporting tool are available in My 
JAKE and My JAKE MMApp.
T&E;
3.2.6.1 My JAKE;
9.2.2.1 Caregiver Reporting 
Tool
Indicated the components of the caregiver reporting tool which will be collected 
on paper if My JAKE and My JAKE MMApp are not available.
3.2.6 JAKE System;
9.2.2.1 My JAKE
Described that there are 2 applications containing the caregiver reporting tool, My 
JAKE and My JAKE MMApp, and that caregivers will use the application that is 
available during their participation in the study.
3.2.6 JAKE System
Added Figure 3 schematic of My JAKE MMApp.
9.2.2.1 Caregiver Reporting 
Tool
Stated that My JAKE MMApp is for use by caregivers and the sponsor.
9.2.2.4 Caregiver Reporting 
Tool: Data Processing
Revised title of Section 9.2.2.4 from “My JAKE Data Pipeline” to “Caregiver 
Reporting Tool: Data Processing.”
Modified description of data processing for the caregiver reporting tool.
9.2.2.7 JAKE Help/Manuals
Revised description of help information available to clinical sites and caregivers 
for the caregiver reporting tool to reflect differences between My JAKE and My 
JAKE MMApp.
15 Materials
Added paper versions of ABI, ABI-S and Daily Tracker to list of study-specific 
materials.
16.1 Design Considerations
Removed statement regarding potential benefit to caregivers of having 
HealthVault information available after the completion of the study.
17.4 Source Documentation
Added statement that if paper forms are used for the Daily Tracker, ABI, or
ABI-S, they will be considered source data.
Attachment 15
Modified the representative page of the Evaluation of JAKE scale to include a 
“NA” option for ratings of JAKE components not available in My JAKE MMApp 
or paper versions. Added the description “(Behaviors, Sleep)” to the Daily 
Tracker component, and removed a redundant scale definition.
Rationale: To add a clinician rating of subjects’ global improvement to augment outcome assessments. A 
clinician evaluation of both severity and improvement may be more sensitive in detecting changes with treatment 
than a severity rating alone.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Abbreviations
Added abbreviation for the Clinical Global Impression of Improvement scale 
(CGI-I)
T&E
Added the CGI-I to table, footnote, and abbreviations.
Synopsis;
2.1.1 Objectives
Added the assessment of CGI-I to the secondary objectives.
Synopsis;
2.1.2 Endpoints;
9.2.1 Endpoints
Added the assessment of CGI-I at Day 85 to the secondary endpoints.
Synopsis;
9.2.2 Evaluations
Added clinicians’ global impressions of disease improvement to efficacy 
evaluations.
9.2.2.6.8 Clinical Global 
Impression
Added description of CGI-I scale.
15 Materials
Added the CGI-I to the list of study-specific materials.
Attachment 11
Added a representative page for the CGI-I scale.
Rationale: To increase the upper age limit of eligible subjects from 30 to 35 years. The upper limit of 30 years 
was considered unnecessarily restrictive, as the study endpoints are unlikely to differ between a 30- and 35-year-
old subject.
Synopsis;
3.1 Study Design;
3.2.2 Study Population;
4 Subject Population;
4.1 Inclusion Criteria;
Changed the upper age limit for eligibility from 30 years to 35 years.
3.1 Study Design
Removed age range in Figure 1.
Synopsis;
3.1 Study Design;
3.2.1 Randomization;
5 Treatment Allocation;
11.3.1 Primary Efficacy 
Endpoints
Revised the second randomization stratum from 18 – 30 years to 18 - 35 years of 
age.
Rationale: To broaden the allowable time window for ADOS-2 administration prior to the screening visit.
ADOS-2 scores are expected to be stable within a 1-year period.
4.1 Inclusion Criteria;
9.2.2.6 Standard 
Instruments
Changed the allowable period for the ADOS-2 administration from 6 months to 
12 months prior to the screening visit. 
Rationale: To obtain predose and postdose PK and 
 samples at Weeks 2 and 12 to 1) enable evaluation of 
the relationship between exposure/pharmacodynamics and efficacy, 2) confirm subject compliance with dosing, 
and 3) assess change in drug exposure and pharmacodynamics from 2 to 12 weeks. In order to collect predose 
samples at Week 12, dosing will need to occur at the clinic.  
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
T&E
Moved information regarding time points for PK and 
 samples from 
footnotes to T&E Table.
Changed the PK postdose sample time point at the Week 2 visit from 0.5-1h to 
2.0-2.5h postdose. 
Added PK samples at the Week 12 visit at predose and 2.0-2.5h postdose.
Add a 
 sample at Week 2 at 2.0-2.5h postdose. 
Added a Week 12 predose 
 sample and specified that the postdose time point 
for the 
 sample at Week 12 will be 2.0-2.5h.
Modified footnote “k” to state that safety laboratories at the Week 2 and 12 visits 
will be collected predose.
T&E;
6 Dosage & Administration
Changed the visits in which dosing will occur in the clinic from Visits 3-6 to all 
visits in the treatment phase.
T&E;
6 Dosage & Administration;
9.1.3 Treatment Phase
Changed the dosing time at Week 12 from approximately 3 hours prior to the visit 
to dosing in the clinic. 
Synopsis;
T&E;
9.4.1 PK Evaluations
Changed the days in which accurate recording of dosing time is needed from 
Days 1, 14, and 15 to Day 1, Week 2, and Week 12 visits, and the day prior to the 
Week 2 and 12 visits.
9.1.1 Overview
Modified Table 1 blood volume information to reflect changes in PK and 
 
sample collection.
Added Week 12 to the statement regarding blood sample collection before and 
after dosing.
In the description of the order of procedures involving the JAKE Task Battery, 
added that the JAKE Task Battery must be completed prior to blood draws and 
removed the reference to Day 1 and Week 4 visits.
Rationale: Minor changes were made to improve clarity or readability, or to correct errors, inconsistencies, or 
omissions and remove unnecessarily redundant information.
T&E
Moved dosing-related information from the previous footnote regarding PK 
samples to footnote e.
Removed “Mood Report” from table and added mood report to description of 
Daily Tracker in footnote “u.”
Synopsis;
9.2.2 Evaluations 
Added clinicians’ global impressions of disease severity to efficacy evaluations.
Synopsis;
11.5 PK and PK/PD
Changed “Day 15” to “the Week 2 visit.”
3.2.2.1 Rationale for 
Including Adolescents
Changed the age in the Section title from “13 to 18 years” to “13 to 17 years”
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JNJ-42165279
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
3.2.6. JAKE System
Removed the previous Section 3.2.6.3, My JAKE Data Pipeline, and moved the 
information not already included elsewhere to Section 9.2.2.4.
Removed the previous Section 3.2.6.4, JAKE Sense Data Pipeline
Added cross-references to Sections 9.2.2.4 and 9.2.2.5 for information on data 
processing.
3.2.6.1 My JAKE/My 
JAKE MMApp
Moved description of Mood Report to bullet for Daily Tracker. 
6 Dosage and 
Administration
Added sentence regarding dosing diaries provided to subjects/caregivers.
Definitions;
9.2.2.1 Caregiver Reporting 
Tool
Removed “subjects” or “study participants” in statements regarding users of My 
JAKE.
9.2.2.1 Caregiver Reporting 
Tool
Changed period in which caregivers should not revoke access to My JAKE and 
Microsoft Health Vault from “until told to do so at the time of database lock” to 
“without investigator approval.”
Removed previous Section 9.2.2.1.3, Mood Report.
9.2.2.1.1 ABI
Added sentence “The ABI-C is completed on paper.”
9.2.2.1.2 Daily Tracker
Revised description of Daily Tracker to include the Mood Report.
Added that caregivers will report on subjects’ overall type of day.
Removed sentence “These items are chosen from a subset of items presented, 
based on the caregiver’s response in the ABI.”
Changed “parents” to “caregivers.”
9.2.2.6.5 CASI-Anx
Corrected the range of values for the CASI-Anx scale. 
Attachment 16
Deleted the following text in the description of anticipated events: “based on 
reports by healthy subjects in Phase 1 studies.”
Throughout the protocol
Minor grammatical, formatting, or punctuation changes were made.
Amendment 2 (17 July 2018)
The overall reason for the amendment: To allow females to participate in this study, including women of 
childbearing potential under conditions of pregnancy testing and use of contraception. Additionally, to update the 
description of the ABI and the JAKE system and assessments, to modify the eligibility criteria, to modify time 
points of procedures, and to add or modify assessments of caregiver and subject global impressions.
Applicable Section(s)
Description of Change(s)
Rationale: To allow females to participate in this study, due to notification of health authority approval for 
women of childbearing potential to participate in clinical trials with JNJ-42165279.
Protocol front page;
Synopsis
Changed protocol title to remove the word “male.”
4.1 Inclusion
Removed requirement for subjects to be male in Inclusion Criterion #1.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Throughout the protocol
Modified text to reflect that participation in the trial is not limited to males.
Rationale: To add requirements that will minimize the chance of pregnancy in female subjects and female 
partners of male subjects and avoid possible exposure of an embryo or fetus to study drug, add pregnancy testing, 
and include pregnancy reporting information. Additionally, to remove the requirement for male subjects to use 
contraception when there is no potential for pregnancy, move restriction for donation of sperm to a separate 
criterion, and move rationale for contraception for male subjects to a different section.
Synopsis: Safety Evaluation; 
Time & Events;  
9.6.6 Laboratory 
Added serum pregnancy test at screening for all female subjects and urine 
pregnancy test at all other subject visits for women of childbearing potential
(WOCBP). 
3.2.2 Study Population
Added rationale for pregnancy testing and use of contraception for female 
subjects.
4.1 Inclusion
The following changes were made:

Added Inclusion Criterion #17 requiring female subjects to have negative 
pregnancy tests at screening and, for WOCBP, at Day 1 before 
randomization.

Added Inclusion Criterion #18 requiring female subjects using oral 
contraceptives to also use a barrier method of contraception with spermicide.

Added Inclusion Criterion #19 requiring female subjects to either be of 
non-childbearing potential or to use a highly effective method of 
contraception during the study and for 90 days after the last dose. 

Added Inclusion Criterion #20 restricting donation of eggs for female 
subjects during the study and within 90 days after the last dose.

Modified Inclusion Criterion #4 to: A male subject who has not had a 
vasectomy must agree to use a condom when having sex with a female 
partner of childbearing potential (See Attachment 1) during the study and for 
3 months after receiving the last dose of study drug. The condom must have a 
spermicide or the partner must use a spermicide. A male subject should also 
be advised to inform their female partner to use a highly effective method of 
contraception, as condoms may break or leak.

Moved restriction for donation of sperm to a separate criterion (#16).
4.1 Inclusion;
3.2.2.1 Rationale for 
Adolescents
Moved rationale for male contraception (previously included as part of Inclusion 
Criterion #4) to Section 3.2.2.1 regarding rationale for inclusion of adolescents.
4.2 Exclusion

Added Exclusion Criterion #21 for male subjects who are sexually active, or 
plan to be sexually active during the trial, with a female who is pregnant.

Added Exclusion Criterion #22 for female subjects who are pregnant or 
breastfeeding, or plan to become pregnant or breastfeed during the trial or 
within 3 months after the last dose.
9.1.1 Overview
Added description of possible additional pregnancy testing during the study. 
Added serum pregnancy test to blood volume table. 
10.2 Discontinuation
Added subject becoming pregnant as a reason for discontinuation from study.
12.3 Adverse Event 
Procedures
Added Section 12.3.3 with information on pregnancy reporting.
16.1 Design Considerations
Added that females will be of nonchildbearing potential or using contraception, 
and that pregnancy testing will be performed.
Attachments
Added Attachment 1 with further information on contraception requirements. 
Renumbered all subsequent Attachments.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: To amend the description of ABI assessments based on health authority feedback and the decision not 
use a structured interview guide for the ABI-C, and to allow for possible revisions to these instruments or the 
JAKE Daily Tracker prior to study start.  
Synopsis Objectives, 
Endpoints;
Time & Events;
Definition of Terms; 
2.1.1. Objectives;
2.1.2. Endpoints;
3.2.6.1. My JAKE;
3.2.7.2. Instruments for 
Measuring Change;
9.2.2.1.1. ABI
The description of the ABI (full version, ABI-S, ABI-C) was amended, including 
a change in approximate number of items, removal of a second anchor, renaming 
of the Mental Health Domain as “Mood & Anxiety,” and removing “structured” 
in descriptions of the ABI-C interview.
Attachments
Replaced previous Attachment 2 (now Attachment 3) to remove the ABI full 
version, ABI-S, and Daily Tracker and replace the ABI-C with a new version.
Rationale: To modify or clarify details of the JAKE system, including data collection and processing, due to 
recent updates.
Throughout the protocol
Changed the name of the JAKE portal, JAKE Biosensor Array, and other 
components of the JAKE system.
Abbreviations;
3.2.6.2 JAKE Sense;
3.2.6.4 JAKE Sense Data 
Pipeline;
9.2.2.5 JAKE Sense Data 
Pipeline
Indicated that JAKE Sense biosensors are used solely for exploratory, proof-of-
concept research, and removed text regarding their validation.
3.2.6 JAKE System;
3.2.6.2.3 Workbench
Indicated that data from My JAKE and JAKE Sense are separated.
Abbreviations;
3.2.6.1 My JAKE;
9.2.2.1.4 Therapy Tracker
Removed medication, diet, and illness as items tracked in Therapy tracker.
3.2.6.2.2 Periodic 
Biosensors;
9.2.2.2.2.2 Actiwave 
Added distinction between the ECG used for the JAKE Task Battery from the 
12-lead ECG for safety assessment.
3.2.6. JAKE System
Replaced JAKE schematic.
3.2.6.4. JAKE Sense Data 
Pipeline
Replaced all text with new description.
3.2.6.2.2. Periodic 
Biosensors
Changed period for continuous biosensors from during normal daily activities to 
throughout the treatment period.
9.2.2. Evaluations

Indicated that the journal and therapy tracker are encouraged but optional.

Added information on actigraphy, EEGs, and ECGs used as part of JAKE 
system.

Modified description of personal information to be collected and shared in My 
JAKE Pipeline and JAKE Sense Data Pipeline.

Indicated that breaks within a set of the JAKE Task Battery are discouraged.

Modified description of JAKE help and manuals.

Modified task durations of the JAKE Task Battery.

Copied text from Time and Events Schedule regarding performance of the 
Task Battery at approximately the same time of day for an individual subject.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
15 Materials
Modified list of equipment related to JAKE system.
Throughout the protocol
Minor changes were made to the description of the JAKE system.
Rationale: To identify subjects taking drugs of abuse during the study and exclude subjects with alcohol intake at 
study visits prior to enrollment, as drug and alcohol use may impact study endpoints. Additionally, to modify the 
allowed use of alcohol to be gender-specific, based on current dietary guidelines, and to include 2 additional 
drugs of abuse in urine drug test.
Time & Events
Added urine drug test at all treatment period visits, and alcohol breath test at 
Screening Visit 1 and Day 1. 
4.2 Exclusion
Modified Exclusion Criterion #9 to exclude subjects with a positive drug or 
alcohol test at screening or Day 1. 
4.2 Exclusion (Criterion 9);
9.6.6 Laboratories
Added phencyclidine and 3,4-methylenedioxy-methamphetamine (MDMA) to list 
of drugs included in urine drug testing.
4.3 Prohibitions
Indicated that alcohol use should be avoided on study visit days, prior to the time 
of a visit, and modified recommended limit to 2 drinks/day for males and 1 
drink/day for females.
Rationale: Eye-tracker calibration can be subject to environment factors in the equipment or room set up, rather 
than the intended purpose of evaluating subject characteristics. Thus, allowing calibration to be repeated to 
determine eligibility is considered appropriate.
Time & Events;
4.1 Inclusion (Criterion 14);
9.1.2 Screening
Indicated that the eye-tracker calibration can be repeated during the screening 
period to meet the criterion of “good” calibration.
Rationale: To assure that only individuals who spend some time every week with their parent/primary caregiver 
are enrolled in the study. The period of reporting for some study evaluations is over the past week. 
4.1 Inclusion
Inclusion Criterion #7: Changed the required period for individuals to spend with 
their parent/caregiver (if not living with them) to: “during each week they must 
either (A) spend at least 3 hours a day for at least 4 days or, (B) spend the 
weekend with a parent or primary caregiver.” 
Rationale: To change the QTc interval used for eligibility and reporting of abnormal intervals to be 
gender-specific, given the gender difference in QTc normal ranges. Additionally, to modify how changes in QTc 
intervals from baseline are summarized.
4.2 Exclusion Criteria
Modified the QTc interval in Exclusion Criterion #2 to indicate that QTcF 
>450 msec applies to males and added QTC interval >470 msec for females.
11.6 Safety Analysis
Modified the reporting of QTc intervals to include QTcF >450 msec for males 
and >470 for females. Modified the change from baseline description from 
30-60 msec to >30 msec.
Rationale: To use the same minimum IQ criterion for eligibility as that used in the previous studies for the 
development and validation of the JAKE system. Additionally, to assure that the KBIT-2 scale is completed for 
determination of eligibility. 
4.1 Inclusion;
4.2 Exclusion;
3.2.7.1 Diagnostic and 
Classification Instruments
Changed the eligibility criterion regarding the KBIT-2 scale from an exclusion 
criterion (previous Criterion #20.1) to an inclusion criterion (Criterion #15). Also 
changed the minimum KBIT-2 composite score from at least 50 to at least 60.
Rationale: To provide greater clarity on informed consent requirements, and add requirement for signing of a 
caregiver consent form to address caregivers’ responsibilities during the study.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
4.1 Inclusion;
9.1.2 Screening;
16.2.3 Informed Consent
Modified description of informed consent requirements, including additional 
requirement for caregivers of all subjects to sign a separate caregiver consent 
form.
Rationale: To exclude individuals with incomplete vaccination status, as this may be applicable to the study 
population, and clarify eligibility criteria for abnormal renal or liver function.
4.1 Inclusion
Modified Inclusion Criterion #6 to clarify that subjects with an AST or ALT >1.5 
times the upper limit of normal cannot be enrolled.
4.2. Exclusion 
Modified Exclusion Criterion #3 to exclude subjects with incomplete vaccination 
status. Changed “renal or liver insufficiency” to “evidence of abnormal liver or 
renal function.”
Rationale: To modify the exclusion criterion regarding planned surgery. 
4.2 Exclusion
Exclusion Criterion #16: Added entry into a major body cavity and significant 
blood loss as examples of major surgery. Modified note regarding allowed 
surgery to specify “minor” surgery, and added requirement for approval by 
sponsor.
Rationale: To correct an error in the exclusion criterion regarding use of drugs with CYP3A4 activity. Correct 
information was included elsewhere in the protocol.
4.2 Exclusion
Modified Exclusion Criterion #5 to include CYP3A4 inducers as well as 
inhibitors. 
Rationale: To clarify the exclusion criterion regarding employees of the investigator or study site.
4.2 Exclusion
Modified description of Exclusion Criterion #19 regarding employees of 
investigator or study site or their family members.
Rationale: To exclude subjects who are unable to perform or comply with all study requirements.
4.2 Exclusion
Added Exclusion Criterion #23 for subjects who are judged by the investigator to 
be unable to perform or comply with all study-specific requirements.
Rationale: To provide additional information regarding determination of eligibility and circumstances in which 
repeat of procedures is allowed. 
Time and Events
Modified footnotes to 1) remove statement regarding repeat of safety labs if 
>28 days have elapsed since the screening labs and 2) refer to screening section 
of protocol for information regarding retesting.
4.1 Inclusion;
4.2 Exclusion
Modified criterion regarding safety laboratory tests (Inclusion Criterion #6 and 
Exclusion Criterion #3) to indicate that they can be repeated once at the discretion 
of the investigator.
4.1 Inclusion
Added note to clarify that the parent or primary caretaker referenced in the 
inclusion criteria (except Inclusion Criterion #8) is the designated caretaker for 
the study.
4.2 Exclusion 
Added information at the end of the exclusion criteria section regarding 
evaluation of eligibility and referenced other sections for additional information 
regarding retesting. 
9.1.2 Screening
Allowed one rescreening and circumstances in which this would be allowed. 
Allowed one retest for abnormal safety laboratory tests or positive drug or alcohol 
test. Copied text from inclusion criterion regarding abnormal labs.
Rationale: To add measurement of 
 at a time point when a PK sample is collected for evaluation of the 
PK/biomarker relationship.
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Time & Events;
9.1.1 Overview
Added blood sample collection for 
 on Day 15 (predose) 
and updated the blood volume collection table.
Rationale: To measure 
at approximately the time of expected peak 
levels after dosing.
Time & Events;
6. Dosage;
9.1.3 Treatment Phase
The time of dosing on the last dosing day (Week 12 visit) was changed from 
during the study visit to 3 hours prior to the scheduled time of the visit. 
Rationale: To add a physical examination immediately prior to enrollment.
Time & Events
A physical examination was added at Day 1.
Rationale: To require completion of the ABC-I in addition to the C-SSRS after screening, regardless of whether 
administration of the C-SSRS is feasible. This was requested by the Health Authority in order to have ABC-I data 
for comparison across time points, in the event that the C-SSRS cannot be completed throughout the trial. In 
addition, the description regarding the timing of these 2 assessments was revised for greater clarity.  
Time & Events;
9.6.2 Suicidality
Information regarding the ABC-I and C-SSRS was removed from the footnote of 
the Time and Events Schedule and added to the body of the protocol. The time 
points in the Time and Events table for these assessments was revised. 
Instructions regarding when the C-SSRS and ABC-I should be administered was 
revised. 
Rationale: To correct the time points for collection of continuous biosensor data.
Time & Events
Changed time points for collection of continuous biosensor data to Weeks 2, 4, 8, 
and 12.
Rationale: To change the scale to be used for caregivers’ global assessment of disease severity to one more 
appropriate for non-clinicians. 
Time & Events
Added a single-item Caregiver Global Impression of Severity (Caregiver GI-S) 
scale at the Day 1, Week 4, Week 8, and Week 12 visits. Removed statement 
regarding completion of the CGI-S by caregiver. 
9.2.2.6 Standard Instruments
Added Subsection 9.2.2.6.9 with description of Caregiver GI-S. 
15 Materials
Added Caregiver GI-S to list of materials.
Rationale: To correct an error in the time points for drug accountability.
Time & Events
Removed the Day 15 time point for drug accountability.
Rationale: To divide the “Self-Assessment of Treatment Experience” into 2 instruments, as the content includes 
2 diverse subject areas (the evaluation of study treatment and the JAKE system). Additionally, to change the title 
of instrument to reflect completion by caregiver rather than the subject.
Time & Events
Deleted the row “Self-Assessment of Treatment Experience” and added 2 new 
rows: “Caregiver Assessment of Treatment” and “Evaluation of JAKE.”
9.2.2.6 Standard Instruments
Added descriptions of both instruments (new Subsections 9.2.2.6.10 and 
9.2.2.6.12)
15 Materials
Added both instruments to list of materials.
Attachments
Split previous Attachment 14, Self-Caregiver Assessment of Treatment 
Experience, into 2 Attachments (Attachments 14 and 15 with new titles of 
questionnaires).
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: To obtain subjects’ impressions of improvement in their disorder.
Time & Events;
15 Materials 
Added a single-item scale entitled “Self-Global Impression of Improvement (Self 
GI-I) at the Week 12 visit.
9.2.2.6 Standard Instruments
Added description of Self GI-I (new Subsection 9.2.2.6.11)
Rationale: To include assessment of 3 additional scales in secondary objectives, evaluations, and endpoints. 
Synopsis Objectives, 
Endpoints, Efficacy;
2.1. Objectives & 
Endpoints;
9.2.1 Endpoints;
9.2.2 Evaluations
Added the Caregiver GI-S, Caregiver Assessment of Treatment, and Self GI-I to 
secondary objectives, evaluations, and endpoints.
Rationale: To update study background information with new information. 
1. Introduction;
1.1 Background;
3.2.2. Study Population
Updated the summary of data on JNJ-42165279 based on the current version of 
the Investigator’s Brochure (Edition 5), and modified the summary of 
Mentis-HV-001 and Mentis-ASD-002 study results.
Rationale: To provide a more detailed description of the exploratory objective regarding pharmacogenomic data 
and to modify the purpose for collection of the pharmacogenomic sample. Additionally, to describe the rationale 
for collection of pharmacogenomic and biomarker data in the Study Design Rationale section.
Synopsis Objectives;
2.1.1. Objectives
Revised description of exploratory objective regarding correlations between 
pharmacogenomic data and treatment outcomes.
3.2 Study Design Rationale;
9.2.2 Evaluations
Added new Section 3.2.5 describing the rationale for pharmacogenomic and 
biomarker evaluations; included information moved or copied from other 
sections. Removed Subsection 9.2.2.7, Genomic Assessments, that was a part of 
Section 9.2.2, Efficacy Evaluations. 
9.5 Pharmacogenomic
Added “efficacy” to the list of outcomes that might be influenced by genetic 
factors. 
Rationale: To assure a balance in treatment assignment by gender and include gender as a factor in analyses due 
to potential gender differences that may impact treatment endpoints. Additionally, to clarify the time point for 
determination of age for stratification. 
Synopsis Overview;
3.1 Overview;
3.2.1. Randomization;
5. Treatment Allocation
Substituted study center with gender as a stratification factor. Indicated that the 
age at the time of first consent will be used for stratification of randomization.
Synopsis Overview, 
Efficacy Analysis;
11.3.1. Primary Efficacy 
Endpoint
Replaced study center with gender as a factor in the primary efficacy analyses.
Rationale: To increase consistency in time of visits and type of day (weekday vs weekend) for visits during the 
treatment period, to reduce potential confounding effect of these on treatment endpoints.
Time & Events; 
9.1.1 Overview
Added recommendation for study visits to occur on the same type of day and 
same period of the day for each subject.  


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: To remove the requirement for study visits to occur in the morning to accommodate subject and 
caregiver schedules.
Time & Events;
6 Dosage;
9.1.1 Overview;
9.1.3 Treatment Phase;
9.4 Pharmacokinetics
Removed “morning,” or changed to indicate that morning is preferred, from 
description of visits and dosing on day of visits.
Rationale: To clarify the visit window for the first screening visit and accommodate caregiver schedules by 
allowing a longer visit window for the second screening visit.
Synopsis Overview;
Time & Events;
3.1. Study Design;
9.1.1 Overview;
9.1.2 Screening
The maximum time between the first screening visit and Day 1 was changed from 
21 days to 26 days. Removed screening visit window of ±5 days. The maximum 
time between the second screening visit and Day 1 was changed from 7 days to 
14 days.
Rationale: The prohibitions and restrictions list did not include all applicable restrictions specified in the 
eligibility criteria.
4.3 Prohibitions
Replaced the first restriction regarding contraception use with one that states that 
subjects must follow all requirements that must be met during the study as noted 
in the eligibility criteria.
Rationale: To add information regarding the order of procedures at study visits.
Time & Events;
6 Dosage;
9.1.1 Overview;
9.1.3 Treatment Phase
Added or replaced information regarding the order of study procedures, and 
provided further information regarding the timing of study drug administration at 
study visits and at home. 
Rationale: To add dosing instructions in the event of a missed dose.
6. Dosage
Added statement that a missed morning dose can be taken later in the day, as long 
as 12 hours remain until the next dose.
Rationale: For consistency in ECG evaluations across study visits, the Follow Up Visit ECG was changed to a 
triplicate ECG.
Time & Events;
9.6.4 Electrocardiogram
Indicated that triplicate ECGs are required at all ECG time points.
Rationale: The subject’s position for collection of vital signs was changed from supine to sitting, as sitting is 
most appropriate for outpatient studies. Additionally, there was an erroneous statement regarding collection of 
standing blood pressure.
Synopsis Safety Analysis;
Time & Events;
9.6.3 Vital signs;
11.6 Safety analysis
Changed the subject’s position for collection of vital signs to sitting.
Rationale: To change restriction durations on days of biomarker collection to be relative to a time that the 
subject can know (time of visits), rather than time of blood draws. Additionally, to add a specific duration for 
following a low-fat diet and simplify description of information collected on restrictions for biomarker collection. 
Time & Events;
4.3 Prohibitions;
8 Concomitant Therapy;
9.3 Biomarkers
Modified durations for restrictions on biomarker collection days to advise 
subjects to follow a low-fat diet for at least 8 hours prior to their scheduled visit. 
Also revised text to indicate that restrictions on strenuous exercise and NSAIDs
are relative to time of study visits. Simplified the description of recording 
compliance to these restrictions.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
4.3 Prohibitions
Removed rationale for restriction on NSAIDs.
Rationale: JAKE Tablets will not be provided to caregivers; they will use their own devices to access the JAKE 
system at home.  
Definition of Terms; 
15. Materials;
9.2.2.1. JAKE Portal
Removed provision of small personal computer or tablet (JAKE Tablet). 
Rationale: Due to a recent change in sponsor privacy policy, the sponsor will not collect the full data of birth. 
Definitions;
3.2.6.3 JAKE Pipeline;
9.2.2.4 My JAKE Pipeline;
17.3 Subject identification
Removed date of birth or changed to either age at time of first informed consent 
or month and year of birth.
Rationale: Measurement of QTcF alone is considered sufficient for evaluation of QT prolongation.
11.6 Safety Analysis
Removed QTcB from ECG data to be summarized.
Rationale: To remove requirement for clinical safety laboratory tests to be collected under fasted conditions in 
order to avoid unnecessary fasting. Safety can be monitored with samples collected under fed or fasted 
conditions.
9.6.6 Laboratory Tests
Removed “under fasted conditions whenever feasible.”
Rationale: Samples collected for future research will not be anonymized and will not be permanently stored.
10.2 Discontinuation;
16.2.5 Retention of Samples
Removed statement regarding possible anonymization of samples used for future 
research, and changed period for long-term storage to up to 15 years.
Rationale: Collection of vital signs from the opposite arm as blood sample collection is unnecessary, as the 
procedures will be performed at different times. 
9.1.1 Overview
Removed statement regarding vital signs collection from opposite arm from 
which blood samples are collected.
Rationale: To specify documentation of a thorough baseline neurological examination at screening, and 
subsequently permit more abbreviated/directed examinations if appropriate, to limit patient fatigue. 
9.6.5 Examinations
Indicated that the description of the neurological examination was for the 
screening examination, and added that examinations subsequent to screening may 
be more abbreviated and directed for follow up of abnormalities. 
Rationale: To remove summaries of C-SSRS data that may not be performed; the planned analyses will be 
described in a separate Statistical Analysis Plan.
11.6 Safety Analysis
Removed C-SSRS shift tables and reporting of separate endpoints for suicidal 
ideation and behavior.
Rationale: To provide additional instruction on reporting and evaluation of anticipated adverse events.
12.3.1. Adverse Events
Added information regarding reporting and assessment of anticipated events.
Rationale: To specify the time period for reporting of product quality complaints (PQCs).
13.1 PQC Procedures
Changed the time period for reporting of PQCs for the site to the sponsor from 
“as soon as possible” to within 24 hours after awareness of the event.
Rationale: To change the number of pills per bottle of study drug, to have sufficient supply to cover the visit 
windows. 
14.1 Study Drug
The number of pills per bottle was changed from 31 to 33.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Minor changes were made to improve clarity or readability, correct errors and inconsistencies, repeat 
or move text to other applicable sections, and remove unnecessarily redundant information.
Time & Events
Modified several footnotes to improve clarity, remove redundant information, add 
or change references to sections of the protocol, or reflect protocol changes that 
are described elsewhere.
Time & Events
Added collection of background information at screening to row with medical 
history and demographics.
Synopsis PK;
Time & Events;
9.4.1 PK Evaluations
Specified that the dosing on Day 15 will be after the “first” PK sample collection.
1. Introduction
Indicated that BIA 10-2474 is a FAAH inhibitor. Clarified that some references to 
“study” are referring to the Platform study/protocol. 
Synopsis Objectives;
2.1 Objectives
Modified the description of the secondary objective regarding the biosensors to 
indicate that comparison will be made between treatments. 
Synopsis Overview;
3.1 Overview
Modified the study design description, including addition of information included 
elsewhere in the protocol.
3.2.2.1 Rationale for 
Adolescents
Clarified the results of the Pacey et al (2016) study.
9.1.1 Overview
Added information regarding the designated caregiver being responsible for all 
caregiver-related activities.
4.3 Prohibitions;
8. Concomitant Medications
Clarified that the period for prohibition for inducers or inhibitors of CYP3A4 is 
from Day 1 through the end of the posttreatment period.
Time & Events;
4.3 Prohibitions
Changed “medications” to “therapy” in the description of information provided in 
Section 8.
5 Treatment Allocation
Added statement to clarify that the investigator is solely responsible for breaking 
the intervention code in emergency situations.
6 Dosage;
9.1.1 Overview;
9.1.3 Treatment Phase
Stated that dosing must occur after confirmation of eligibility and subjects’ 
baseline safety assessments on Day 1 and after administration of the JAKE Task 
Battery at the Day 1 and Week 4 visits.
Synopsis Overview;
3.1 Overview;
6. Dosage;
9.1.3 Treatment Phase
Clarified that the baseline assessments at Day 1 are the baseline safety 
assessments, and that the Baseline Visit is the Day 1 visit. 
Synopsis;
6. Dosage
Changed description of tablets (JNJ-42165279/placebo) from physically identical 
to identical in appearance.
Synopsis Efficacy;
9.2.2 Evaluations
Removed genomic measurements from list of efficacy evaluations.
9.2.2.1.1 ABI
Clarified a statement regarding the same caregiver or same site personnel 
completing the ABI. Deleted statement regarding completion of the ABI on the 
same days as completion of the caregiver and clinician-rated scales.
9.2.2.6.4 SRS-2;
Attachments
Removed the Preschool version of the SRS-2 as an option for use in the study. 
Replaced the SRS-2 representative page with the School Age version. 
11 Statistical Methods
Deleted subsection entitled “Pharmacodynamic Analysis,” and moved section text 
to Section 11.5, PK and PK/PD Analysis.


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Applicable Section(s)
Description of Change(s)
11.4 Biomarker and 
Pharmacogenomic Analysis
Indicated that the baseline biomarkers are collected at screening.
15. Materials
Updated list of materials to be provided.
16.1 Design Considerations
Corrected inconsistency with Section 10.2 by replacing specific liver function 
criteria for stopping treatment with general statement regarding elevated liver 
function analytes. 
17.4 Source Documentation
Removed description of source documents for the JAKE system (to avoid 
confusion regarding available source documents) and revised description of the 
instruments and scales.
References
Deleted 2 references that were removed from body of protocol. 
Throughout protocol
Indicated that attachments with questionnaires are representative examples.
Throughout protocol
Other minor changes in text were made.
Rationale: Minor errors were noted  
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made. 
Amendment 1 (9 March 2017)
The overall reason for the amendment: The overall reason for the amendment is to revise the eligibility age group 
of subjects in the study, add an interim PK analysis that will be conducted after randomization of at least 8 subjects
(aged 13-17 years) on the active drug, include additional assessment visits for neurological examination and ABC, 
and to add ABC-I among safety assessments that will be performed for patients for whom C-SSRS is not feasible.
Applicable Section(s)
Description of Change(s)
Rationale: In order to ascertain the robustness of the ABI, a new secondary objective was included that examined
its performance with that of the ABC.
Synopsis; 2.1.1 Objectives
The following secondary objective was added:

To compare the performance of the ABI with that of the ABC.
Rationale: Based on health authority feedback, the eligibility age group of subjects enrolled in the study was 
revised from between 12 and 30 years (inclusive) to between 13 and 30 years (inclusive).
Throughout protocol 
The eligibility age group of subjects enrolled in the study was updated from 
between 12 and 30 years (inclusive) to between 13 and 30 years (inclusive).
4.1 Inclusion Criteria
Inclusion criterion 1 was revised to read:
Subject must be a male between 13 and 30 years of age, inclusive. At least 50% of 
subjects in the study should be between 13 and 17 years of age, inclusive.
Inclusion criterion 3 was revised to read:
Subjects (18 years of age or older) must have a body mass index 
(BMI=weight/height²) between 18 and 35 kg/m2, inclusive, at screening. Subjects 
(between 13 and 17 years of age, inclusive) must have a BMI ≥5th percentile and 
<95th percentile on the Centers for Disease Control and Prevention BMI-for-age 
percentile growth charts.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Neurological safety examinations were defined, and additional assessment visits for neurological 
examination were included in the Time and Events Schedule for clarity.
Time and Events Schedule
In the Time and Events Schedule, additional assessment visits for neurological 
examination were added for Day 1, Week 4, and Week 8. Also, a new footnote f 
was included and subsequent footnotes were renumbered:
f. A neurological examination should be conducted in the event of any adverse 
events of special interest as described in Section 9.6.6.
9.6.6 Physical and 
Neurological Examination
Section 9.6.6 was revised to include criteria for neurological safety examinations:
The neurological examination can be adapted as necessary but should include 
mental status (orientation and memory); oculomotor motion and vision for cranial 
nerve testing; limb strength and abnormal movements for motor function; and tests 
of cerebellar function: gait, finger-to-nose, heel-to-shin, and rapid alternating 
movements. Tests of sensation (eg, pain, vibration, etc) should be included only if 
indicated by clinical history/symptoms.
Rationale: Based on health authority feedback, it was determined that ABC-I would be performed for patients for 
whom C-SSRS was not feasible. As such, ABC-I was included as a safety assessment that would be performed 
consistently throughout the study for patients for whom C-SSRS was not feasible.
Time and Events Schedule
In the Time and Events Schedule, specified that ABC-I would be performed 
consistently throughout the study for patients for whom C-SSRS was not feasible. 
In addition, footnote g was revised to reflect the addition of ABC-I.
4.2 Exclusion Criteria
Exclusion criterion 1 was modified in order to include that ABC-I would be 
performed consistently throughout the study for patients for whom C-SSRS was not 
feasible.
9.6.3 Aberrant Behavior 
Checklist-Irritability 
Subscale
A new Section 9.6.3 Aberrant Behavior Checklist-Irritability Subscale was added 
(subsequent sections were renumbered).
Synopsis; 11.7 Safety 
Analysis
In the Synopsis and Section 11.7 Safety Analysis, a new subsection Aberrant 
Behavior Checklist-Irritability Subscale was included.
Rationale: In the JAKE Portal procedures, ABI (Caregiver) and ABI-S (Caregiver) assessment visits were revised 
for accuracy. Also, abbreviation for ABI (Clinician structured interview) was revised for clarity.
Time and Events Schedule;
9.2.2.1.1 ABI
In the Time and Events Schedule and Section 9.2.2.1.1 ABI, an additional 
assessment visit for ABI (Caregiver) was added for Week 8. ABI-S (Caregiver) 
assessment visits were updated to be completed on Week 2 (site), Week 6 (home), 
and Week 10 (home). Accompanying footnote q was updated to read:
q. The full ABI will be completed by the primary caregiver at screening, Day 1, 
Week 4, Week 8, and Week 12. The ABI must be completed at the site. The ABI-S 
will be completed by the primary caregiver on Week 2 (site), Week 6 (home), and 
Week 10 (home). The ABI-C will be completed by the PI or delegate at Day 1, 
Week 4, and Week 12.
The Daily Tracker is completed twice daily by the caregiver. The caregivers are 
required to select 3 items to track on a daily basis. Following completion of the ABI 
at the screening visit, a clinician at the site will discuss possible items to track with 
the parents and help them with their selection. See Section 9.2.2.1.1 for details on 
ABI administration.
Throughout protocol
Abbreviation for ABI (Clinician structured interview) was updated from ABI-SI to 
ABI-C for consistency.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: The assessment visits for completing ABC were updated for alignment with that of ABI.
Time and Events Schedule
Additional assessment visits for completing ABC were included for Screening 
(Days -7 to 1), Week 4, and Week 8. 
Rationale: The assessment visits for completing CGI-S and CGI-I were revised for clarity.
Time and Events Schedule
An additional assessment visit for completing CGI-S was included for Week 8.
CGI-I was deleted from the Time and Events Schedule.
Rationale: Assessment visits for collection of venous blood samples for measurement of plasma JNJ-42165279 
concentrations were revised for specificity. 
Time and Events Schedule
In the Time and Events Schedule, blood sample collection for JNJ-42165279 was 
revised to occur on Day 1 and Day 15. In addition, associated footnote s was 
updated:
s. A venous blood sample will be collected for measurement of plasma JNJ-
42165279 concentrations between 0.5 to 1 hour postdose (Day 1 and Day 15) and 
prior to the morning dose (Day 15 only). The date and time of study drug 
administration on Day 1, Day 14, and Day 15 must be accurately recorded. Subjects 
will be instructed to take the morning dose of study drug on Day 15 at the clinical 
site after collection of the PK blood sample.
Rationale: Definitions of terms was updated to include ABI-S and ABI-C for accuracy.
Definitions of Terms
Added definitions for ABI-S and ABI-C.
Rationale: Added text describing study being intended as the first cohort in a planned platform study of autism 
using the JAKE system and ABI for clarity.
1 Introduction
Paragraph was revised to read:
The current study will be conducted to assess the efficacy, safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of treatment with 
JNJ-42165279 using the Janssen Autism Knowledge Engine (JAKE®) system in 
adolescent and adult male subjects with ASD. This study is intended as the first 
cohort in a planned ‘Platform’ study of autism using the JAKE system and the 
Autism Behavior Inventory (ABI). Additional cohorts, using different 
investigational compounds may be added, either one at a time or even in parallel 
over the course of the study. Additional cohorts may be added through ‘Intervention 
Specific Appendices’ to the protocol. Information may be shared between cohorts 
particularly on placebo subjects enabling fewer placebo subjects in later cohorts. 
The study would thus not be considered completed until the final cohort completes. 
The results from the study will afford a more comprehensive understanding of ASD, 
and will support the development of JNJ-42165279 as a potential treatment for the 
core and/or associated symptoms of ASD.
Rationale: Secondary objectives and secondary endpoints were updated to include ABI-C and CGI-S rating scales 
for accuracy.
Synopsis; 2.1.1 Objectives
The following secondary objective was updated to include ABI-C and CGI-S:

Aberrant Behavior Checklist (ABC), Autism Behavior Inventory-Short Form 
(ABI-S), Autism Behavior Inventory-Clinician structured interview (ABI-C), 
Clinical Global Impression-Severity (CGI-S), Repetitive Behavior Scale-
Revised (RBS-R), Zarit Burden Interview (ZBI), Child Adolescent Symptom 
Inventory-Anxiety (CASI-Anx), and Social Responsiveness Scale 2 (SRS-2) 
scales.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Synopsis; 2.1.2 Endpoints; 
9.2.1 Endpoints
The following secondary endpoint was updated to include ABI-C and CGI-S:

The change from baseline to Day 85 in the ABC, ABI-S, ABI-C, CGI-S, RBS-
R, ZBI, CASI-Anx, and SRS-2 scales.
Rationale: Study design section was revised to specify the collection of a PK blood sample from eligible subjects 
on Day 1, and conducting an interim PK analysis following randomization of at least 8 subjects (aged 13-17 years) 
on active drug.
Synopsis; 3.1 Overview of 
Study Design
In the Double-Blind Treatment Phase section, paragraph was revised to read:
A pharmacogenomic blood sample will be collected from all eligible subjects at the 
time point described in the Time and Events Schedule. Participation in the 
pharmacogenomic research component is requested for the identification of genetic 
factors that may influence PK, pharmacodynamics (PD), safety and/or tolerability of 
JNJ-42165279. 
Subjects (aged 13-17 years) will be randomized until at least 8 subjects are on the 
active drug, following which screening of subjects of that age range will be 
temporarily paused while an interim PK analysis is conducted.
Rationale: In the rationale for dose selection section, text pertaining to use of allometric scaling to predict 
concentration-time profiles of 25 mg q.d. doses in adolescent subjects was revised for accuracy.
3.2.3 Rationale for Dose 
Selection
Paragraph was updated to read:
Allometric scaling was applied to predict the concentration-time profiles produced 
by 25 mg q.d. doses in adolescent subjects (12-17 years). Based on these 
simulations, exposures (ie, plasma Cmax and AUC) up to 1.5 fold higher than in 
adults can be expected in subjects who are 12 years of age. Exposures up to 1.2 fold 
higher than in adults can be expected in subjects who are 15 years of age. Exposures 
in the 17 years age group are expected to be very similar to exposures observed in 
adults. Based on these results, no dose adjustments are recommended for adolescent 
subjects. Based on FDA age classification, enrollment will include subjects 13 years 
of age and older.
Rationale: A new section on the rationale for pharmacokinetic evaluations was added for clarity.
3.2.4 Rationale for 
Pharmacokinetic Evaluations
In the new section, the following text was added:
If warranted at the time of the interim analysis and after completion of the study, the 
plasma concentration-time data of JNJ-42165279 will be analyzed using population 
PK modeling. Concentration-time data will allow estimation of individual PK 
parameters for JNJ-42165279. It will also help to understand potential differences 
between ASD subjects treated with JNJ-42165279 and those treated with placebo. 
Time and days of JNJ-42165279 plasma concentration assessment were chosen to 
gather maximal information about the PK properties of JNJ-42165279 while 
minimizing subject burden regarding blood sampling.
Rationale: Descriptions of the components of the JAKE Portal were revised for accuracy.
3.2.5.1 JAKE Portal
Descriptions of the components of the JAKE Portal were revised.
Rationale: The tasks and stimuli for use with the Periodic Biosensors were clarified for accuracy.
3.2.5.2.2 Periodic Biosensors 
and JAKE Task Battery
Descriptions of tasks and stimuli for use with the Periodic Biosensors were 
clarified.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: The Periodic Biosensor of Interest: Electroencephalogram Portion section was updated for better 
readability.
3.2.5.2.2.1 Periodic 
Biosensor of Interest: 
Electroencephalogram 
Portion
Sections on Kanwisher Videos and Event Related Potentials to Direct/Averted Gaze 
Facial Stimuli were deleted.
Section on NimStim Emotional was re-titled Event-related Potential Faces 
Compared to High Autism Interest Objects, and associated text was updated.
Rationale: Chawarska Videos was renamed Social Information Processing Task.
3.2.5.2.2.2 Periodic 
Biosensor of Interest: Eye 
Tracking Portion
Chawarska Videos was replaced with Social Information Processing Task 
throughout.
Rationale: Section on FACET Portion was renamed Affect Detection Portion for clarity.
3.2.5.2.2.3 Affect Detection 
Portion
FACET Portion was re-titled Affect Detection Portion.
Rationale: Section on Instruments for Measuring Change and Validating the ABI was renamed Instruments for 
Measuring Change for accuracy.
3.2.6.2 Instruments for 
Measuring Change
Instruments for Measuring Change and Validating the ABI was re-titled Instruments 
for Measuring Change.
Rationale: Inclusion criterion 2 was modified to specify that an ADOS-2 completed by a trained professional within 
6 months prior to screening visit would be acceptable if the item responses were available for entry into the eCRF as 
opposed to database.
4.1 Inclusion Criteria
Inclusion criterion 2 was modified to read:
Diagnosis of ASD in subjects must be according to DSM-5 criteria and made or 
confirmed using the ADOS-2 (minimum score of 8 [autism spectrum]). (An ADOS-
2 completed by an adequately trained professional within the 6 months prior to 
screening visit will be acceptable if the item responses are available for entry into 
the electronic case report form [eCRF].)
Rationale: In order to promote subject eligibility and participation in the study, inclusion criterion 10 was revised to 
indicate that primary caregivers must have a means of obtaining internet connectivity for a desktop, laptop or tablet 
computer as opposed to possessing a portable electronic device capable of running the JAKE mobile applications.
4.1 Inclusion Criteria
Inclusion criterion 10 was modified to read:
Primary caregivers must have a reliable means of obtaining internet connectivity for 
a desktop, laptop or tablet computer.
Rationale: A new exclusion criterion was added to specify exclusion of subjects currently taking or those who have 
taken within the past month recreational or medically prescribed cannabis.
4.2 Exclusion Criteria
A new exclusion criterion 7 was added (subsequent criteria were renumbered):
Subject is currently taking or has taken within the past month recreational or 
medically prescribed cannabis.


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Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion 20 was updated to specify that a KBIT-2 conducted within the past 6 months was
acceptable, as opposed to any IQ test.
4.2 Exclusion Criteria
Exclusion criterion 20 was revised to read:
Subject has a measured composite score on KBIT-2 of less than 50. A KBIT-2 
conducted within the past 6 months is also acceptable provided the scores are 
available for entry into the eCRF.
Rationale: Prohibitions and Restrictions 2 was updated to specify that subjects must abstain from using recreational 
or medically prescribed cannabis, in addition to illegal drugs, from screening through the end of the posttreatment 
phase of the study.
4.3 Prohibitions and 
Restrictions
Prohibitions and Restrictions 2 was modified to read:
Subjects must abstain from using illegal drugs or recreational or medically 
prescribed cannabis from screening through the end of the posttreatment phase.
Rationale: In Prohibitions and Restrictions 6, replaced test battery with Task Battery for clarity.
4.3 Prohibitions and 
Restrictions
Prohibitions and Restrictions 6 was modified to read:
Subjects must not take any sedating medications on the day of the Task Battery
(other than any preexisting daily medications) and must not consume caffeine 
within 2 hours prior to the battery.
Rationale: In the randomization section of Treatment Allocation and Blinding, text pertaining to conducting an 
interim PK analysis following randomization of at least 8 subjects (aged 13-17 years) on the active drug, was added 
for clarity.
5 Treatment Allocation and 
Blinding
A new paragraph was added to the randomization section.
Rationale: In Section 9.2.2.1.1 ABI, created a new heading on ABI-C with a description of the assessment for 
clarity.
9.2.2.1.1 ABI
A new heading on ABI-C was added:
ABI-C
The ABI-C is an abbreviated version of the ABI-S for completion by the clinician 
following a semi-structured interview with the caregiver or individual with ASD, as 
appropriate. The clinician is required to rate the severity of behaviors or level of 
impairment observed or described on a scale of 1 to 7, where 1 indicates no 
impairment of behavior and 7 indicates severe difficulties with an area of 
functioning. There are 14 items across each of the 5 domains.
Rationale: Section Recording Mood was renamed Mood Report for consistency with the rest of the protocol.
9.2.2.1.3 Mood Report
Section Recording Mood was re-titled Mood Report.
Rationale: Section 9.2.2.1.7 Other Sections was deleted for accuracy.
9.2.2.1.7 Other Sections
Section was deleted.


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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Section Continuous Biosensors was renamed Continuous Biosensor. Content was revised to reflect a 
truly continuous plan.
9.2.2.2.1 Continuous 
Biosensor
Section Continuous Biosensors was re-titled Continuous Biosensor.
Paragraph on use of the biosensor was revised to read:
The Continuous Biosensor is the Actigraph GT9X Link Wristband. The Actigraph 
is a wireless wristband biosensor that measures activity. This sensor should be worn 
continuously except when necessary to remove it for charging or other reasons.
Rationale: Section iMotions Attention Tool: FACET Module was renamed iMotions Biometric Research Platform: 
Emotient FACET Module. Content was updated for accuracy.
9.2.2.2.2.4 iMotions 
Biometric Research 
Platform: Emotient FACET 
Module
Section iMotions Attention Tool: FACET Module was re-titled iMotions Biometric 
Research Platform: Emotient FACET Module.
Paragraph was revised to read:
iMotions® Biometric Research Platform: Emotient™FACET Module (https://imotio
ns.com/blog/facial-expression-analysis/) will be used for affect detection via 
computer recognition of subject affect. Facial recognition will take place throughout 
the administration of the JAKE Task Battery using a standard computer web 
camera.
Rationale: Content in JAKE Task Battery section was revised for accuracy. 
9.2.2.3 JAKE Task Battery: 
Tasks and Stimuli for use 
With Periodic Biosensor
Section was revised for accuracy.
Rationale: Content from subsections of the JAKE Task Battery was consolidated and described in tabular format 
for better readability.
9.2.2.3 JAKE Task Battery: 
Tasks and Stimuli for use 
With Periodic Biosensor
Sections 9.2.2.3.1, 9.2.2.3.1.1, 9.2.2.3.1.2, 9.2.2.3.1.3, 9.2.2.3.1.4, 9.2.2.3.1.5, 
9.2.2.3.2, 9.2.2.3.2.1, 9.2.2.3.2.2, 9.2.2.3.2.3, 9.2.2.3.2.4, 9.2.2.3.3, 9.2.2.3.3.1, 
9.2.2.3.3.2, and 9.2.2.3.4 were deleted. Content from deleted sections were 
consolidated and described in tabular format.
Rationale: In the Child Adolescent Symptom Inventory Anxiety section, specified the range of responses in the 
scale for clarity. 
9.2.2.5.5 Child Adolescent 
Symptom Inventory Anxiety
Paragraph was revised to read:
This study will use only the 21-point anxiety scale (CASI-Anx) which was 
recommended as a possible outcome measure for autism.65 Responses will range 
from 0 (never) to 4 (very often).
Rationale: In the Repetitive Behavior Scale-Revised (parent) section, defined the range of responses in the scale for 
clarity.
9.2.2.5.6 Repetitive Behavior 
Scale-Revised (parent)
Section was revised to read:
The RBS-R (Attachment 8) is a 43-item report scale to indicate occurrence of 
repetitive behaviors and degree to which a behavior is a problem on a range 
between 0 (behavior does not occur) and 3 (behavior is a severe problem).


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Section Clinical Global Impression-Improvement was renamed Clinical Global Impression-Severity for 
accuracy. Content was updated to specify that the scale will be completed by both the clinician and caregiver for 
clarity.
9.2.2.5.8 Clinical Global 
Impression-Severity
Section Clinical Global Impression-Improvement was re-titled Clinical Global 
Impression-Severity.
Section was revised to read:
The CGI-S scale assesses the severity of all illness. The CGI-S is a 7-point scale 
that requires the clinician and caregiver to assess the severity of the subject’s illness 
at baseline and other visits as per the Time and Events Schedule. Versions of this 
scale used in this study are provided in Attachment 10.
Rationale: With regards to pharmacokinetic evaluations, added text to indicate that date and time of study drug 
administration must be recorded for accuracy. Also, included instructions on taking the morning dose of the study 
drug on Day 15 after collection of the PK blood sample on that day, for clarity.
Synopsis; 9.4.1 Evaluations
Added a new paragraph:
The date and time of study drug administration on Day 1, Day 14, and Day 15 must 
be accurately recorded. Subjects will be instructed to take the morning dose of study 
drug on Day 15 at the clinical site after collection of the PK blood sample on that 
day.
Rationale: Erroneously placed text pertaining to rationale was removed from the analytical procedures.
9.4.2 Analytical Procedures
The following text was removed:
Concentration time data will allow estimation of individual PK parameters for JNJ-
42165279 using a population PK modeling approach. It will also help to understand 
potential differences between ASD subjects treated with JNJ-42165279 and those 
treated with placebo. Time and days of JNJ-42165279 plasma concentration 
assessment were chosen to gather maximal information about the PK properties of 
JNJ-42165279 while minimizing subject burden regarding blood sampling
Rationale: Section on PK parameters that will be evaluated was revised for accuracy.
9.4.3 Pharmacokinetic 
Parameters
Section was revised for accuracy.
Rationale: Section on PK and PK/PD analysis was updated to describe conducting an interim PK analysis after at 
least 8 subjects (aged 13-17 years) were randomized to the active drug, for clarity.
Synopsis; 11.6 
Pharmacokinetic and 
Pharmacokinetic/Pharmacod
ynamic Analysis
Section was updated to describe conducting an interim PK analysis after at least 8 
subjects (aged 13-17 years) were randomized to the active drug.
Rationale: Attachment 1 was re-titled Examples of Prohibited Cytochrome P450 Inhibitors and Inducers for clarity.
Attachment 1: Examples of 
Prohibited Cytochrome P450 
Inhibitors and Inducers
Attachment title was updated.


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Attachment 2 was re-titled Janssen Autism Knowledge Engine (JAKE) ABI (Long Form, ABI-S, and 
ABI-C) and Daily Tracker for accuracy. Updated representative pages of scales were added.
Attachment 2: Janssen 
Autism Knowledge Engine 
(JAKE) ABI (Long Form, 
ABI-S, and ABI-C) and 
Daily Tracker
Attachment title was updated, and revised representative pages of scales were 
added.
Rationale: Included representative pages of C-SSRS scales (children version, and adults and adolescents version) in 
Attachments 11 and 12 for accuracy.
Attachment 11: Columbia 
Suicide Severity Rating 
Scale – BASELINE; 
Attachment 12: Columbia 
Suicide Severity Rating 
Scale – Since Last Visit
Included representative pages of C-SSRS scales (children version, and adults and 
adolescents version).
Rationale: List of anticipated events was updated in Attachment 13 for clarity.
Attachment 13: Anticipated 
Events
List of anticipated events, based on reports by healthy subjects in Phase 1 studies, 
was updated to include:

anxiety

depression

self-injurious behavior

disruptive/challenging behavior
Rationale: Attachment 14 was re-titled Self/Caregiver-Assessment of Treatment Experience for accuracy. Revised
pages of scale were added.
Attachment 14: 
Self/Caregiver-Assessment 
of Treatment Experience
Attachment title was updated. Revised pages of scale were added.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
SYNOPSIS
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study Investigating 
the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Subjects with 
Autism Spectrum Disorder
JNJ-42165279 is a potent, selective, and orally bioavailable inhibitor of the enzyme fatty acid amide 
hydrolase (FAAH). This enzyme is primarily responsible for the degradation of a variety of fatty acid 
amides (FAAs), including the endocannabinoid N-arachidonoylethanolamine, or anandamide (AEA), the 
first identified endogenous cannabinoid receptor agonist. The endocannabinoid system is believed to play 
important roles in the regulation of the immune system, pain perception, affect, motivation, emotion, fear 
and anxiety responses. As such, the endocannabinoid system and FAAH inhibition could modulate the 
core symptoms associated with social communication deficits, and restrictive and repetitive behaviors
(RRB). Evidence has demonstrated that the endocannabinoid system is involved in behavior and emotion 
directly relevant to Autism Spectrum Disorder (ASD). Modulation of behavior and emotion related to 
ASD is the basis for testing JNJ-42165279 for therapeutic effect in adolescent and adult subjects with 
ASD.
JNJ-42165279 has been studied in 7 Phase 1 studies and 2 Phase 2a studies. The Phase 1 studies included
a single ascending dose regimen up to 250 mg and a multiple dose regimen of 100 mg once daily in 
healthy males, a study with healthy Japanese males administered a single dose and multiple dose regimen
of 25 mg once daily for 10 days, a multiple dose study with cohorts receiving 10, 25, 75 or 100 mg for 10 
days, a brain FAAH occupancy study using positron emission tomography (PET), a drug-drug interaction 
study (DDI), an oral bioavailability study, and a functional magnetic resonance imaging (fMRI) study 
with a dose of 100 mg once daily over 4 days to healthy males. Both Phase 2a studies evaluated the safety 
and efficacy of once daily dosing of JNJ-42165279 25 mg using a double-blind, randomized, 
placebo-controlled design. One of the Phase 2 studies included patients with severe social anxiety 
disorder, while the other evaluated patients with major depressive disorder with anxious distress.
OBJECTIVES AND HYPOTHESIS
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of JNJ-42165279 compared with placebo in 
the improvement of symptoms of ASD during 12 weeks of treatment on the following parameters:

Autism Behavior Inventory (ABI) Core Domain Score (Social Communication and RRB).

ABI Social Communication Domain Score.

ABI RRB Domain Score.
Secondary Objectives

To assess the safety and tolerability of JNJ-42165279 compared to placebo.

To assess the effect of JNJ-42165279 compared with placebo on the following parameters in subjects 
with ASD:

ABI Mood & Anxiety, Challenging Behavior, Self-Regulation domains.

Aberrant Behavior Checklist (ABC), Autism Behavior Inventory-Short Form (ABI-S), Autism 
Behavior Inventory-Clinician interview (ABI-C), Clinical Global Impression-Severity (CGI-S),
Clinical Global Impression-Improvement (CGI-I), Repetitive Behavior Scale-Revised (RBS-R), 
Zarit Burden Interview (ZBI), Child Adolescent Symptom Inventory-Anxiety (CASI-Anx),


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
Social Responsiveness Scale 2 (SRS-2), Caregiver Global Impression of Severity (Caregiver 
GI-S), Caregiver Assessment of Treatment, and Self Global Impression of Improvement (Self 
GI-I) scales.

To correlate changes in the ABI with changes in biosensors, Janssen Autism Knowledge Engine 
(JAKE®) components and standard scales (ABC, CGI-S, RBS-R, ZBI, CASI-Anx, and SRS-2).

To compare the performance of the ABI with that of the ABC.

To compare the effect of JNJ-42165279 to placebo using the JAKE Task Battery biosensor data.

To assess the pharmacokinetics (PK) of JNJ-42165279 in subjects with ASD using a population PK
approach and explore its relationship with efficacy and safety parameters where appropriate.

To evaluate the relationship between plasma concentrations of 
and efficacy.
Exploratory Objectives
The exploratory objectives are:
Endpoints
Primary Endpoint
The primary endpoints will be measured as follows:

Change from baseline to Day 85 in the ABI Core Domain Score (Social Communication and RRB).

Change from baseline to Day 85 in the ABI Social Communication Domain Score.

Change from baseline to Day 85 in the ABI RRB Domain Score.
Secondary Endpoints
The secondary efficacy endpoints are:

The change from baseline to Day 85 in the ABI Mood & Anxiety, Challenging Behavior, and Self-
Regulation domains.

The change from baseline to Day 85 in the ABC, ABI-S, ABI-C, CGI-S, RBS-R, ZBI, CASI-Anx, 
SRS-2, and Caregiver GI-S.

Caregiver Assessment of Treatment, Self GI-I, and CGI-I at Day 85.
Hypothesis
The primary hypothesis for this study is that JNJ-42165279 is superior to placebo in reducing the core 
symptoms associated with ASD as assessed by the ABI Core Domains (Social Communication and RRB), 
Social Communication Domain, or RRB Domain.
CCI
CCI


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Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
The study will be deemed positive if any of the primary efficacy endpoints are statistically superior to 
placebo using a 1-sided 0.10 significance level.
OVERVIEW OF STUDY DESIGN
This is a randomized, multi-center, double-blind, placebo-controlled, parallel group, outpatient study 
assessing the efficacy, safety, and tolerability of JNJ-42165279 during 12 weeks of treatment in
adolescent and adult subjects with ASD. 
Approximately 80 adolescent and adult subjects (between 13 and 35 years of age, inclusive) will be
randomized in a 1:1 ratio to receive double-blind treatment of either JNJ-42165279 or placebo. The 
randomization will be stratified by gender and age (13-17 years and 18-35 years). Subjects enrolled prior 
to Protocol Amendment 5 were randomized to receive once daily dosing of placebo or 25 mg 
JNJ-42165279 throughout the treatment period. All other subjects will receive twice daily (BID) dosing 
of placebo or 25 mg JNJ-42165279 (total daily dose of 50 mg).
Study procedures include safety and efficacy evaluations and blood sample collections for 
pharmacogenomic assessment, pharmacokinetics, and biomarkers of treatment activity. An interim PK 
analysis is planned following Week 2 PK sample collection from approximately 8 adolescent subjects 
randomized to active drug. 
This study consists of a 26-day eligibility screening period, a 12-week double-blind treatment period and 
a follow up examination (to occur 14 days [±1 week] after last dose of study drug). The study duration for 
each subject will be approximately 4 months.
Screening (Day -26 to Day -1)
Subjects will be screened within 26 days prior to Day 1 of the double-blind period to assess their 
eligibility for the study, according to the inclusion and exclusion criteria. Caregivers will return for a 
second screening visit for set up and training for the caregiver reporting tool (My JAKE/My JAKE 
Mobile Medical App v 1.0 [My JAKE MMApp]), and for completion of select scales.
Double-Blind Treatment Phase
Subjects who successfully complete the screening phase will visit the clinical site/unit to be randomized
on Day 1 (Baseline visit) of the double-blind phase. 
Subjects will visit the study site with their caregiver at 2, 4, 8, and 12 weeks after the start of treatment. 
Throughout the treatment period, caregivers will record information in the caregiver reporting tool and 
subjects will wear a continuous biosensor wristband that measures activity.
Follow Up Phase
Subjects will return to the clinical site for a safety follow up visit at 14 days (±1 week) following the last 
dose of study drug (Day 85).
SUBJECT POPULATION
Subjects (13 to 35 years of age) with a definitive diagnosis of ASD using the Autism Diagnostic 
Observation Schedule, Second Edition (ADOS-2), who have an IQ as measured by the KBIT-2 of ≥60, 
and who are capable of completing and complying with all study-specific requirements will be enrolled.
DOSAGE AND ADMINISTRATION
Following Protocol Amendment 5, subjects will self-administer double-blind study medication twice 
daily for 12 weeks. Study medication will be provided as JNJ-42165279 25 mg tablets, or matching 
placebo, packaged in bottles. All tablets (JNJ-42165279 /placebo) are identical in appearance. 


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
EFFICACY EVALUATIONS
Evaluations throughout the study will encompass several categories:

My JAKE/My JAKE MMApp, including the ABI, ABI-S, and Daily Tracker, as well as system 
components available only in My JAKE (Journal and Event Tracker, Therapy Tracker, and 
Medical/Development History), to be completed periodically as instructed.

The ABI-C, to be completed periodically by the PI or delegate as instructed.

The JAKE Sense Continuous Biosensor, with training and manuals to guide appropriate use.

The JAKE Task Battery with the JAKE Sense Periodic Biosensors.

Standard assessment instruments and rating scales for evaluating ASD core and related symptoms, 
functioning, clinicians’ global impressions of disease severity and improvement, and caregiver 
stress.

Caregivers’ and subjects’ global impressions (Caregiver GI-S, Caregiver Assessment of Treatment, 
Self GI-I).
PHARMACOKINETIC EVALUATIONS
Venous blood samples for analysis of JNJ-42165279 in plasma will be collected at the time points 
indicated in the Time and Events Schedule.  
BIOMARKER EVALUATIONS
During the study, the following PD evaluations will be performed at the time points indicated in the Time 
and Events schedule: plasma concentrations of 
.
Additionally, blood biomarkers related to autism (including but not limited to cytokines and miRNAs) 
will be investigated to allow for exploratory immunophenotyping and for an exploratory PD evaluation. 
Biomarkers may be added or deleted based on scientific information or technical innovations under the 
condition that the total volume of blood collected will not be increased.
The biomarker data obtained from this study may also be included in an ongoing cross-study analysis to 
investigate the relationship between ASD and phenotypes and biomarkers.
PHARMACOGENOMIC (DNA) EVALUATIONS
A pharmacogenomic blood sample will be collected from all eligible subjects. Deoxyribonucleic acid 
(DNA) samples will be analyzed for FAAH gene variants. Additional analyses may be conducted if it is 
hypothesized that this may help resolve issues with the clinical data. DNA samples may also be used for 
the identification of genetic and/or epigenetic factors that may influence the PK, PD, efficacy, safety 
and/or tolerability of JNJ-42165279, and for exploratory genetic and/or epigenetic analyses, including of 
autism.
DNA samples will be used for research related to JNJ-42165279 or ASD. They may also be used to 
develop tests/assays related to JNJ-42165279 or ASD. Pharmacogenomic research may consist of the 
analysis of 1 or more candidate genes or of the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate) in relation to JNJ-42165279 or ASD clinical endpoints.
The pharmacogenomics data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between ASD and phenotypes and biomarkers.
CCI


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
SAFETY EVALUATIONS
During the study, regular safety assessments will be performed as listed in the Time and Events Schedule. 
These safety assessments include but are not limited to: vital signs, electrocardiogram (ECG), physical 
examination, adverse events, Columbia Suicide Severity Rating Scale (C-SSRS), Aberrant Behavior 
Checklist-Irritability Subscale (ABC-I), and clinical laboratory tests.
STATISTICAL METHODS
Sample Size Determination
The sample size for the study is based on all subjects who are enrolled under BID dosing. The assumption 
used in the determination of sample size was a treatment effect size of 0.63 for the difference between the
JNJ-42165279 treatment group and placebo, calculated as the mean change in the primary endpoints from 
baseline to Day 85. To detect the treatment effect size of 0.63 in any of the primary endpoints with a 
power of 90% at an overall 1-sided significance level of 0.10, 25 subjects in each group are required.
When adjusted for a drop-out rate of approximately 15% of subjects, this will require 60 subjects (under 
BID dosing) to be randomly assigned to treatment in a 1:1 ratio (30 per group).
Efficacy Analysis
The primary efficacy analysis will be based on the ITT-BID analysis set. The primary efficacy endpoints
are the changes from baseline to Day 85 in the ABI Core Domain Score, ABI Social Communication 
Domain Score, and ABI RRB Domain Score during the double-blind treatment phase. Each will be 
analyzed using a mixed effects model for repeated measures (MMRM). The model will include time, 
treatment, time-by-treatment interaction, age group (13-17 years and 18-35 years, inclusive), and gender
(male and female) as factors, and baseline score as a continuous covariate. An unstructured variance-
covariance matrix will be used. In case of convergence problems, simpler variance-covariance structures 
such as Toeplitz or autoregressive order 1 (AR[1]) will be considered. The study will be deemed positive 
if any of the primary efficacy endpoints are statistically superior to placebo using a 1-sided 0.10 
significance level.
For the secondary efficacy endpoints, comparisons between JNJ-42165279 and placebo will be performed 
by means of an MMRM model as described for the primary efficacy endpoints. Relationships between
select biosensors and scales will be measured with the appropriate correlation analyses.
Biomarker and Pharmacogenomic Analysis
Baseline biomarker values (collected during screening) and changes from baseline to the time points
specified in the Time and Events Schedule will be assessed. Biomarker values will be tabulated by 
treatment group over time points and summary statistics will be calculated. Associations between 
biomarkers and clinical endpoints will be explored. Correlations between 
values with efficacy and 
other clinical evaluations will be assessed.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association analyses in 
relation to treatment response.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis
An interim analysis will be conducted to evaluate the concentrations of JNJ-42165279 in plasma of 
adolescent subjects. The analysis would be performed after approximately 16 adolescent subjects (ie, 8 
adolescent subjects randomized to active drug) have been randomized and participated in the PK
sampling at the Week 2 visit.
The individual plasma JNJ-42165279 concentration-time values will be listed and summarized 
descriptively.
CCI


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
A population PK modeling of plasma concentrations of JNJ-42165279 will be undertaken, if warranted at 
the time of the interim analysis and after completion of the study.
Where appropriate, the relationship between plasma concentrations of JNJ-42165279 and corresponding 
plasma concentrations of 
 will be plotted to evaluate the relationships graphically.
Population PK/PD analysis of biomarkers and/or efficacy markers may also be performed, and a suitable 
dose- and/or exposure-response model may be developed. 
Safety Analysis
All randomized subjects who receive at least 1 dose of study medication will be included in the safety 
analysis set. Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). All reported adverse events with onset during the double-blind treatment phase (ie, 
treatment-emergent adverse events [TEAEs], and adverse events that have worsened since baseline) will 
be included in the analysis. For each TEAE, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group and dose level. Serious adverse 
events will be summarized separately.
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated for 
each laboratory analyte at baseline, and for observed values and changes from baseline at each scheduled 
time point.
Descriptive statistics of pulse, blood pressure (systolic and diastolic), temperature, and body weight 
values and changes from baseline will be summarized at each scheduled time point.
Subjects with abnormal findings in ECG will be listed.
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment group in 
incidence tables.
Irritability, aggression, and self-injurious behavior based on the ABC-I will be summarized descriptively 
at each scheduled visit by treatment group.
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JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
TIME AND EVENTS SCHEDULE 
Phase
Screening
Double-Blind Treatment a
Posttreatment a,b
(Follow up)
ET/EW b
Visit Number  
1
2 c
3
4
5
6
7
8
Week (end of)
-
-
-
2
4
8
12
Day
-26 to -3
-14 to -1
1
15
29
57
85
14 Days (±1 
Week) After Last 
Dose
Clinic Visit (C) 
C
C
C
C
C
C
C
C
Study Procedures
Screening/Administrative
Informed consent (and assent, if applicable)
X
Inclusion/exclusion criteria
X
X
Medical history, demographics, and background 
information
X
Prestudy therapy d
X
Preplanned surgery/procedure(s)
X
ADOS-2/Diagnosis of ASD 
X
KBIT-2
X
My JAKE/My JAKE MMApp account set-up e
X
GUID Generation
X
Study Drug Administration
Randomization
X
Dispense bottles of JNJ-42165279 or placebo
X
X
X
Oral dose of study medication f
Twice daily from Days 1 to 85
Drug accountability
X
X
X
Safety Assessments
Physical examination
X
X
X
X
Neurological examination g
X
X
X
X
X
X
C-SSRS (if feasible) h
X
X
X
X
X
X
X
ABC-I h
X
X
X
Vital signs i
X
X
X
X
X
X
X
Body weight j
X
X
X
X
X
Height
X
Clinical laboratory assessments k
X l
X
X
X
X m
Serology n
X
12-lead ECG (triplicate)
X
X
X
Urine drug screen 
X l
X l
X
X
X
X


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
Phase
Screening
Double-Blind Treatment a
Posttreatment a,b
(Follow up)
ET/EW b
Visit Number  
1
2 c
3
4
5
6
7
8
Week (end of)
-
-
-
2
4
8
12
Day
-26 to -3
-14 to -1
1
15
29
57
85
14 Days (±1 
Week) After Last 
Dose
Clinic Visit (C) 
C
C
C
C
C
C
C
C
Serum pregnancy test (-hCG) (all women)
X
Urine pregnancy test (WOCBP) o
X
X
X
X
X
X
My JAKE /My JAKE MMApp Procedures p
ABI (Caregiver, full version) q,r
X
X
X
X
X
ABI-S (Caregiver) r,s
Completed on Week 2 (site), Week 6 (home), and Week 10 
(home)
ABI-C (Clinician interview) t
X
X
X
Daily Tracker r,u
Continuous (twice daily)
Therapy Tracker v
Continuous (as items are identified)
Medical/Developmental History v
Continuous
Journal and Event Tracker v
Continuous (3 events per week)
Other Rating Scalesw
CASI-Anx
X
X
X
X
RBS-R
X
X
X
X
SRS-2
X
X
X
X
ZBI
X
X
ABC h
X
X
X
X
X
Caregiver GI-S
X
X
X
X
CGI-S
X
X
X
X
CGI-I
X
X
X
Caregiver Assessment of Treatment
X
Evaluation of JAKE
X
Self GI-I
X
JAKE Sense  
Eye Tracker Calibration Check x
X
JAKE Task Battery with periodic Biosensors 
(counterbalanced for order) y
X
X
X
Continuous Biosensor training (caregiver)
X
X
Wear Continuous Biosensor (subject) p
Continuous
Continuous Biosensor data collection (subject)
X
X
X
X


JNJ-42165279
Clinical Protocol 42165279AUT2001 Amendment 6
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Status: Approved, Date: 29 September 2020
Phase
Screening
Double-Blind Treatment a
Posttreatment a,b
(Follow up)
ET/EW b
Visit Number  
1
2 c
3
4
5
6
7
8
Week (end of)
-
-
-
2
4
8
12
Day
-26 to -3
-14 to -1
1
15
29
57
85
14 Days (±1 
Week) After Last 
Dose
Clinic Visit (C) 
C
C
C
C
C
C
C
C
Pharmacokinetics
Blood sample collection for JNJ-42165279
0.5–1.0h
postdose
predose, 
2.0-2.5h
postdose
predose, 
2.0-2.5h
postdose
Pharmacogenomics (DNA) 
Blood sample collection for pharmacogenomics z
X
Biomarkers aa
Blood sample collection for 
X
predose, 
2.0-2.5h
postdose
predose, 
2.0-2.5h
postdose
Exploratory biomarkers (cytokines and miRNAs)
X
X
Ongoing Subject Review
Concomitant therapy bb
Continuous
Adverse events
Continuous
Footnotes:
a.
Visits after Day 1 should be conducted within ±3 days of the scheduled visit day, except where otherwise specified. For each subject, treatment period visits should 
occur on the same type of day (weekday or weekend) and same period of the day (morning, afternoon; mornings are preferable), when possible. 
b.
If a subject discontinues treatment before the end of the double-blind treatment phase, early withdrawal (EW) assessments should be obtained. Follow up visit will 
take place 14 days (±1 week) after the early withdrawal visit. 
c.
Should not take place until all laboratory results become available. Only primary caregivers are required to attend; subject attendance is optional.
d.
Prestudy therapy will include all medications taken within the 3 months before screening.
e.
This includes set up of various accounts necessary for the study, including caregiver’s Microsoft Account (for login authentication) and Microsoft HealthVault 
account for My JAKE users, or set up of My JAKE MMApp account.
f.
Dosing on all treatment phase visit days will occur at the clinic. The in-clinic dose should be the subject’s first dose for the day. The date and time of study drug 
administration in the clinic must be accurately recorded on Day 1, Week 2 and Week 12 visits, and the day immediately prior to the Week 2 and 12 visits (both 
morning and evening doses). Subjects will be instructed to take the study drug at the clinical site on Weeks 2 and 12 after collection of the first blood sample.
g.
In addition to the time points indicated, a neurological examination should be conducted in the event of any adverse events of special interest as described in 
Section 12.2.
h.
See Sections 9.6.2 and 9.6.2.1 for details on evaluation of suicidality, including when the C-SSRS and ABC-I will be administered and versions of the C-SSRS to be 
used. The irritability subscale (ABC-I) is part of the ABC; thus, the table above includes only ABC-I time points other than those in which the full ABC is 
administered.
i.
Sitting blood pressure, pulse, and oral temperature.
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j.
Body weight will be measured with subjects lightly clothed.
k.
Serum chemistry, hematology, and urinalysis. Samples at the Week 2 and 12 visits will be collected predose.
l.
See Section 9.1.2 for circumstances in which repeat testing during screening is allowed. 
m. Any clinically significant abnormalities observed at Week 12 or at EW should be repeated at follow up.
n.
Including thyroid-stimulating hormone.
o.
If the urine pregnancy test is positive, a serum β-hCG test will be performed. Investigators may perform additional pregnancy testing at their discretion, as clinically 
needed.
p.
Continuous Biosensors and My JAKE/My JAKE MMApp components (other than the ABI) are used throughout the study and not restricted to discrete study visits.
q.
The full ABI will be completed by the primary caregiver. The ABI must be completed at the site.
r.
Paper versions are available for participants to use in the event that My JAKE and My JAKE MMApp are not available.
s.
The ABI-S will be completed by the primary caregiver at the Week 2 visit (site), at home at the end of Week 6 (Day 43 ± 3 days), and at home at the end of Week 10
(Day 71 ±3 days).
t.
The ABI-C will be completed by the PI or delegate.
u.
The Daily Tracker will be completed twice daily by the caregiver (sleep quality rating each morning, tracking 3 behaviors and mood report in the evening). 
Following completion of the ABI at the screening visit, a clinician at the site will discuss possible behaviors to track with the caregiver and help them with their 
selection.
v.
The Therapy Tracker, Medical and Developmental History, and Journal & Events are only available for participants who are using My JAKE and not My JAKE 
MMApp.
w.
The CGI-S and CGI-I rating scales will be completed by the clinician. The Self GI-I will be completed by the subject. The remaining rating scales will be completed 
by the caregiver.
x.
Eye tracker calibration can be repeated during the screening period, either at the Screening Visit 2 or at unscheduled visits, in order to meet the eligibility criterion. 
y.
Sites should make every effort to perform the Task Battery at approximately the same time of day for an individual subject throughout the study.
z.
The pharmacogenomics (DNA) sample should be collected at the specified time point. However, if necessary, it may be collected at a later time point without
constituting a protocol violation.
aa. A venous blood sample will be collected for multi-analyte biomarkers and for 
analysis. Subjects should be advised to follow a low-fat diet for at least 8 hours 
prior to their scheduled visit. Subjects should be advised to refrain from strenuous exercise and use of NSAID medications for 24 hours before their scheduled visit.
bb. Concomitant therapies must be recorded throughout the study beginning with the signing of the informed consent to the final follow up visit (Visit 8).
Notes:
See Section 9.1.1 for the recommended order of procedures at study visits.
Abbreviations: ABC=Aberrant Behavior Checklist; ABC-I=Aberrant Behavior Checklist-Irritability Subscale; ABI=Autism Behavior Inventory; ABI-C=Autism 
Behavior Inventory-Clinician interview; ABI-S=Autism Behavior Inventory-Short Form; ADOS-2=Autism Diagnostic Observation Schedule, Second Edition;
ASD=Autism Spectrum Disorder; Caregiver GI-S=Caregiver Global Impression-Severity; CASI-Anx=Child Adolescent Symptom Inventory-Anxiety; CGI-I=Clinical 
Global Impression-Improvement; CGI-S=Clinical Global Impression–Severity; C-SSRS=Columbia Suicide Severity Rating Scale; ECG=Electrocardiogram; ET=End of 
Treatment; EW=Early Withdrawal;
; GUID=globally unique identifier; JAKE=Janssen Autism Knowledge Engine; KBIT-2=Kaufman Brief 
Intelligence Test, Second Edition; MMApp= Mobile Medical App; NSAID=nonsteroidal anti-inflammatory drug; PI=principal investigator; PK=pharmacokinetics; 
RBS-R=Repetitive Behavior Scale–Revised; Self GI-I=Self Global Impression-Improvement; SRS-2=Social Responsiveness Scale 2; WOCBP=women of childbearing 
potential; ZBI=Zarit Burden Interview.
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ABBREVIATIONS
ABA
applied behavior analysis
ABC
Aberrant Behavior Checklist 
ABC-I
Aberrant Behavior Checklist-Irritability Subscale
ABI
Autism Behavior Inventory
ABI-C
Autism Behavior Inventory-Clinician interview
ABI–S
Autism Behavior Inventory-Short Form
ADI-R
Autism Diagnostic Interview-Revised 
ADOS-2
Autism Diagnostic Observation Schedule, Second edition
AEA
N-arachidonoylethanolamine
anti-HCV
hepatitis C antibody
ASD
Autism Spectrum Disorder
BID
twice daily
BMI
body mass index
C-SSRS
Columbia Suicide Severity Rating Scale
CASI-Anx
Child Adolescent Symptom Inventory – Anxiety
CGI-I
Clinical Global Impression-Improvement
CGI-S
Clinical Global Impression–Severity
CRF
case report form (paper or electronic as appropriate for this study)
CSF
cerebrospinal fluid
CYP
cytochrome P450
DDI
drug-drug interaction
DIF
Differential Item Functioning 
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders - 5th Edition 
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
EEG
electroencephalogram
EFA
Exploratory Factor Analysis 
EMG
electromyogram
EOG
electrooculogram
ERP
event-related potential
FAA
fatty acid amide
FAAH
fatty acid amide hydrolase
FACET
Facial Expression Analysis
FDA
Food and Drug Administration 
fMRI
functional magnetic resonance imaging
GABA
gamma-aminobutyric acid
GCP
Good Clinical Practice
GMR
geometric mean ratio
GSR
galvanic skin response
GUID
globally unique identifier
HAI
high autism interest 
HBsAg
hepatitis B surface antigen
HR
heart rate
HRV
heart rate variability
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISI
interstimulus interval
IWRS
interactive web response system
JAKE
Janssen Autism Knowledge Engine
JDP
My JAKE Data Pipeline
JSW
JAKE Sense Workbench


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KBIT-2
Kaufman Brief Intelligence Test, Second Edition
LAI
low autism interest
MDMA
3,4 methylenedioxy methamphetamine
My JAKE MMApp
My JAKE Mobile Medical App
MMRM
mixed effects model for repeated measures
NDAR
National Database for Autism Research
NIH
National Institute of Health 
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drug
OEA
N-oleoylethanolamide
PD
pharmacodynamics
PEA
N-palmitoylethanolamide
PET
positron emission tomography
PHI
protected health information
PI
principal investigator 
PK
pharmacokinetics
PQC
product quality complaint
PRT
Pivotal Response Training 
RBS-R
Repetitive Behavior Scale – Revised
RDI
Relationship Development Intervention 
RRB
Repetitive/Restrictive Behavior
SAE
serious adverse event
SAP
Statistical Analysis Plan
SRS-2
Social Responsiveness Scale 2
TBL
total bilirubin level
TD
typically-developing
TEACCH
Treatment and Education of Autistic and related Communication Handicapped Children 
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
ULN
upper limit of normal
WBC
white blood cell
WOCBP
women of childbearing potential
ZBI
Zarit Burden Interview
DEFINITIONS OF TERMS
Autism Behavior Inventory
(or “ABI”) - A module of My JAKE; a series of approximately 65
questions related to the core and associated symptoms of ASD
Autism Behavior Inventory-Short
(or “ABI-S”) - A shorter version of the ABI with approximately 20
questions
Autism Behavior Inventory-Clinician
(or “ABI-C”) - Approximately 14-item version of the ABI to be 
completed by the clinician following an interview
Continuous Biosensor(s)
A wearable wrist-based biosensor worn over extended periods of 
time throughout the day and during sleep
JAKE
Janssen Autism Knowledge Engine. Refers generally to the set of 
tools and technologies developed by Janssen Research & 
Development, LLC, for the purpose of tracking outcomes and 
enabling research of new treatments in autism spectrum disorders.
JAKE Sense
A component of the JAKE System; all biosensors (Continuous and 
Periodic) used by the JAKE System. JAKE Sense (and its hosted 
biosensors) are used solely for exploratory, proof-of-concept 
research.
JAKE Sense Data Pipeline
(or “JSDP”) - a component of the JAKE System; the JAKE Sense
Data Pipeline refers to all feature extraction methods, processes, and 
procedures, as well as the study data archive for maintaining 
traceability of all JAKE Sense datasets. Data collected and archived 
via the JSDP may contain limited personal identifiers. This data is 
available only to employees and contractors of Janssen Research & 
Development, and its affiliates. 


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JAKE Sense Workbench PC (JBW PC)
(or “JSW LAB PC”) - The laptop / desktop computer used for 
administration of the JAKE Task Battery and configuration / 
synchronization of Periodic Biosensors
My JAKE Data Pipeline
(or “JDP”) - a component of the JAKE System; the My JAKE Data 
Pipeline refers to all feature extraction methods, processes, and 
procedures, as well as the study data archive for maintaining 
traceability of all My JAKE datasets. Data collected and archived via 
the JDP may contain limited personal identifiers. This data is 
available only to employees and contractors of Janssen Research & 
Development, and its affiliates.
My JAKE Event Tracker
(or “Event Tracker”) - A module of My JAKE; an interface for 
tracking both positive and negative events (tantrum, stereotypy, 
social interaction, etc.) as they occur.
My JAKE Journal
(or “Journal”) - A module of My JAKE; an interface for ad hoc free-
text entry by caregivers and members of a subject's extended care 
team.
My JAKE Mobile
The mobile-based view of My JAKE/My JAKE MMApp. The My 
JAKE Mobile interface is available for 2 platforms: Android and iOS 
(v7+).
My JAKE
The original caregiver reporting application used in this study. A 
component of the JAKE System; the web and mobile based platform 
used by caregivers to interact with the JAKE System.
My JAKE Mobile Medical Application
A redesigned caregiver reporting application for use in this study. 
My JAKE Mobile Medical Application V1.0. MMApp is a web and
mobile system used to collect caregiver information about the 
individual with autism spectrum disorder (ASD), or symptoms of 
ASD, for monitoring and outcomes assessment. My JAKE MMApp 
is not to be used as a standalone diagnostic tool.
JAKE System
The core elements of JAKE: My JAKE/My JAKE MMApp, JAKE 
Sense, My JAKE Data Pipeline, and JAKE Sense Data Pipeline.
JAKE Task Battery
(or “Task Battery”) - A set of challenge tasks and stimuli, 
approximately 30 minutes in length, used in conjunction with 
Periodic Biosensors
My JAKE Therapy Tracker
(or “Therapy Tracker”) – A module of My JAKE; an interface for 
tracking a subject’s various medical and other treatments and 
therapies.
JAKE Uploader
An internally-developed application used on the JSW LAB PC to 
facilitate the secure transfer of data collected by JAKE Sense. The 
JAKE Uploader organizes and encrypts submissions before sending 
them to the sponsor’s secure file transfer protocol (SFTP) server.
My JAKE Web
The web-based view of My JAKE/My JAKE MMApp. The My 
JAKE Web interface is supported by most modern Internet browser 
programs.
Mentis
An internally-used project codename used to label activities and 
research studies (described in Section 1.1, Background).
Periodic Biosensors
A set of wearable and stationary biosensors used during a discrete 
period of assessment at a study visit; representative devices include 
EEG, ECG, eye tracking, and video
PHI
Protected health information. PHI is 18 classes of information 
defined by United States law and regulation (45 CFR 164.514) that 
can be used to identify an individual.
RAVE
sponsor’s eCRF system


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1.
INTRODUCTION
There is a growing interest in developing novel medicines for the treatment of Autism Spectrum 
Disorder (ASD). The emerging evidence from genomics, neuroimaging, and neurobiologic 
research is elucidating new molecular targets with the potential for clinical benefit. Given the 
high incidence of ASD (1 in 68 births in the United States of America [USA]), the significant 
unmet medical need, and long-term associated morbidity, there are multiple facets of the disorder 
that could benefit from novel treatments. There are currently no medications approved for the 
treatment of core symptoms of ASD.
JNJ-42165279 is a potent, selective, and orally bioavailable inhibitor of the enzyme fatty acid 
amide hydrolase (FAAH). This enzyme is primarily responsible for the degradation of a variety 
of fatty acid amides (FAAs), including the endocannabinoid N-arachidonoylethanolamine, or 
anandamide (AEA), the first identified endogenous cannabinoid receptor agonist. The 
endocannabinoid system is believed to play important roles in the regulation of the immune 
system, pain perception, affect, motivation, emotion, fear and anxiety responses. As such, the
endocannabinoid system and FAAH inhibition could modulate the core symptoms associated 
with social communication deficits, and restrictive and repetitive behaviors (RRB). Evidence has 
demonstrated that the endocannabinoid system is involved in behavior and emotion directly 
relevant to Autism Spectrum Disorder (ASD).122 Modulation of behavior and emotion related to 
ASD is the basis for testing JNJ-42165279 for therapeutic effect in adolescent and adult subjects 
with ASD.
JNJ-42165279 has been studied in 7 Phase 1 studies and 2 Phase 2a studies. The Phase 1 studies 
included a single ascending dose regimen up to 250 mg and a multiple dose regimen of 100 mg 
once daily in healthy males, a study with healthy Japanese males administered a single dose and
multiple dose regimen of 25 mg once daily for 10 days, a multiple dose study with cohorts 
receiving 10, 25, 75 or 100 mg for 10 days, a brain FAAH occupancy study using positron 
emission tomography (PET), a drug-drug interaction study (DDI), an oral bioavailability study, 
and a functional magnetic resonance imaging (fMRI) study with a dose of 100 mg once daily 
over 4 days to healthy males. Both Phase 2a studies evaluated the safety and efficacy of once 
daily dosing of JNJ-42165279 25 mg using a double-blind, randomized, placebo-controlled 
design. One of the Phase 2 studies included patients with severe social anxiety disorder, while 
the other evaluated patients with major depressive disorder with anxious distress.
The participation, dosing, and enrollment in the Phase 2a studies was voluntarily suspended by 
Janssen on 16 January 2016 following the report of serious adverse events (SAEs) occurring in a 
Phase 1 clinical study conducted by Biotrial, Rennes, France while evaluating BIA 10-2474, a 
FAAH inhibitor from Bial Pharmaceutical company, Trofa, Portugal. Janssen received formal 
notification from the US FDA of the full clinical hold of 3 active Investigational New Drug 
Applications (INDs) related to JNJ-42165279, pending further investigation into the cause of the 
Bial trial’s serious adverse events. Investigations were completed by European and US health 
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Results from preclinical studies on ASD have determined that variation/mutation/disruption of 
the endocannabinoid system is associated with behavioral and electroencephalogram (EEG) 
changes.45,59,132 Specifically, the CB1 cannabinoid receptors and their endogenous ligands (AEA 
and 2-arachidonoyl-sn-glycerol [2-AG]) have been associated with modulating social play and 
social anxiety, 2 pivotal facets of social behavior.14,49,96,131 In a study that examined genes with 
abnormal expression levels in the cerebella of subjects with autism compared with control 
subjects, it was determined that the CB1 gene demonstrated a 30% down-regulation in subjects 
with autism.98 Furthermore, CB1 gene variations contributed to regulating the perception of 
signals of social reward, such as happy faces, suggesting that CB1 is a critical component in the 
molecular perception of social behavior.25 FAAH inhibitors and other endocannabinoid 
modulators reverse core ASD behaviors and comorbidities in preclinical models.59,132 For 
instance, a recent study in mice has demonstrated that AEA signaling at CB1 receptors modulates 
the incentive salience of social interactions, and this was independent of AEA’s ability to 
regulate anxiety.141 Oxytocin receptor activation by endogenous oxytocin enhances AEA 
mobilization in the mouse nucleus accumbens. This indicates that oxytocin functions as a social 
reinforcement signal within this limbic region. Furthermore, heightened AEA signaling (via 
FAAH inhibition) stimulates social reward and occludes the prosocial effects of oxytocin. These 
results suggest that pharmacologic modulation of oxytocin-driven AEA signaling via a FAAH 
inhibitor (such as JNJ-42165279) may be beneficial in the treatment of social impairment in 
ASD. Overall, these findings support the hypothesis that modulation of the endocannabinoid 
system by a FAAH inhibitor may improve the core symptoms of ASD.
The current study will be conducted to assess the efficacy, safety, tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) of treatment with JNJ-42165279 using the Janssen Autism 
Knowledge Engine (JAKE®) system in adolescent and adult subjects with ASD. This study is 
intended as the first cohort in a planned ‘Platform’ study of autism using the JAKE system and 
the Autism Behavior Inventory (ABI). Additional cohorts, using different investigational 
compounds may be added to the Platform study, either one at a time or even in parallel over the 
course of the study. Additional cohorts may be added through ‘Intervention Specific 
Appendices’ to the Platform protocol. Information may be shared between cohorts, particularly 
data from placebo subjects, enabling fewer placebo subjects in later cohorts. The Platform study 
would thus not be considered completed until the final cohort completes. The results from the 
study will afford a more comprehensive understanding of ASD, and is intended to support the 
development of JNJ-42165279 as a potential treatment for the core and/or associated symptoms 
of ASD.
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
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of JNJ-42165279, refer to the latest version of the Investigator’s Brochure (IB) for 
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Pharmacokinetics and Product Metabolism in Animals
During pregnancy, rat and rabbit fetuses were well exposed to JNJ-42165279 and the drug 
distributed to the eyes of both species. In concert with the substantially higher (4-fold) plasma 
exposures in rabbit compared to rat dams, the rabbit fetus also had higher exposure (2 to 4 –fold 
comparing plasma and whole fetus exposure in rats and rabbits) to JNJ-42165279. In addition, 
the exposure in rabbit fetal eyes was 3-fold higher than that in rat fetal eyes. Comparing total 
radioactivity to JNJ-42165279 levels, it is evident that JNJ-42165279 was more extensively 
metabolized in rats than rabbits leading to a higher metabolite burden in the rat fetuses (fetal eye, 
plasma, and whole) than in rabbits despite the generally higher exposures in rabbits.
No information is currently available about any pharmacology of any metabolites of 
JNJ-42165279.
Toxicology
The oral toxicity of JNJ-42165279 was characterized in GLP 2-week and 3-month toxicity 
studies in rats and dogs. In the GLP 3-month studies, adverse effects on coagulation parameters 
(increased prothrombin time [PT] and activated partial thromboplastin time [aPTT]) and the 
reproductive organs (decreased sperm motility and abnormal sperm morphology) were observed
in male rats at all doses. In female rats, microscopic changes were observed in the kidney 
(mineralization and vacuolar degeneration) at 25 mg/kg, while there were no findings at the low 
dose of 5 mg/kg. Based on these findings, the no observed adverse effect level (NOAEL) could 
not be established in male rats and was 5 mg/kg in female rats. Relative to exposures at the 
intended clinical dose of 25 mg BID (Cmax= 273 ng/mL and AUC = 3886 ng.h/mL), Cmax and 
AUC exposures in the female rats provide 8-fold and 3-fold margins respectively. In dogs, doses 
of 5 and 15 mg/kg were well tolerated, while adverse effects at 10050 mg/kg were noted in the 
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liver and gall bladder (vacuolation with cellular degeneration or necrosis that correlated with 
mild increases in aspartate transaminase [AST], alanine aminotransferase [ALT], alkaline 
phosphatase [ALP], and gamma-glutamyltransferase [GGT]), thymus (atrophy), bone 
(hypercellularity of the erythroid cell line in sternal bone marrow), and epididymis/testis 
(decreased sperm numbers and secondary spermatid degeneration/depletion). Based on these 
findings, the NOAEL in dogs was 15 mg/kg, providing Cmax and AUC margins of at least 21-fold 
and 20-fold over those at the anticipated human exposures.
Reproductive and embryo-fetal safety was evaluated in rats and rabbits. Male rats treated with 
JNJ-42165279 for 4 weeks had significantly reduced sperm motility and increased number of 
abnormal sperm at doses of 100 and 200 mg/kg but not at 25 mg/kg; these changes were fully 
reversible following a 4-week recovery period and are considered exaggerated effects of FAAH 
inhibition. JNJ-42165279 at the high dose of 100 mg/kg, but not at ≤30 mg/kg, induced changes 
in female rat oestrus cycling (regularity and cycle length), which is also likely an exaggerated 
effect of FAAH inhibition. The Cmax (3,280 ng/mL) and AUC (9280 ng.h/mL) exposures in male 
rats at 25 mg/kg (the NOAEL for fertility findings) provide margins of 12- and 2.4-fold over the 
anticipated human effective levels. In pregnant rats and rabbits, JNJ-42165279 induced minimal 
maternal toxicity in both species (decreased food consumption and body weight gain). There 
were no fetal changes in rabbits. In rabbits, the NOAEL for fetal toxicity was the highest dose 
tested, offering Cmax and AUC margins of over 64-fold. Rat fetuses at the high dose of 
100 mg/kg showed a significant increase in incidence of background primary lens fiber swelling 
and degeneration with or without fragmentation on histological evaluation. When offspring of 
pregnant rats dosed with JNJ-42165279 were allowed to grow to maturity, ophthalmoscopy 
revealed a significant increase in the incidence of nuclear cataracts at the high dose of 100 mg/kg 
with a slight trend at 30 mg/kg. Primary lens fiber swelling, focal degeneration and nuclear 
cataracts are common background findings in rats, but these were exacerbated by treatment with 
JNJ-42165279. Following an integrated assessment of the lens findings in 3 rat studies, the 
NOAEL for fetal toxicity was 10 mg/kg. At this dose, Cmax and AUC exposures (3,660 ng/mL 
and 19,200 ng.h/mL) provide 13-fold and 5-fold margins over anticipated mean human 
exposures at the dose of 25 mg BID. Adjusting for plasma protein binding (6.4% free in humans 
vs 9.1% free in rats), the Cmax and AUC margins are 19- and 7-fold, respectively. No treatment 
related changes were noted in adult eyes exposed to JNJ-42165279 for up to 3 months.
JNJ-42165279 was not genotoxic in the in vitro bacterial/microsomal activation assay, the mouse 
lymphoma assay, or the in vivo chromosome aberration test in rats.
Clinical Studies
JNJ-42165279
This will be the tenth study (7 Phase 1 studies completed, 2 Phase 2a studies completed, and this 
study) involving the administration of JNJ-42165279 to humans.
A double-blind Phase 1 study (Study 42165279EDI1001) was completed with 29 healthy male 
subjects to evaluate the safety, tolerability, PK, and PD activity of JNJ-42165279 after single and 
repeated oral dosing. In Part 1, 2 cohorts (both n=9) received single ascending doses of 






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coagulation parameters. There were no deaths, SAEs, or discontinuations due to adverse events. 
Subjects receiving 100 mg reported slight similarity to sedatives and dissimilarity to stimulants 
on the Addiction Research Center Inventory-53; no groups reported similarity to cannabinoids. 
No subjective effects were reported in any of the cohorts by Bond-Lader visual analogue scales.  
During the DDI study 42165279EDI1004 16 subjects received a single 30 mg JNJ-42165279 
dose on Day 1. Thereafter, they received single oral doses of 200 mg itraconazole from Day 4 to 
Day 10 (inclusive). Subjects also received a dose of 30 mg JNJ-42165279 along with 200 mg 
itraconazole on Day 8.
In the safety analysis, the most frequently reported TEAEs (n=2) were
dry throat 
(JNJ-42165279), rhinitis (itraconazole), and erythema (JNJ-42165279 and itraconazole). All 
other TEAEs were reported as a single incident. All the TEAEs were mild in intensity except for 
2 TEAEs (dry throat after JNJ-42165279, and bone contusion after JNJ-42165279 and
itraconazole treatments) which were moderate in intensity. None of the TEAEs were reported as 
severe and all of the TEAEs resolved at the end of the study. None of the TEAEs were probably
or very likely related to the study drug. Two subjects had TEAEs of elevated ALT. However, 
both events were mild in intensity and were considered possibly related to itraconazole by the 
investigator.
An analysis of brain FAAH occupancy by JNJ-42165279 using PET of 11C-MK-3168 has been 
conducted (study 42165279EDI1003). 
 
 
 
 
 
From the analysis of safety data, it was determined that all TEAEs reported in the study 
were mild in severity and all TEAEs were considered to be not related to the study agent, except 
for the event of headache, which was reported as possibly related to the study agent.
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Study 42165279ANX1001 examined whether JNJ-42165279 (100 mg administered once daily
over 4 days) affected blood oxygen level dependent (BOLD) fMRI signals in the amygdala
elicited by an Emotional Face Processing Task, in healthy young male subjects. In the safety 
analysis, no deaths or other SAEs were reported. A total of 14 (63.6%) subjects in the 
JNJ-42165279 group and 9 (42.9%) subjects in the placebo group reported at least 1 TEAE. The 
most frequently reported TEAE in the JNJ-42165279 group was headache (reported in 4 subjects 
[18.2%]), followed by fatigue, nasal congestion, and nasopharyngitis (each reported in 2 subjects 
[9.1%]). The most frequently reported TEAEs in the placebo group were headache, fatigue, 
dizziness, nausea (each reported in 2 subjects [9.5%]). All TEAEs were mild in severity, with the 
exception of 1 moderate TEAE (blood creatine phosphokinase increased, in a subject assigned to 
placebo). Most TEAEs were considered to be unrelated or of doubtful relationship to study agent 
by the investigator. Five subjects in the JNJ-42165279 group and 5 subjects in the placebo group 
had a TEAE that was considered possibly or probably related to study agent by the investigator; 
no subject had a TEAE that was considered by the investigator to be very likely related to study 
agent. TEAEs considered possibly or probably related were headache, dizziness, fatigue, nausea, 
palpitations, migraine, energy increased, nasal congestion, and insomnia. All TEAEs had 
resolved by the end of the study. No suicidal ideation or suicidal behavior was reported based on 
the results of the Columbia Suicide Severity Rating Scale (C-SSRS). No clinically relevant 
changes in mean vital sign parameters and mean laboratory parameters were observed in the 
JNJ-42165279 or placebo group. There were no clinically relevant changes observed in liver 
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function tests. In light of the reports from the Biotrial study, T1 weighted scans obtained during 
the Day 4 MRI session were evaluated by an independent neuroradiologist, and no findings of 
concern were noted.
The clinical effects of JNJ-42165279 in patients with severe social anxiety disorder were
investigated in a double-blind, parallel-group, Phase 2a study (42165279SAX2001). A total of 
149 patients were randomized to receive once daily treatment with either JNJ-42165279 25 mg 
or placebo for 12 weeks. The treatment groups did not significantly differ in improvement in the 
Liebowitz Social Anxiety Scale (LSAS) total score (primary endpoint), nor in other measures of 
anxiety and depression. The percentage of subjects with ≥30% improvement on the LSAS total 
score was significantly higher in subjects treated with JNJ-42165279. Additionally, the 
percentage of subjects much improved or very much improved on the CGI was also significantly 
higher in subjects treated with JNJ-42165279. The occurrence of TEAEs was similar across the 
2 treatment groups (62.2% JNJ-42165279 versus 56% placebo). The most frequent TEAEs in 
subjects treated with JNJ-42165279 were headache, fatigue, upper respiratory infection, diarrhea, 
and nasopharyngitis. There were 2 SAEs reported in the JNJ-42165279 treatment group: 
anaphylaxis due to accidental egg ingestion in a subject with known allergy, considered 
unrelated to study drug, and alcohol use disorder considered doubtfully related to study drug. 
There were no SAEs reported in the placebo group.  
Another Phase 2a study, 42165279MDD2001, investigated the effects of JNJ-42165279 in 
patients diagnosed with major depressive disorder with anxiety symptoms who were not 
receiving adequate control with their SSRI/SNRI treatment. In this randomized, double-blind, 
parallel-group study, patients received once daily treatment with JNJ-42165279 25 mg or 
placebo for 6 weeks after a placebo lead-in period. There were no significant treatment 
differences in the primary endpoint, the Hamilton Depression Rating Scale (HDRS17), or in other 
efficacy measures. The proportion of patients experiencing TEAEs was 23.4% in the 
JNJ-42165279 group and 36.8% in the placebo group. TEAEs occurring in 2 or more subjects 
treated with JNJ-42165279 were headache and nasopharyngitis (3 subjects each), and 
neutropenia (2 subjects). There were 2 SAEs experienced by subjects in the JNJ-42165279 
treatment arm: a bunion resulting in elective/corrective surgery and an anaphylactic reaction due 
to accidental shrimp ingestion by a subject with known shellfish allergy, which occurred 14 days 
into the withdrawal period. One placebo subject experienced an SAE of gastroenteritis during the 
treatment period. See Section 3.2.3 for information on PK/PD analyses performed for this study. 
For more details about the clinical data please refer to the IB. 
JAKE System
A series of studies have been conducted leading up to the present study to test and assess various 
components of the overall JAKE System.
MENTIS-HV-001
The primary objective of this study was to assess the functionality of preliminary, testable 
components of JAKE, for use as a digital health data capture system in adult subjects without 


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autism. The secondary objective was to assess the feasibility of deployment and in-home use of 
JAKE for up to 24 weeks. This included an examination of use patterns of preliminary, testable 
JAKE components. The exploratory objective was to explore the relationship between biosensor 
data and self-reported information on health, mood, and activity.
The JAKE preliminary, testable components included in the study were the following: 
1.
A pre-production-environment (PPE) version of Microsoft HealthVault  
2.
The web-based JAKE User Interface (UI)
3.
The JAKE smart phone application (App) that prompted participants for information about 
mood, sleep, and activity throughout the day (available on Android and iOS devices)
4.
FitBit®Flex™, a wrist band biosensor that measures activity and sleep 
5.
Affectiva Q™, a wrist band biosensor that measures skin conductance
6.
FitBit®Aria™ WiFi Scale to measure body weight
7.
A confidential, private database where information collected through JAKE and biosensors 
was stored
8.
Cerora MindReader™, a portable, single-lead wireless EEG
device (OPTIONAL 
COMPONENT).
A total of 25 subjects (17 males, 8 females) were screened and enrolled in the trial. Of those, 
21 subjects completed the trial. 
In general, the results of the System Usability Scale suggested that subjects had a favorable view 
of the system. Scores on individual items generally improved between Visit 2 and Visit 3, as 
subjects gained more experience with the system. Examples of items that were more favorably 
rated included: “I think I would like to use this website frequently” (median=agree), “I thought 
the website was easy to use” (median=agree), and “I found the various functions in this website 
were well integrated” (median=agree). Less favorably rated included: “learning how to use it 
required a little / no time” (median=agree somewhat), “after using it for a while you can’t 
imagine not having it” (median=neither agree nor disagree), and “makes me feel in control when 
managing various aspects of Autism” (median=neither agree nor disagree). Some of the less 
favorable items, however, were more oriented towards a clinical population ie, ASD, rather than 
a healthy volunteer population, and this may have affected subjects’ ability to respond 
appropriately. 
Several system problems and software bugs were identified, including scaling problems with 
items on the phone application, registration difficulties and problems with initial application 
downloads, and difficulties with visualization of data from symptom ratings. These were fixed 
during the course of the trial, and retested with a successful outcome. 
Subjects entered a large amount of presumed fictitious medical history information, ranging from 
vital signs (blood pressure example provided below), to family history, to medical conditions and 
medications. As an example, 17 subjects provided hypothetical blood pressure ratings (not from 
actual sphygmomanometer measurements), with a total of 35 observations. This demonstrates 


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the feasibility of transferring dynamic measures of vital signs from HealthVault (in this case, a 
fictitious PPE account) into the research data warehouse. In the future, these data could be 
generated from automated devices, from medical records obtained directly from physicians’ 
offices, or self-entered data.
Subjects were also able to successfully utilize the Affectiva Q sensor band, and data from this 
band were uploaded for further analysis showing readings of activity/movement, sleep (in some 
cases), and galvanic skin response within expected levels for healthy adults. A large proportion 
of subjects were able to complete the voluntary EEG portion of the study, and a total of n=11 
participants completed at-home administration of the EEG battery. Data demonstrated that it is 
feasible to conduct home-based self-administration of EEG and computer-based tasks. This was 
true across the various tasks included in the approximately 20-minute EEG battery. Several data 
discrepancies were noted which suggest that careful instruction and training may still result in 
minor inaccuracies that could have an impact on data quality, particularly in a clinical population 
(ie, individuals with ASD, with tests administered by a parent). 
Of the 21 subjects who completed, a total of 3 subjects reported adverse events. All 3 adverse 
events were related to the Affectiva Q sensor: all events were skin irritation and itching (2 mild, 
1 moderate severity). 
Results of this study confirmed the feasibility of utilizing a web-and-mobile system, as well as 
home and lab-based biosensors, for use in clinical trials. Important information was gleaned 
about the registration process, other procedures including connection and synchronization of 
devices, system bugs, and on the form factor of the MLE. The system itself was deemed to be 
easy to use once registration and linking of devices was complete. Further, connection of the 
MLE to, and biosensor data transfer into, Microsoft HealthVault was successful, as was data 
extraction from the HealthVault PPE to the Janssen Research Data Warehouse. Feedback 
provided on the MLE resulted in identification of pain points, as well as myriad constructive 
suggestions for how to improve the system.
Overall, the frequency and severity of adverse device effects was limited, resolved without 
intervention, and did not result in any long-term consequences to subjects.
MENTIS-AUT-0001
This Investigator Initiated pilot research study helped to evaluate how well-established JAKE 
System features would work in an applied setting, as well as informed future directions for JAKE 
System development.
This study utilized the Affectiva Q sensor device and a prototype web interface and personal 
health record platform developed by ilumivu, Inc. (the ilumivu Platform).
The following specific aims guided the pilot study:


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1. Evaluate the usability and feasibility of stakeholders (ie, healthcare professionals) using the 
ilumivu Platform to collect behavioral and physiological data from individuals with ASD 
multiple times per day over several days.
2. Learn what elements of the ilumivu Platform will make multimodal data collection easy, 
useful, and compelling for stakeholders to use.
3. Assess the functionality of specific components of the ilumivu Platform, including:
A. Symptom ratings (both routine and momentary);
B. Biosensor data collection;
C. Stakeholder journaling;
D. Charting/visually displaying obtained information; and
E. Communicating between parents, school staff, and researchers.
From February 1, 2014 through April 25, 2014 (82 days), 91 Center for Discovery (CfD) staff 
members and parents used the ilumivu Platform to record information about 20 children in their 
care.
The trial successfully accomplished its goal by providing the research team with a clear 
understanding of what the JAKE System will be required to do in order to be clinically useful in 
a real-world setting. Responses from participants were critical in helping to determine clinical 
use and research needs while shaping the system into an effective tool for these particular 
stakeholder groups. Many new features and ideas were gained from talking to the staff and 
parents who used the system. A rich multi-user dataset was created to help inform both the 
Center for Discovery's clinical practice and their staff management policies.
MENTIS-HV-002
This study, conducted across 3 laboratories at Northeastern University, aimed to compare the 
usability, sensitivity, and accuracy of various experimental biosensors to that of their 
gold-standard, laboratory instrumentation counterparts. Feedback from this study informed
decisions on future development of the JAKE Biosensor Array.
The study was conducted in healthy, adult subjects and utilized tasks and stimuli to test the 
full-range of sensing capabilities of the various sensors in a single session.
The sensors modalities tested were actigraphy, galvanic skin response (GSR), ECG, EEG, and 
eye tracking.
Ten subjects were tested with EEG, 10 with eye tracking and 20 with actigraphy, GSR and ECG.
The study demonstrated that mid-range actigraph, eye tracking and EEG equipment were
logistically feasible to use and provided data quality sufficient for the intended analyses in future 
studies.
The mid-range ECG device was superior to the lab instrumentation.


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The GSR devices tested were not comparable to the lab instrumentation, likely due to the lack of 
wet electrodes and to the placement on the wrist rather than the palm or fingertips. It is 
questionable whether these devices would provide adequate data.
MENTIS-ASD-001
MENTIS-ASD-001 was the first study conducted in subjects with ASD utilizing the complete 
JAKE System. Thirty-five subjects were enrolled; with approximately 15 of those undergoing 
the JAKE Task Battery and the remainder using only the JAKE Portal. Subjects in Stage 1 
participated for 1 week, while those in Stage 2 participated for 4 weeks. This study began the 
process of validating and optimizing the JAKE System, enabling the sponsor to optimize 
platform components such as the JAKE Task Battery, JAKE Biosensor Array, and JAKE Portal 
(including its subcomponents, such as the JAKE Symptom Tracker, later renamed ABI). 
Based on scale correlations for the ABI, it was determined that most correlations were 
statistically significant (p<0.001). Also, most of the standard scale correlation values between the 
baseline and endpoint visit were statistically significant (p<0.001). Most of the estimated 
correlations for the scales between the baseline and endpoint were >0.7. Correlations between 
the total ABI and domains of the ABI with the standard scale total and domain scores with which 
they might be expected to correlate were generally high (>0.7) and statistically significant 
(p<0.001).
The overall correlations between the key biosensor features with some standard scales such as 
SRS Social Communication and Child Adolescent Symptom Inventory-Total Score and 
Symptom Tracker, measured using Pearson’s correlations were strongly positive (r= ≥0.70) and 
considered significant (p<0.001) for ASD subjects. However, due to limited data available and 
small sample size during each stage, no definitive conclusions could be reached.
The experiences in this study led to many improvements, both in the biosensor devices used, the 
JAKE Portal software and processes, the Task Battery, and the Janssen Research Data 
Warehouse. As a whole, the System appeared to be a viable platform to be used in clinical 
studies of ASD. There were no safety issues observed with any components of the overall 
system. 
MENTIS-ASD-002
This was a non-interventional study that aimed to continue from MENTIS-ASD-001, and tested
and validated the final JAKE System. The testing and validation of the final JAKE System
included the subcomponents of the JAKE Portal (later renamed My JAKE), as well as the 
selected biosensors and procedures for biosensor testing that will be used for objective 
measurement of core and associated symptoms of ASD in a population of children, adolescents, 
and adults. The study also examined the JAKE Task Battery and selected components of the 
JAKE Biosensor Array (later renamed JAKE Sense) on a cohort of typically-developing (TD) 
children and adults in order to obtain comparative data. Feedback on both the My JAKE
interface and JAKE Sense biosensors were obtained, and data obtained via the interface and 
biosensors were compared to symptom measures commonly used in clinical research.


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The study consisted of children and adults with ASD and a TD group for comparison. A total of 
185 participants (ASD, 144; TD, 41) were enrolled in this observational study. The majority of 
participants were male (ASD, 77.8%; TD, 65.9%); the mean (SD) age of participants was 
14.6 (7.83) years (ASD group) and 16.3 (13.18) (TD group). The ASD group participated in the 
JAKE Task Battery 3 times at approximately 4-week intervals. TD participants had a single visit 
wherein they underwent a single session with the JAKE Task Battery and biosensors.
The results demonstrated support for the utility of the ABI in measuring the clinical symptoms of 
ASD. The results supported the usability of the JAKE System (including subcomponents of 
My JAKE and selected JAKE Sense biosensors) for monitoring clinical outcomes in ASD. Key 
sensor variables of Periodic and Continuous Biosensors were identified using data mining 
approaches. Examination of sensor variables as change measures in the full dataset was
performed.
At the end of this study the sponsor validated the ABI, completed computer system validation on 
My JAKE and all of its subcomponents, developed the algorithms to extract meaningful features 
from My JAKE and JAKE Sense input, and identified the combination of biosensors and 
task/stimuli most likely to be able to detect changes in response to treatment.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of JNJ-42165279 compared with 
placebo in the improvement of symptoms of ASD during 12 weeks of treatment on the following
parameters:

Autism Behavior Inventory (ABI) Core Domain Score (Social Communication and RRB).
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
ABI Social Communication Domain Score.

ABI RRB Domain Score.
Secondary Objectives

To assess the safety and tolerability of JNJ-42165279 compared to placebo.

To assess the effect of JNJ-42165279 compared with placebo on the following parameters in 
subjects with ASD:

ABI Mood & Anxiety, Challenging Behavior, Self-Regulation domains.

Aberrant Behavior Checklist (ABC), Autism Behavior Inventory-Short Form (ABI-S),
Autism Behavior Inventory-Clinician interview (ABI-C), Clinical Global Impression-
Severity (CGI-S),
Clinical Global Impression-Improvement (CGI-I), Repetitive 
Behavior Scale-Revised (RBS-R), Zarit Burden Interview (ZBI), Child Adolescent 
Symptom Inventory-Anxiety (CASI-Anx), Social Responsiveness Scale 2 (SRS-2), 
Caregiver Global Impression of Severity (Caregiver GI-S), Caregiver Assessment of 
Treatment, and Self Global Impression of Improvement (Self GI-I) scales.

To correlate changes in the ABI with changes in biosensors, Janssen Autism Knowledge 
Engine (JAKE®) components and standard scales (ABC, CGI-S, RBS-R, ZBI, CASI-Anx, 
and SRS-2).

To compare the performance of the ABI with that of the ABC.

To compare the effect of JNJ-42165279 to placebo using the JAKE Task Battery biosensor 
data.

To assess the pharmacokinetics (PK) of JNJ-42165279 in subjects with ASD using a 
population PK approach and explore its relationship with efficacy and safety parameters
where appropriate.

To evaluate the relationship between plasma concentrations of 
and efficacy. 
Exploratory Objectives
The exploratory objectives are:
CCI
CCI


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2.1.2.
Endpoints
Primary Endpoint
The primary endpoints will be measured as follows:

Change from baseline to Day 85 in the ABI Core Domain Score (Social Communication and 
RRB).

Change from baseline to Day 85 in the ABI Social Communication Domain Score.

Change from baseline to Day 85 in the ABI RRB Domain Score.
Secondary Endpoints
The secondary efficacy endpoints are:

The change from baseline to Day 85 in the ABI Mood & Anxiety, Challenging Behavior,
and Self-Regulation domains.

The change from baseline to Day 85 in the ABC, ABI-S, ABI-C, CGI-S, RBS-R, ZBI, 
CASI-Anx, SRS-2, and Caregiver GI-S.

Caregiver Assessment of Treatment, Self GI-I, and CGI-I at Day 85.
2.2.
Hypothesis
The primary hypothesis for this study is that JNJ-42165279 is superior to placebo in reducing the 
core symptoms associated with ASD as assessed by the ABI Core Domains (Social 
Communication and RRB), Social Communication Domain, or RRB Domain.
The study will be deemed positive if any of the primary efficacy endpoints are statistically 
superior to placebo using a 1-sided 0.10 significance level.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, multi-center, double-blind, placebo-controlled, parallel group, outpatient
study assessing the efficacy, safety, and tolerability of JNJ-42165279 during 12 weeks of 
treatment in adolescent and adult subjects with ASD. 
Approximately 80 adolescent and adult subjects (between 13 and 35 years of age, inclusive) will 
be randomized in a 1:1 ratio to receive double-blind treatment of either JNJ-42165279 or 
placebo. The randomization will be stratified by gender and age (13-17 years and 18-35 years). 
Subjects enrolled prior to Protocol Amendment 5 were randomized to receive once daily dosing 
of placebo or 25 mg JNJ-42165279 throughout the treatment period. All other subjects will 
receive twice daily (BID) dosing of placebo or 25 mg JNJ-42165279 (total daily dose of 50 mg).
See Section 3.2.3 for the rationale for the change in dose of JNJ-42165279 during the study. 
Study procedures include safety and efficacy evaluations and blood sample collections for 
pharmacogenomic assessment, pharmacokinetics, and biomarkers of treatment activity. An 




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Follow Up Phase
Subjects will return to the clinical site for a safety follow up visit at 14 days (±1 week) following 
the last dose of study drug (Day 85).
Study Extension
No extension is planned for this study.
3.2.
Study Design Rationale
3.2.1.
Randomization, Blinding, and Control
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Stratified randomization will be used for
gender (male and female) and age (13-17 years and 18-35 years). Blinded treatment will be used 
to reduce potential bias during data collection and evaluation of clinical endpoints as well as 
adverse events. A placebo control will be used to establish the frequency and magnitude of 
changes in clinical endpoints that may occur in the absence of active treatment.
3.2.2.
Study Population 
ASD is a neurodevelopmental disorder consisting of the core symptoms of social communication 
deficits and RRB. Associated symptoms include deficits in self-regulation, irritability, anxiety, 
depression, problems with attention, and challenging behaviors such as aggression. These criteria 
are laid out in the Diagnostic and Statistical Manual of Mental Disorders - 5th Edition (DSM-5)
and are widely accepted in the field.
The overall goal of subject selection is to identify subjects, aged 13 to 35 years old (inclusive),
with a definitive diagnosis of ASD using the Autism Diagnostic Observation Schedule, Second 
Edition (ADOS-2), who have an IQ as measured by the KBIT-2 of ≥60, and are capable of 
completing and complying with all study-specific requirements.
Given observations in the rat reproductive toxicology studies (see Section 1.1), women of 
childbearing potential (WOCBP) will only be included if they agree to ongoing use of a highly 
effective method of contraception (i.e. one that results in a less than 1% per year failure rate 
when used consistently and correctly). Pregnancy testing will be done at screening and at each 
study visit during the treatment phase. Safety and efficacy data in this population are important 
for future clinical studies.
3.2.2.1.
Rationale for Including Adolescent Subjects, Aged 13 to 17 Years
JNJ-42165279 has been evaluated for general toxicity in rat and dog studies of up to 3 months in 
duration. Evaluation of embryo-fetal toxicity has been completed in rats and rabbits, while 
fertility performance has been assessed in rats. Cardiovascular safety was evaluated in dogs and 
acute neurobehavioral effects assessed in rats. Animals used in the multiple dose toxicology 
studies straddled early to late reproductive maturity at study start. Specifically, animals used in 


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the rat 2-week and 3-month studies were at least 8 weeks old, and therefore considered at the top 
end of adolescence, while those used in the neurobehavioral study were 6 weeks old (at start of 
adolescence). In dog studies, those for the 2-week study were 7 months old (adolescents), while 
those in the 3-month study were 10 months old at start of dosing (considered young adults). 
Several target organs were identified, mostly in the 3 month and reproductive safety studies. 
These included changes in kidneys of female rats only, coagulopathy in male rats only, liver 
changes in dogs only, testicular changes in both rats and dogs, and lens fiber swelling and 
fragmentation in fetuses of pregnant rats treated with JNJ-42165279 during the period of 
organogenesis.  
A key consideration in assessing the potential risk to human adolescents in a clinical trial is 
whether the target organs identified in the general and reproductive toxicity studies continue to 
undergo significant growth and development, which may not have been evaluated in young adult 
or adult animals used in the toxicity studies. In general, most human organs are fully developed 
by the age of 13 years with the notable exception of the brain cortex, the reproductive and 
skeletal systems. The endocannabinoid system is integral to brain development and reproductive 
function but has not been linked with skeletal development.
Reproductive function: Endocannabinoids are known to control multiple reproductive functions 
in both males and females through precisely orchestrated steps and levels requiring either up- or 
down regulation of various endocannabinoids particularly anandamide. Changes in anandamide 
levels play an integral role in sperm viability, acquisition of motility, and capacitation ability, 
amongst others.11,66,126 FAAH inhibition has also been demonstrated in preclinical models to 
modulate male fertility in a manner similar to exogenous CB1 agonists such
as 
tetrahydrocannabinol (THC).65,66,126 Mating wild-type female mice with FAAH knockout male 
mice had only a minimal effect on litter size while the effect was more significant when FAAH -/-
males were mated with FAAH -/- females. Sperm motility was also reported to be reduced in 
FAAH -/- males and this correlated with increased anandamide levels. In a study looking at 
endocannabinoid levels in sperm from fertile and infertile men, Lewis et al (2012) reported a 
substantial modulation of AEA metabolism in infertile men.66 Anandamide biosynthesis 
(3-fold lower) and to a lesser extent FAAH activity (2-fold lower) were significantly impaired in 
infertile versus fertile sperm plasma. In a case reference study by Pacey et al (2014), recent 
cannabis use emerged as a modifiable risk factor for <4% normal sperm morphology (criterion
for significant infertility).91 Although FAAH inhibition is expected to represent a selective 
stimulation of the CB1 receptors in specific regions as opposed to the broad and nonselective 
effects of exogenous CB1 agonists such as THC, the testicular effects in JNJ-42165729-treated 
rats and dogs appear to mirror those of THC administration. Therefore, in the absence of human 
data from FAAH inhibitors, it is reasonable to consider data on reproductive effects of cannabis 
use as the maximal possible pharmacological expression of FAAH inhibition. Treatment with 
JNJ-42165279 resulting in increased levels of anandamide is therefore expected to modulate 
sperm motility and possibly fertility. However, these effects were shown in the studies in rats 
and dogs to be dose dependent and reversible on treatment cessation as they are limited to 
spermatids, the last phase in spermatogenesis. In the GLP 3-month study in dogs, testicular 
effects were not seen at NOAEL AUC exposures 26-fold over the anticipated clinical AUC 


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exposure. In the GLP rat 3-month study, sperm motility was reduced by 25%, and 39% of the 
spermatozoa were abnormal at the lowest dose tested (2.4-fold exposure ratio over the human 
exposures) but this level of change was shown to have no impact on pregnancy rates in the rat 
fertility study. In conclusion, FAAH inhibition through dosing with JNJ-42165279 has the 
potential to modulate sperm and fertility parameters in adolescents and adults but these effects at 
the clinical dose are expected to be minimal and reversible based upon preclinical studies and the 
known effects of CB1 agonists in humans.
Based on these observations, male subjects must use a condom and spermicide during the study 
and for a minimum of 1 spermatogenesis cycle after the last dose of study drug.
Neurobehavioral effects: There is limited literature data on the effects of FAAH inhibition on 
the developing brain and behavior. In the 3-month studies in rats and dogs, central nervous 
system-related clinical signs were mostly seen in dogs and limited to the high dose group. They 
included ataxia, excessive licking, salivation, tremors, and uncoordinated movement. In the 
Modified Irwin assay in rats, behavioral changes were limited to reduced muscle tone and 
reduced body temperature, well-recognized cannabimimetic effects. FAAH inhibition represents 
tonic activation of the endocannabinoid system. Although there is a growing body of evidence 
suggesting that chronic use of exogenous CB1 agonists such as cannabis (as distinct from FAAH 
inhibition) during adolescence could have deleterious neurocognitive effects, preclinical and 
clinical data have not reported any neurocognitive effects with JNJ-42165279. There is also 
evidence that CB1 activation including via heightened AEA signaling as a result of FAAH 
inhibition may be beneficial in the treatment of social impairment in ASD. Moreover, subjects 
with ASD have been shown to have altered expression levels of the CB1 gene, suggesting that 
intervention outcomes with FAAH inhibition could be different relative to normal subjects 
exposed to cannabis.
3.2.3.
Rationale for Dose Selection
Based on preclinical models of JNJ-42165279 efficacy with adjustment for differences in affinity 
of JNJ-42165279 for human FAAH, a 25 mg once daily regimen was chosen as the dose to carry 
forward into the Phase 2 proof of concept studies.
 
 
However, a post-hoc analysis of the Phase 2 studies 
42165279SAX2001 and 42165279MDD2001 found that the AEA concentrations observed in the 
JNJ-42165279 treatment group were only about 3-fold greater than the pre-drug concentrations.
AEA trough concentrations in these 2 studies exhibited a high degree of variability, and the
distribution of AEA trough concentrations in the JNJ-42165279 treatment group was found to 
overlap with that in the placebo group. These findings suggest that elevated AEA levels and 
FAAH inhibition associated with 25 mg JNJ-42165279 administered once daily was not 
sufficiently sustained for all subjects throughout the 24-hour dosage interval. 
The relationship between AEA trough concentrations and clinical outcomes was explored using 
the data from these Phase 2 studies. In the MDD2001 study, subjects with higher trough AEA 
concentrations after 6 weeks of treatment exhibited greater reductions in anxiety (measured by 
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the Hamilton Anxiety Rating Scale) and depression (measured by the HDRS17) than subjects 
with lower trough AEA levels.
 
 
 
See Section 1.1, Background, for information on safety margins. 
In view of these analyses
 
 
 the dose in the 42165279AUT2001 study will be changed to 
25 mg BID (50 mg total daily dose). 
CYP3A4 plays an important role in the metabolic elimination of JNJ-42165279. In the presence 
of the strong CYP3A4 inhibitor itraconazole, 
 
 respectively (Study 42165279EDI1004). CYP3A4 inhibitors will be restricted 
in this study. 
3.2.4.
Rationale for Pharmacokinetic Evaluations
If warranted at the time of the interim analysis and after completion of the study, the plasma 
concentration-time data of JNJ-42165279 will be analyzed using population PK modeling. 
Concentration-time data will allow estimation of individual PK parameters for JNJ-42165279. It 
will also help to understand potential differences between ASD subjects treated with 
JNJ-42165279 and those treated with placebo. Time and days of JNJ-42165279 plasma 
concentration assessment were chosen to gather maximal information about the PK properties of 
JNJ-42165279 while minimizing subject burden regarding blood sampling.
3.2.5.
Rationale for Pharmacogenomic and Biomarker Evaluations
A blood sample will be collected from all eligible subjects. Participation in the genomics 
research component is required to assess whether the subject is carrier of the A-allele variant for 
FAAH and to identify genetic factors that may influence the PK, PD, efficacy, safety and/or 
tolerability of JNJ-42165279.
Plasma concentrations of 
 will be used as biomarkers of JNJ-42165279 activity. 
Correlations between 
 values with efficacy and other clinical evaluations will be assessed.
Blood biomarkers related to autism (including but not limited to cytokines and miRNAs) will 
allow for exploratory immunophenotyping and for an exploratory PD evaluation. The biomarker 
data obtained from this study may also contribute to an ongoing cross-study analysis to 
investigate the relationship between ASD and phenotypes and biomarkers.
3.2.6.
JAKE System
The JAKE system is an integrated system of tools and technologies designed to optimize clinical 
trials for ASD. The JAKE System includes JAKE Sense, which collects biosensor data, and a 
reporting tool which collects caregivers’ reports on the behavior and mood of the subjects.
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Caregivers will use 1 of 2 versions of a caregiver reporting tool: My JAKE (the first application 
used in this study) or My JAKE MMApp (the second application used in this study). Caregivers
will use the application which is operational during the time of their participation.
The input from My JAKE/My JAKE MMApp (which includes the ABI) and JAKE Sense will be 
processed separately. Additionally, case report form (CRF) data (study events, concomitant 
medications, demographics, etc) and data from the standard caregiver and clinician rating scales 
will be incorporated in the analysis.
See Sections 9.2.2.4 and 9.2.2.5 for information on data processing for the caregiver reporting 
tool and JAKE Sense, respectively.
It should be noted that the JAKE Sense and the individual sensors and components working as 
part of the array have been qualified for signal and processing compatibility but have not yet 
undergone full Computer Systems Validation. As such, any data derived from them should be 
considered exploratory. JAKE Sense (and its relevant processing and storage systems) are 
virtually isolated from the My JAKE/My JAKE MMApp system to ensure integrity of the 
primary endpoint measurement.
The following schematics show the overall structure of the JAKE System and its data flows for 
My JAKE (Figure 2) and My JAKE MMApp (Figure 3).


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Figure 2: 
My JAKE System
Abbreviations: ABI=Autism Behavior Inventory; ABI-S=Autism Behavior Inventory-Short Form; 
eCRF=electronic case report form; EEG=electroencephalogram; JAKE=Janssen Autism Knowledge Engine.


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Figure 3:
My JAKE MMApp
Abbreviations: ABI=Autism Behavior Inventory; ABI-S=Autism Behavior Inventory-Short Form; 
EEG=electroencephalogram; JAKE=Janssen Autism Knowledge Engine


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3.2.6.1.
My JAKE /My JAKE MMApp
All of the following components are included in My JAKE:

ABI: A rating scale consisting of approximately 65 questions related to the core and 
associated symptoms of ASD.

ABI-S: A shorter version of the ABI, consisting of approximately 20 questions.

Daily Tracker: In the morning, the caregiver will be asked to report on their dependent’s 
quality of sleep the night before. Additionally, the caregiver will be required to select 
3 behaviors related to ASD to track on a daily basis. After 6 PM each day, the caregiver is 
required to report on these behaviors, on their dependent’s overall type of day, and on their 
dependent’s mood, in terms of emotion and energy levels.

Journal and Event Trackers: A tracking system that allows caregivers to quickly log key 
‘events’ and information as they happen – such as a bad night’s sleep or a positive 
improvement. This can be in the form of free-text journal entries or common ASD events 
from a pick-list.

Therapy Tracker: A calendar-like ‘therapy tracker’ that allows caregivers to keep track of 
their dependent’s care-related appointments, organized in weekly or monthly views. In 
addition, it can keep track of treatments, and other therapies. It can also be used to set up and
schedule study visits.

Medical/Developmental History: A detailed medical and developmental history form 
designed to construct a picture of the subject’s ASD including treatments and other 
information, and personalize the caregiver’s view of this information.
My Jake MMApp includes only the ABI, ABI-S, and Daily Tracker. If My JAKE and My JAKE 
MMApp are not available, paper versions of the ABI, ABI-S, and Daily Tracker will be used.
Currently there are no measures which have been specifically designed to measure change in 
behavior in ASD. This impacts the development of new treatments for autism, since 
effectiveness cannot be established and compared across interventions. Many of the existing 
scales, such as the ADOS and SRS have been developed to diagnose and classify, rather than 
detect change over time. They are limited in their use as change indicators by their long recall 
periods, or lack of variability in response options. This has led to the prevalence of use of 
outcome measures such as changes in IQ, adaptive behavior, and language, which are often 
unrelated to the main focus of treatment, and/or rely on measures which are developed for 
individuals without intellectual or developmental disabilities.19
Therefore, the pressing need for research in autism is around more systematized measures, 
developed for the ASD population, which are sensitive to change over time and capable of 
capturing the heterogeneity of presentations. The ABI, its short form the ABI-S, and 
accompanying components of the JAKE System are designed to capture sufficiently variable 
presentations across all the key domains, while providing a high level of utility – effectively 
making it simple for caregivers and other observers to record critical information on 
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3.2.6.2.
JAKE Sense
The literature has shown that differences between TD children and autistic children can be 
detected by various physiologic and cognitive biomarkers. These modalities were chosen to 
detect differences between TD subjects and ASD subjects as well as potentially to detect 
differences between ASD subjects, treatment-induced changes and changes over time. As 
subjects improve on treatment, it is expected that biosensor signals will be more like TD 
individuals.
The following sections describe the rationale for the various sensor-experimental modalities used 
in this study, while subjects are monitored continuously (see Section 3.2.6.2.1) or assessed
through a periodic experimental battery (see Section 3.2.6.2.2).
JAKE Sense (and its hosted biosensors) are used solely for exploratory, proof-of-concept
research. While JAKE Sense may host medical devices, and while these devices are being used 
in compliance with their intended use, no portion of JAKE Sense is being used in such a way as 
to diagnose, treat, or prevent any disease or disorder, nor is the output being used in (or in 
support of) any regulatory filing (now or in the future).
3.2.6.2.1.
Continuous Biosensor
Continuous Biosensors can be worn over extended periods of time such as throughout the day or 
during sleep. They will also be worn and assessed during study visits as with the Periodic 
Biosensors below. It is expected that biosensors will provide more direct characteristics of the 
ASD population than indirect assessment via questionnaires filled in by caregivers. It is also 
expected that changes in features extracted from the biosensors will be detected prior to changes 
observed in scales.
During day/night time, recordings will be done with an actigraphy device to monitor activity. All 
biosensors were reported to have been successfully used in children (including those under 
10 years old) previously, including cohorts of individuals with ASD.1,78,134
3.2.6.2.1.1.
Actigraphy/Accelerometry
An actigraph measures activity while worn on a subject’s wrist like a watch. Based on data 
recorded during the day, time periods of child involvement in sedentary, light, moderate, and 
moderate-to-vigorous activities are expected to correlate with disease severity, where an ASD 
population is expected to spend more time in sedentary activity, with less time in light, moderate 
and moderate-to-vigorous activity than TD children of the same age.134 At the same time it was 
reported that the prevalence of sleep problems ranges from around 50% to 80% for children with 
ASD compared with 9% to 50% for a TD group.101 The use of an actigraph for sleep monitoring 
provides an easy-to-use way (in comparison to polysomnography) of sleep monitoring with 
about 90% sensitivity of sleep estimation.78
ASD is characterized by repetitive behaviors (which are included in gold standard diagnostic 
tools such as the ADOS-2 and the Autism Diagnostic Interview-Revised [ADI-R]), which 
includes body rocking, hand flapping and others.105,106,133 The frequency and durations of such 


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activity are usually estimated via caregivers’ reports. 
 
 
3.2.6.2.2.
Periodic Biosensors and JAKE Task Battery
Periodic Biosensors will only be worn or used for a discrete period of assessment during a study 
visit. As opposed to the Continuous Biosensor, which will be worn continuously throughout the 
treatment period, Periodic Biosensors will be assessed only during the time that the subject is 
exposed to specific visual and auditory tasks or stimuli via a computer interface (the JAKE Task 
Battery).
The Periodic Biosensor array consists of an EEG, an eye-tracker and a device for ECG 
recordings (different from the medical ECG used for drug safety evaluation). These devices have 
been extensively used in child and adolescent populations.8,23,35,37,56,115,138 In addition, the
subject’s affect (apparent emotion) will be measured with the use of a standard web camera and 
the iMotions® Biometric Research Platform Emotient™Facial Expression Analysis (FACET) 
module. The FACET module will analyze facial expressions across all task presentations, with 
particular focus on the analysis of the funny videos task.
The JAKE Task Battery includes a number of different experiments which aim to detect changes 
in core symptoms of ASD (description and rationale provided below). The experiments are 
distributed across 2 sets. Some of the experiments were developed for specific biosensors, but all 
of the biosensors are used throughout the Task Battery in order to identify new biomarkers 
across different biosensor modalities.
ECG will be monitored during the entire battery and will provide assessment of such 
characteristics as HR and HRV to study potential impairments in the autonomic nervous system 
associated with ASD.35 In addition, change in HR response to auditory stimuli will be measured 
specifically during an auditory task and a short physical challenge task. Since emerging ASD 
literature associates autonomic nervous system activity with social function, ECG recordings 
could provide a link between measurable biological activity and both social behavior and 
cognitive function.8,72,92,135
The tasks and stimuli for use with the Periodic Biosensors were chosen based on the literature 
and scientific advice to elicit physiologic and behavioral differences between ASD and TD 
populations using the various sensor modalities, and the battery was adapted following the 
ASD-002 study preliminary results.
 
 
 
 
 
The battery encompasses both static and dynamic stimuli in an 
attempt to elicit the broadest range of responses.
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The tasks are divided across 2 sets. Each set includes a variety of tasks which induce behaviors 
measured by EEG, eye tracking, FACET, and HR changes, which are associated with symptom 
severity in ASD.
The entire Periodic Biosensor array will be used during each portion of the Task Battery in order 
to look for new biomarkers which could provide added value to the primary sensor for a 
particular modality. Literature suggests that some tasks have utility beyond the individual sensor. 
As such, data from all sensors on a particular task may be highly informative.
Though not part of the Periodic Biosensor array, subjects are required to wear the Continuous 
Biosensor during administration of the Task Battery.
3.2.6.2.2.1.
Periodic Biosensor of Interest: Electroencephalogram Portion
While the primary biosensor is an EEG recording device, changes in biomarkers derived from 
other modalities are also expected. This portion of the JAKE Task Battery consists of the 
following experiments:
Resting State
ASD populations exhibit an increase in brain white matter activity, which is evident from 
magnetic resonance studies.31,50 White matter reflects myelinated axons that transmit signals 
between neurons within 1 or several cortical areas. EEG recorded from electrodes on the scalp 
reflects synchronous activity among thousands of neurons in the tissue underlying a particular 
location. Thus, changes in local neural connectivity will influence changes in EEG from single 
electrodes. At the same time, EEG coherence reflects functional cortical connectivity, which 
could serve as an index of changes in long range connectivity, which could be altered due to 
changes in white matter. Those EEG indexes are best assessed during resting state in order to 
exclude EEG changes induced by any task or stimuli.
ASD subjects have memory problems: some show severely impaired memory, while others fall 
into the other extreme with 'savant' memory.83,89 Executive control of memory processing is 
mediated by the frontal cortex and also involves the integrated actions of multiple brain 
areas.20,40,44, 90,112,123 As such, abnormalities in neural connectivity may underlie memory deficits 
in ASD.102 This is especially so in theta waves in EEG during rest, which relate to memory 
processing.62
ASD subjects have increased attention to details. It was found that resting state alpha power of 
EEG recordings is linked to attention.63 As such, we may expect abnormal alpha in an ASD 
population during resting state.
ASD subjects have abnormalities in processing, perceiving and showing emotions. ASD is also 
associated with depression and anxiety. There is evidence that the frontal lobe is involved in 
emotional processing with a difference in lobes (right vs. left) for different emotions.36,46 Thus 
patterns of frontal EEG (asymmetry) may serve as an index of abnormalities in emotion 
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ASD is also related to abnormal functioning of gamma-aminobutyric acid (GABA)-ergic tone in 
inhibitory circuitry, which influences the functioning and development of the brain.140 Abnormal 
functioning of GABA-ergic tone is thought to modulate power at high-frequency and 
low-frequency EEG bands while increasing power of middle range frequencies (alpha band).140
Event-related Potential: Faces Compared to High Autism Interest Objects
The study will use event-related potentials (ERPs) to investigate brain activity related to the 
presentation of faces (social) or objects determined to be high autism interest (HAI; 
non-social).42
According to the social motivation hypothesis, disrupted social motivation mechanisms may 
represent a primary deficit in ASD. This could include a decreased preference for social images 
and/or an increased preference for certain classes of non-social information, known as HAI 
objects.42,109
ERP studies have demonstrated differences in P300 (stimulus evaluation, novelty detection) and 
N170 (facial recognition response) between TD and ASD. Longer latency and reduced amplitude 
to faces, but not objects, have been seen in ASD.33,34,38,41,70,77
These differences may be seen in amplitudes and latencies of ERP components (especially the 
face-sensitive adult N170 component) and their hemispheric asymmetry relation, and changes in 
amplitude and latency responses may correlate with changes in symptoms.
Recently the response of the last positive potential – a centro-parietal ERP positive component at 
approximately 300 ms after stimulus onset and lasting to 1500 ms, has been found to be greater 
for HAI relative to faces in ASD, when compared with TD.13
In addition, attention to key facial features, especially the eye and mouth region, may relate to 
ASD symptoms.56 Fixation features estimated from eye-tracker data (number of fixations, total 
time spent in gazing) on key facial features, 
, will also be 
measured.
3.2.6.2.2.2.
Periodic Biosensor of Interest: Eye Tracking Portion
The eye tracking portion of the periodic biosensor array consists of following tasks:
Social Information Processing Task
The Social Information Processing Task involves actors engaging in child-directed speech and 
includes a bid for joint attention (the shared focus of 2 individuals on an object).
Visual information processing in TD subjects is reinforced with additional speech information,
which shows TD children’s ability to integrate multimodal input for faster encoding and 
recognition of faces.6,21,48,67,107,127 There is evidence that face detection is facilitated when it is 
combined with directed speech in TD infants.61,137 At the same time, ASD children are 
characterized by their limited attention to faces combined with under-responsivity to 
speech.23,26,28,87,93 Limitation in attention to faces in ASD subjects is mainly prominent for 
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dynamic (videos) face stimuli, when they are presented in complex naturalistic context.55,129 It is 
possible that limited attention to faces is a direct result of increased salience of objects, which are 
of high autism interest (HAI).110,111
 
 
ASD subjects will show diminished attention assessed with the eye-tracker 
to the entire scene and spend less time monitoring the speaker’s face in general and mouth in 
particular. Instead, they will direct their attention toward the toys as well as the hand/action area.
Visual Search
ASD is characterized by interests that are restricted to some particular things (so-called HAI
objects), social difficulties and stereotyped repetitive behavior.105,106,133
 
 
 
 
 
 
Biological Motion
TD subjects show a preference for biological motion from birth.120 At the same time, children 
and adults with ASD do not show such preferences.4,86
 
 
 
 
It is also known that in TD individuals the mirror neuron system activates when they either 
watch someone perform a task or perform the task themselves.103 Response of this system is 
characterized via suppression of mu waves in EEG.103 In contrast,, in an ASD population, mirror 
neurons become active (and consequently mu waves are suppressed) only when the individual 
performs the task him- or herself.15,1
 
 
Activity Monitoring
It is known that the ability to understand intentional and goal-directed actions of others arises 
early in infancy in a TD population.5,117,129 Attention to the actions and activities of others is a 
critical component of the learning and development of cognitive and social skills.117 Attention to 
others and their actions facilitates learning about affordances, is a pre-requisite for imitation and 
emulation, and is crucial to the development of higher-level cognitive skills such as joint 
attention, 
social 
play, 
and 
the 
comprehension 
of 
intentions, 
goals, 
and 
motivations.1,7,24,47,51,52,69,79,81 The fact that skills such as affordance learning, imitation, and joint 
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attention emerge in a regular fashion, together with their relationships with later development of 
language and theory of mind skills, argue for mutual interdependencies and suggest that common 
requirements, such as activity monitoring, may evolve together with the skills themselves.117 At 
the same time, many of the skills outlined above have been found to be impaired in the ASD
population.117,125,133,142
 
 
 
3.2.6.2.2.3.
Affect Detection Portion
It has been found that facial expressions activated via automatic or intentional mimicry influence 
corresponding emotions in controls, but that the influence of facial expressions is impaired in the 
ASD population.124 Consequently it is expected that ASD individuals will show fewer facial 
emotional responses (less variance in emotion) in response to funny videos than TD individuals. 
A more neutral flatness of affect has also been found in the activated facial expressions of 
autistic children.144
 
It is known that humans automatically mimic a variety of behaviors, including but not limited to 
emotional facial expressions.76 ASD individuals have been found not to automatically mimic 
facial expressions presented to them whereas TD individuals do.76
 
 
 
When asked to produce a specific emotion, ASD individuals are also known to produce more 
ambiguous or “bizarre” expressions, a behavior that is not apparent in the TD population.68,144
 
3.2.6.2.2.4.
HRV Portion
A review of the literature on physiological reactivity to sensory and social and emotional stimuli 
indicates that abnormalities exist for some individuals with ASD.71
In addition to looking at patterns of autonomic nervous system activity across portions of the 
Task Battery, the Auditory Processing task is designed to measure HR responsivity to auditory 
stimuli, and the physical task measures HR responsivity to change in posture from sitting to 
standing.
The toilet flush and ticking clock are presented as examples of non-biological, ecologically valid 
stimuli. They are similar to those rated in the IADs Affective Ratings of sounds. They were 
selected as they elicited similar medium level values of valence and arousal in TD adults and are 
therefore considered ‘neutral’ and non-aversive.17
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Parents report increased sensory sensitivity in children with ASD and there is evidence that these 
atypical sensitivities are particularly present in the auditory domain.58,75 There are indications 
that differences in sensitivity in ASD subjects are related to underlying differences in autonomic 
nervous system responsivity, as measured by, for example, HRV.
It is also thought that these differences may be related to other behavioral differences in ASD, 
such a repetitive behaviors and anxiety.
 
There could also be different patterns observed within ASD and these differences may 
correspond with other ASD symptoms.16
3.2.6.2.3.
JAKE Sense Workbench
The JAKE Sense Workbench is a platform that will link together and synchronize all 
components of the Periodic Biosensor collection (as well as the Continuous Biosensor) while 
presenting the JAKE Task Battery. Data collected through the JAKE Sense Workbench (JSW) is 
transmitted directly to the JAKE Sense Data Pipeline via the secure file transfer protocol 
application 
 – permitting comprehensive analysis of all biosensor data inputs and 
integration with the separately-processed manually-entered data from the caregiver reporting 
tool.
3.2.7.
Standard Instruments and Rating Scales
Throughout the study, data collected from the caregiver reporting tool and JAKE Sense will be 
compared and correlated with standard instruments and scales. The scales form a selection of the 
secondary outcome measures, in addition to contributing to the process of validation of the 
JAKE System as a tool for measuring clinical outcomes in ASD.
3.2.7.1.
Diagnostic and Classification Instruments
These instruments will be given a single time to establish the diagnosis of autism or help rule it 
out, to help classify subjects by IQ, or to rule out or rule in the presence of other psychiatric 
disorders in subjects.
Autism Diagnostic Observation Schedule, Second Edition
The ADOS-2 is a diagnostic measurement tied to the inclusion criteria.
Kaufman Brief Intelligence Test, Second Edition
The KBIT-2 is a diagnostic measurement tied to the inclusion criteria.
3.2.7.2.
Instruments for Measuring Change
The scales have been selected based on their ability to detect changes over time in the ASD 
population. As described in Section 3.2.6.1, there are no existing scales which are specifically 
designed for measuring changes in behavior in ASD. Therefore, instruments were selected based 
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on input from scientific advisors and current use as outcome measures in ASD interventional 
studies.
Autism Speaks commissioned 3 reports on current scales for Social Communication, Restrictive 
Repetitive Behaviors, and Anxiety, which were suitable for use in clinical trials for Autism.3,64,113
The findings of these reports, compiled by experts in the field, were influential in the
consideration of scales for comparison.
Scales were selected to ensure comparisons across all 5 domains measured by the ABI. The 
scales to be used in this study and the rationale for their use are described in the table below:
3.2.7.2.1.
Zarit Burden Interview
In addition to the behavioral scales, a measure of parent burden is also included in order to assess 
the impact of behaviors and the impact of behavioral change on the caregiver and family life. 
There are no specific scales developed to measure this aspect. The ZBI was originally developed 
to assess burden of care for dementia patients, but has also been used to assess burden in those 
who care for children and adults with ASD.22
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3.2.8.
National Database for Autism Research/Global Unique ID
The National Database for Autism Research / Globally Unique Identifier (NDAR GUID) system 
was established as a mechanism to share data on individual subjects among the research 
community without sharing subjects’ protected health information (PHI). 
More information on NDAR can be found at http://ndar.nih.gov/.
4.
SUBJECT POPULATION
Subjects (13 to 35 years of age) with a definitive diagnosis of ASD using the Autism Diagnostic 
Observation Schedule, Second Edition (ADOS-2), who have an IQ as measured by the KBIT-2 
of ≥60, and who are capable of completing and complying with all study-specific requirements
will be enrolled. 
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 unless 
otherwise specified:
1.
Criterion modified per Amendment 1.
1.1. Criterion modified per Amendment 2.
1.2. Criterion modified by Amendment 3.
1.3. Criterion modified per Amendment 5.
1.4. Subject must be between 13 and 35 years of age, inclusive..
2.
Criterion modified per Amendment 1.
2.1. Criterion modified per Amendment 3.
2.2. Criterion modified per Amendment 6.
2.3. Diagnosis of ASD in subjects must be according to DSM-5 criteria and made or 
confirmed using the ADOS-2 (minimum score of 8 [autism spectrum]). (An 
ADOS-2 completed by an adequately trained professional within the 24 months
prior to screening visit will be acceptable if the item responses are available for 
entry into the electronic case report form [eCRF].)


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3.
Criterion modified per Amendment 1. 
3.1. Subjects (18 years of age or older) must have a body mass index 
(BMI=weight/height²) between 18 and 35 kg/m2, inclusive, at screening. Subjects 
(between 13 and 17 years of age, inclusive) must have a BMI ≥5th percentile and 
<95th percentile on the Centers for Disease Control and Prevention BMI-for-age 
percentile growth charts.
4.
Criterion modified per Amendment 2. 
4.1. Criterion modified per Amendment 5.
4.2. A male subject who has not had a vasectomy must agree to use a condom when 
having sex with a female partner of childbearing potential (see Attachment 1) 
during the study and for 3 months after receiving the last dose of study drug. The 
condom must have a spermicide or the partner must use a spermicide. A male 
subject should also be advised to inform their female partner to use a highly 
effective method of contraception over the same time period, as condoms may 
break or leak. 
5. 
Subjects must be otherwise healthy for their age group or medically stable with or 
without medication on the basis of physical examination, medical history, vital signs, 
and 12-lead ECG performed at screening. If there are abnormalities, they must be 
consistent with the underlying illness in the study population with written concurrence 
with the sponsor's medical monitor.
6.
Criterion modified per Amendment 2.
6.1. Subject must be otherwise healthy or medically stable on the basis of clinical 
laboratory tests performed at screening. If the results of the serum chemistry 
panel, hematology, or urinalysis are outside the normal reference ranges, the 
subject may be included only if the investigator judges the abnormalities or 
deviations from normal to be not clinically significant. This determination must 
be recorded in the subject’s source documents and initialed by the investigator. 
However, subjects with an AST or ALT >1.5x ULN cannot be enrolled. These 
tests may be repeated once during the screening period at the discretion of the 
investigator.
7.
Criterion Modified per Amendment 2.
7.1. Subject must live with a parent or primary caregiver or, if not, during each week 
they must either (A) spend at least 3 hours a day for at least 4 days or, (B) spend 
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8.
Subject must be able to be compliant with self-administration of medication if living 
independently or have a parent or caregiver be able to administer medication.
9.
Subject and primary caregiver must speak and understand English.
10.
Criterion modified per Amendment 1.
10.1. Primary caregivers must have a reliable means of obtaining internet connectivity 
for a desktop, laptop or tablet computer.
11.
Subject must be able to swallow the study medication whole with aid of water.
12.
Criterion modified per Amendment 2.
12.1. A subject ≥18 years of age must sign an informed consent document (and/or 
their legally acceptable representative must sign) indicating that he or she 
understands the purpose of and procedures required for the study and is willing 
to participate in the study, is willing to attend all site visits, and is willing and 
able to adhere to the prohibitions and restrictions specified in this protocol. For a 
subject <18 years of age, parent(s) (preferably both if available or as per local 
requirements) (or their legally acceptable representative) must sign an informed 
consent form (ICF) indicating that he or she understands the purpose of, and 
procedures required for, the study and is willing to allow the child to participate 
in the study. Assent is also required of adolescents (<18 years of age) capable of 
understanding the nature of the study as described in Section 16.2.3, Informed 
Consent. The subject’s caregiver must also sign a caregiver consent form 
indicating that he or she understands and is willing and able to adhere to the 
caregiver’s responsibilities in the study.
13.
Any pharmacologic, diet, or behavioral intervention for the core or associated 
symptoms of ASD such as, but not limited to, an applied behavior analysis (ABA) 
program, Pivotal Response Training (PRT), Treatment and Education of Autistic and 
related Communication Handicapped Children (TEACCH), Floor Time and DIR, 
Relationship Development Intervention (RDI), Early Start Denver Model, Discrete 
Trial Training or a social skills program whether school-based or not must:
A) Have begun at least 1 month prior to the baseline visit and continue unchanged 
through the double-blind period, or;
B) Have ended at least 1 month prior to the baseline visit.
If such therapy is started, discontinued or changed substantially during the course 
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14.
Criterion modified per Amendment 2.
14.1. Subject must achieve at least ‘GOOD’ calibration on the eye-tracker in no more 
than 4 attempts/visit, at any time during the screening period.
15.
Subject has a measured composite score on KBIT-2 of at least 60. A KBIT-2 
conducted within the past 6 months is also acceptable provided the scores are 
available for entry into the eCRF.
16.
A male subject must agree not to donate sperm during the study and for a minimum of 
90 days after receiving the last dose of study drug.
17.
A female subject must have a negative highly sensitive serum pregnancy test (β-hCG) 
at screening and, for women of childbearing potential, a negative urine pregnancy test 
on Day 1 before randomization.   
18.
A female subject using oral contraceptives must also use a barrier method of 
contraceptive (a male or female condom, diaphragm, or cervical cap) with spermicide
(above that required in Inclusion Criterion 19).
19.
Criterion modified per Amendment 5.
19.1. A female subject must be (as defined in Attachment 1, Contraceptive Guidance 
and Collection of Pregnancy Information):
a.
Not of childbearing potential; or
b.
Of childbearing potential and:
o
Practicing a highly effective method of contraception (failure rate of 
<1% per year when used consistently and correctly) and agrees to 
remain on a highly effective method while receiving study intervention 
and until 30 days after last dose. Examples of highly effective methods 
of contraception are described in Attachment 1, Contraceptive Guidance 
and Collection of Pregnancy Information.
20.
Criterion modified per Amendment 5.
20.1. A female subject must agree not to donate eggs (ova, oocytes) for the purposes 
of assisted reproduction during the study and for a period of 30 days after 
receiving the last dose of study drug.
NOTE: All references to a caregiver in the inclusion criteria, except Criterion #8, should be the 
designated caregiver for this study, fulfilling all of the caregiver responsibilities as described 
throughout the protocol.


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4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study unless otherwise specified:
1.
Criterion modified per Amendment 1.
1.1. Subject has a current or recent history of clinically significant suicidal ideation 
within the past 6 months, corresponding to a score of 4 (active suicidal ideation 
with some intent to act, without specific plan) or 5 (active suicidal ideation with 
specific plan and intent) for ideation on the C-SSRS, or a history of suicidal 
behavior within the past year, as validated by the C-SSRS at screening or Day 1. 
Subjects with a prior suicide attempt, or prior serious suicidal ideation/plan 6 
months ago, should be carefully screened for current suicidal ideation and only 
included at the discretion of the investigator. If the C-SSRS is unable to be 
administered, the principal investigator (PI) must document that there is no 
evidence of suicidality based on history and the Aberrant Behavior 
Checklist-Irritability Subscale (ABC-I).
2.
Criterion modified per Amendment 2.
2.1. Subject has a clinically significant abnormal physical examination or clinically 
relevant abnormal neurological examination, vital signs or 12-lead ECG 
(including QTcF >450 msec for males and >470 msec for females, Left Bundle 
Branch Block, AV Block second degree or higher, permanent pacemaker or 
implantable cardioverter defibrillator [ICD]) at screening or baseline (Day 1 
predose), which in the opinion of the investigator is not appropriate and 
reasonable for the population under study. ECG recordings and vital signs may be 
repeated once and if in question, a cardiologist should be consulted. 
3. 
Criterion modified per Amendment 2.
3.1. Criterion modified per Amendment 6.
3.2. Subject has a history of or current evidence of abnormal liver or renal function; 
incomplete vaccination status, has relevant clinically significant and/or unstable 
cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic (including 
seizures), hematologic, rheumatologic, immunologic, or metabolic disturbances 
(eg, unstable situations needing monitoring or regular dose adaptations). Stable 
conditions (eg,
epilepsy, attention deficit hyperactivity disorder, certain 
neurodevelopmental or psychiatric conditions) are permitted at the discretion of 
the investigator, and with consultation with the sponsor, if warranted. Any 
clinically relevant medical condition that could potentially alter the absorption, 
metabolism, or excretion of the study drug is exclusionary. Subjects with liver 
function analytes higher than the ULN at screening should be reviewed with the 
sponsor. If the subject has ALT or AST >1.5 times the ULN, he/she should not be 


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enrolled. Any test may be repeated once at the discretion of the investigator.
4.
Subject has a history of malignancy within 5 years before screening (exceptions are 
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or 
malignancy that in the opinion of the investigator, with written concurrence with the 
sponsor's medical monitor, is considered cured with minimal risk of recurrence).
5. 
Criterion modified per Amendment 2.
5.1. Criterion modified per Amendment 6.
5.2. If a subject is using a drug or supplement with moderate/strong CYP3A4 
inhibiting or inducing properties at, or prior to, screening, it must be discontinued 
at least 30 days or five half-lives (whichever is longer) prior to Day 1. Note: an 
existing medication should not be stopped solely for the purpose of the subject
entering the study. Moderate and strong inducers or inhibitors of CYP3A4 are 
prohibited during the study (See some examples in Attachment 2).
6.
Subject has a history of positive tests for hepatitis B surface antigen (HBsAg) or 
hepatitis C antibody (anti-HCV), or other clinically active liver disease, or tests 
positive for HBsAg or anti-HCV at screening.
7.
Subject is currently taking or has taken within the past month recreational or 
medically prescribed cannabis.
8.
Subject has a history of human immunodeficiency virus (HIV) antibody positive, or 
tests positive for HIV at screening.
9.
Criterion modified per Amendment 2.
9.1. Criterion modified per Amendment 6.
9.2. Subject has a history of drug or alcohol use disorder according to DSM-5 criteria
within 6 months before screening or positive test result(s) for drugs of abuse 
(including 
barbiturates, 
opiates, 
cocaine, 
cannabinoids, 
amphetamines,
benzodiazepines, phencyclidine, and 3,4 methylenedioxy methamphetamine 
[MDMA]) at screening or Day 1 (except if related to current treatment; eg,
benzodiazepines).
10.
Subject has a clinically significant acute illness within 7 days prior to study drug 
administration.
11.
Subject has known allergies, hypersensitivity, or intolerance to JNJ-42165279 or its 
excipients (refer to Investigator's Brochure). 


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12.
Subject has received an investigational drug or used an investigational medical device 
within 3 months before the planned start of study or is currently enrolled in an 
investigational study.
13.
It has been less than 6 months since the subject was previously enrolled in another 
Mentis program study (endpoint visit of that study) to the screening visit of the 
current study.
14.
Subject is a man who plans to father a child while enrolled in this study or within 
3 months after the last dose of study drug.
15.
Subject has any condition (eg, vision abnormalities such as ptosis) 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.
16.
Criterion modified per Amendment 2.
16.1. Subject has had major surgery, (eg, requiring general anesthesia, entry into a 
major body cavity, or significant blood loss) within 8 weeks before screening, 
or will not have fully recovered from surgery, or has surgery planned during the 
time the subject is expected to participate in the study or within 4 weeks after 
the last dose of study drug administration. 
Note: subjects with planned minor surgical procedures to be conducted under local 
anesthesia may participate, with approval of sponsor.
17.
Subject has a history of spontaneous, prolonged or severe bleeding.
18.
Subject has donated 1 or more units (approximately 450 mL) of blood or had acute 
loss of an equivalent amount of blood within 90 days prior to study drug 
administration.
19.
Criterion modified per Amendment 2.
19.1. Subject is an employee of the investigator or study site, with direct involvement 
in the proposed study or other studies under the direction of that investigator or 
study site, or is a family member of a site employee or the investigator.
20.
Criterion modified per Amendment 1.
20.1. Criterion deleted per Amendment 2.
21. 
Subject is a male who is sexually active with a pregnant female, or plans to be 
sexually active with a pregnant female while enrolled in this study.


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22.
Subject is pregnant or breast-feeding, or planning to become pregnant or breastfeed 
while enrolled in this study or within 3 months after the last dose of study drug.
23.
Subject is judged by the investigator to be unable to perform or comply with all 
study-specific requirements.
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 9.1.2, Screening Phase, describes options for retesting. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
4.3.
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.
Criterion modified per Amendment 2.
1.1. Subjects must agree to follow all requirements that must be met during the 
study as noted in the Inclusion and Exclusion Criteria (eg, contraceptive 
requirements; prohibitions on donation of blood, sperm, and eggs [ova, 
oocytes]). 
2.
Criterion modified per Amendment 1.
2.1. Subjects must abstain from using illegal drugs or recreational or medically 
prescribed cannabis from screening through the end of the posttreatment phase.
3.
Criterion modified per Amendment 2.
3.1. On study visit days, alcohol must be avoided prior to the time of the visit. At all 
other times after enrollment, subjects at or above the legal drinking age will be 
instructed to limit their alcohol consumption to that consistent with moderate 
drinking (ie., up to 1 drink/day for women and 2 drinks/day for men).
4.
Criterion modified per Amendment 2.
4.1. Moderate and strong inducers or inhibitors of CYP3A4 are prohibited from 
Day 1 through the end of the posttreatment phase.


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5.
Subjects are prohibited from taking/consuming grapefruit, grapefruit juice, Seville 
oranges or poppy seeds from screening through the end of the posttreatment phase.
6.
Criterion modified per Amendment 1.
6.1. Subjects must not take any sedating medications on the day of the Task Battery
(other than any preexisting daily medications) and must not consume caffeine 
within 2 hours prior to the battery.
7.
Criterion modified per Amendment 2.
7.1. On days when biomarker blood samples are drawn, subjects should be advised 
to follow a low-fat diet for at least 8 hours prior to their scheduled visit.
Subjects should be advised to refrain from strenuous exercise and use of 
nonsteroidal anti-inflammatory drug (NSAID) medications for 24 hours before 
their scheduled visit. Information regarding compliance with these restrictions 
should be recorded on the CRF or lab requisition form.
8.
Criterion modified per Amendment 2.
8.1. Refer to Section 8, Prestudy and Concomitant Therapy, for details regarding 
prohibited and restricted therapy during the study.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Randomization 
Central randomization will be implemented in this study. At the start of the double-blind phase, 
subjects will be randomly assigned to 1 of 2 treatment groups (JNJ-42165279 or placebo) based 
on the computer-generated randomization schedule prepared before the study by, or under the 
supervision of the sponsor. The randomization will be balanced by using randomly permuted 
blocks and will be stratified by gender (male and female) and age at time of first consent 
(13-17 years and 18-35 years), with an allocation ratio of 1:1 to placebo and JNJ-42165279. 
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kits for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
Subjects (aged 13-17 years) will be randomized until at least 8 subjects are on the active drug, 
following which screening of subjects of that age range will be temporarily paused while an 
interim PK analysis is conducted. The analysis will be performed when all 8 adolescent subjects 
have participated in the PK sampling at Week 2. Adolescent subjects already in screening may 
be randomized, and screening and randomization of subjects 18-35 years will continue as 


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normal. Any adolescent subjects already randomized will continue per protocol. If PK samples 
are not able to be obtained from 1 of the adolescent subjects, it may be necessary to screen 
and/or randomize additional adolescent subjects. If PK results are consistent with prespecified 
parameters (see Section 11.5) screening and randomization of adolescent subjects will resume. If 
not, unless agreement is obtained from FDA to continue enrolling adolescent subjects it may be 
necessary to complete enrollment with only adult subjects. 
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject for reasons related to the subject’s safety.
Data that may potentially unblind the treatment assignment (eg, study medication plasma 
concentrations, plasma biomarkers) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making 
special provisions, such as segregating the data in question from view by the investigators, 
clinical team, or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. While the responsibility to break the intervention code in 
emergency situations resides solely with the investigator, it is recommended that the investigator 
contact the sponsor or its designee if possible to discuss the particular situation, before breaking 
the blind. In the event the blind is broken, the sponsor must be informed as soon as possible. The 
date, time, and reason for the unblinding must be documented in the appropriate section of the 
CRF, and in the source document. The documentation received from the IWRS indicating the 
code break must be retained with the subject's source documents in a secure manner. 
Subjects who have had their treatment assignment unblinded should continue to return for 
required follow up evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim data review by the Data Monitoring 
Committee (DMC) is specified, the randomization codes and, if required, the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those subjects included in the interim review.
6.
DOSAGE AND ADMINISTRATION
Following Protocol Amendment 5, subjects will self-administer double-blind study medication 
twice daily for 12 weeks. Study medication will be provided as JNJ-42165279 25 mg tablets, or 
matching placebo, packaged in bottles. All tablets (JNJ-42165279 /placebo) are identical in 
appearance. 


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On all visits in the treatment phase, study medication will be taken at the clinic. Treatment Phase 
visits should be scheduled to occur in the morning, and the dose administered in the clinic should 
be the first dose of the day for each subject. Dosing should occur after all subject-related 
procedures, except as noted for blood draws, when feasible. Dosing must occur after 
confirmation of eligibility and subjects’ baseline safety assessments on Day 1 and after 
administration of the JAKE Task Battery at all applicable visits. On all other days between visits, 
subjects will be instructed to take their study medication at home once in the morning and once 
in the evening, with as close as possible to a 12-hour interval between dosings. No more than 
2 pills should be taken in one day (defined here as midnight to midnight). There should be at 
least 6 hours between doses; if this is not possible, a dose should be skipped. Subjects should be 
informed of the importance of taking the evening dose on the day prior to the Week 2 and 
12 visits as close as possible to their routine evening dose time. 
Diaries will be provided to subjects/caregivers to record dates of non-compliance (missed doses 
or >2 pills taken), as well as the time of morning and evening dosings on the day prior to the 
Week 2 and 12 visits. 
A study-site investigational product manual including instructions for dispensing, storage (on site 
and at home) and intake of the study medication will be supplied to the study site. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
In case of any change in dose levels prior to study start or during the study the responsible 
Ethical Committee(s) and Health Authorities, if applicable, will be notified.
7.
TREATMENT COMPLIANCE
The investigator or designated study-site personnel will maintain a log of all study drug 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study. 
Study drug will be self-administered by subjects. As such the number of study drug tablets 
dispensed will be recorded and compared with the number returned. 
At study visits on which the dose is to be held, study drug will be self-administered on site, 
which will be witnessed by designated study-site personnel at the study sites.
Subjects will receive instructions on compliance with study drug administration upon study 
medication (bottle) dispensing. During the course of the study, the investigator or designated 
study-site personnel will be responsible for providing additional instruction to re-educate any 
subject who is not compliant with taking the study drug.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 3 months before screening must be recorded at screening. 


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Concomitant therapies must be recorded throughout the study beginning with signing of the 
initial informed consent until the end-of-study visit (Follow up). Concomitant therapies should 
also be recorded beyond this time only in conjunction with new or worsening adverse events 
until resolution of the event.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. 
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
Any pharmacologic, diet, or behavioral intervention for the core or associated symptoms of ASD 
such as but not limited to an ABA program, PRT, TEACCH, Floor Time and DIR, RDI, Early 
Start Denver Model, Discrete Trial Training or a social skills program whether school-based or 
not must:
A) Have begun at least 1 month prior to the baseline visit and continue unchanged through 
the double-blind period, or
B) Have ended at least 1 month prior to the baseline visit
If such therapy is started, discontinued or changed substantially during the course of the 
double-blind study the subject should be discontinued.
Subject should not take any sedating medications on the day of the Test Battery (other than 
preexisting daily medications) and should not consume caffeine within 2 hours prior to the 
battery.
Moderate and strong inducers or inhibitors of CYP3A4 are prohibited through the end of the 
posttreatment phase. Attachment 2 provides examples of moderate and strong inducers or
inhibitors of CYP3A4. The investigator should evaluate all prestudy and concomitant 
medications to assess whether they are moderate or strong inducers or inhibitors of CYP3A4 and 
consult with the Sponsor if unsure. 
On biomarker blood collection days, subjects should be informed to refrain from use of NSAID
medications for 24 hours before their scheduled visit. This is because the use of NSAIDs may 
impact biomarker measurements, specifically via altering circulating and inducible cytokine 
levels. In addition, NSAIDs also have been reported to inhibit FAAH directly so there is a 
particular need in FAAH studies to restrict their use. Any use of NSAIDs within 24 hours prior 
to the visit should be recorded on the CRF or lab requisition form.
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
9.1.1.
Overview
The Time and Events Schedule summarizes the visits as well as the frequency and timing of 
assessments applicable to this study. A visit window of ±3 calendar days will be allowed for all
visits after Day 1, unless otherwise indicated in the Time and Events Schedule. All visits are in 
principle single day visits; however, they may be performed over multiple days within the 
allowed visit window in case of logistical issues or subject’s preference. Visits during the 
treatment period should be scheduled on the same type of day (weekday vs weekend).
Information regarding collection, handling, shipment, and labeling of biological samples 
(including safety labs) will be provided in a separate lab manual. Any changes to the lab manual 
will not result in a protocol amendment.
In the event of abnormal safety findings during the conduct of the study, additional 
measurements may be made immediately and subsequently at a frequency considered 
appropriate by the attending physician.
The person that will serve as the designated caregiver for the trial will be determined at 
screening. This person will perform all caregiver responsibilities described in this protocol, 
including attending all study visits and completing all caregiver assessments.
The time points for individual measures may be changed by the sponsor (with or without 
affecting the overall frequency of these investigations) prior to and during the study based on 
newly obtained data (eg, interim analysis, DMC) to allow for optimal fit to the actual safety or 
PK/PD profile of the study drug. This modification may result in a change in the overall 
frequency of the individual measures (eg, safety measures, blood samplings) provided the 
maximal total blood volume collected per subject defined will not be exceeded. Such 
modifications, where performed only to allow optimal fit to the actual safety, PK/PD profile of 
the study drug, will not be considered to be an (substantial) amendment to the protocol.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The following describes the order of procedures at study visits:

The order of blood draws versus dosing, when both occur at a visit, is as follows (see the 
Time and Events Schedule for further information):

On Day 1, blood samples will be collected postdose. 

At the Week 2 and 12 visits, blood samples will be collected both prior to and after 
dosing.

At the Week 4 and 8 visits, blood samples may be collected before or after dosing. 


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
The order of procedures, other than the order of blood draws relative to dosing, is as 
follows:

On Day 1, all procedures required for determination of eligibility and all safety 
assessments must be completed prior to randomization and dosing.

For all visits, including screening, all subject-related procedures should be completed 
prior to blood sample collection.

It is recommended that dosing at study visits occur after all subject-related procedures. 

For each subject, the JAKE Task Battery should be conducted at approximately the 
same time of day, when feasible, and must be completed prior to blood draws and 
dosing.
Venous blood will be collected for all blood-based analysis. Actual dates and times of 
assessments will be recorded in the source documentation and CRF or lab requisition form. The 
exact times for each blood draw will be recorded in the lab requisition form. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should preferably be performed in the following order: ECG(s), vital signs, blood draw. The 
order of multiple assessments within 1 protocol time point should also be the same throughout 
the study. Blood may be drawn by using a cannula or by venipuncture. The volume of blood to 
be collected from each subject is summarized in Table 1. For each subject, the maximum amount 
of blood drawn in this study will not exceed 200 mL.
Table 1:
Volume of Blood to be Collected From Each Subject
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL)a
Safety (including screening and posttreatment assessments)
Serum chemistry
2.5
5
12.5
TSH (with reflex to T3/T4 if needed)
3.5
1
3.5
Hematology
2.0
5
10.0
PT (INR) and aPTT 
1.8
5
9.0
Serology
     Hepatitis B virus surface antigen and Hepatitis C virus    
    antibody
2.5
1
2.5
    HIV ½ antibody diff. and HIV-1/HIV-2 antibodies
2.5
1
2.5
- Serum -hCG pregnancy test (females)b
0
1
0
PK sample
2
5
10
 biomarker sample 
6
5
30
Cytokines and miRNA sample
10
2
20
Pharmacogenomics sample (DNA)
2
1
2
Approximate Totalb
NA
102.0
a
Calculated as number of samples multiplied by amount of blood per sample.
b
Volume for serum chemistry sufficient for pregnancy testing as well.
c
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
Note: Blood may be drawn by using a cannula or by venipuncture.
Abbreviations: 
aPTT= activated partial thromboplastin time; DNA= deoxyribonucleic acid; 
 
; HIV= human immunodeficiency virus; INR= international normalized ratio; PK= 
pharmacokinetics; PT= prothrombin time; TSH= thyroid-stimulating hormone.
CCI
CCI


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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
See Attachment 16 for guidance on study conduct during the COVID-19 pandemic.
9.1.2.
Screening Phase
Before any study specific procedures are conducted and following an explanation of the purpose 
and risks of the study, written consent, and if applicable, assent, will be obtained
(see Section 16.2.3, Informed Consent and Assent Form, for further information).
Subjects will be screened within 26 days prior to Day 1 of the double-blind period, to assess their 
eligibility for the study, according to the inclusion and exclusion criteria.
Recording of adverse events/concomitant medication will start following consent and will 
continue until completion of the study.
During screening, assessments/procedures will be performed as described in the Time and 
Events Schedule.
If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal 
reference ranges, the subject may be included only if the investigator judges the abnormalities or 
deviations from normal to be not clinically significant.
Retesting of abnormal laboratory values that may lead to exclusion will be allowed one time.
Retesting will take place during an unscheduled visit in the screening phase or at the second 
screening visit.
Urine drug screens to determine eligibility may be repeated once, at the discretion of the 
investigator.
Eye calibration may be repeated during the screening period if “good” calibration is not achieved 
at the first screening visit.
If a subject is not able to complete all screening procedures within the screening window, or does 
not meet all inclusion and exclusion criteria (ie, is a screen failure), but at some time in the future 
is expected to meet the subject eligibility criteria, the subject may be rescreened on 1 occasion 
only. Subjects who are rescreened will be assigned a new subject number, undergo the informed 
consent process, and then restart a new screening phase.
9.1.3.
Double-Blind Treatment Phase
Throughout the treatment phase, study medication will be dispensed at study visits and subjects 
will self-administer the medication as outlined in Section 6, Dosage and Administration. Clinic 
visits should be scheduled for the morning, as the in-clinic dosing should be a subject’s first dose 
of the day.


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On Day 1, subjects who successfully complete the screening phase will visit the clinical site/unit 
to be randomized on Day 1 of the double-blind phase. Prior to dosing, eligibility will be 
confirmed and the baseline safety assessments and the JAKE Task Battery will be performed as 
described in the Time and Events Schedule.
During the double-blind treatment period, following Day 1, subjects will return to the 
investigational site at Week 2 (Day 15), Week 4 (Day 29), Week 8 (Day 57), and Week 12 
(Day 85). Assessments will be performed as specified in the Time and Events Schedule.
9.1.4.
Posttreatment Phase (Follow up)
At 14 days (±1 week) following last dosing (Week 12), subjects will return to the clinical site for 
a safety follow up visit. The procedures to be completed during the follow up visit are listed in 
the Time and Events Schedule.
Investigators may re-contact the subject to obtain long-term follow up information to determine 
the subject's safety or survival status (refer to Section 16.2.3, Informed Consent).
9.2.
Efficacy
9.2.1.
Endpoints
Primary
The primary endpoints will be measured as follows:

Change from baseline to Day 85 in the ABI Core Domain Score (Social Communication and 
RRB). 

Change from baseline to Day 85 in the ABI Social Communication Domain Score.

Change from baseline to Day 85 in the ABI RRB Domain Score.
Secondary
The secondary endpoints are as follows:

The change from baseline to Day 85 in the ABI Mood & Anxiety, Challenging Behavior,
and Self-Regulation domains.

The change from baseline to Day 85 in the ABC, ABI-S, ABI-C, CGI-S, RBS-R, ZBI, 
CASI-Anx, SRS-2, Caregiver GI-S scales.

Caregiver Assessment of Treatment, Self GI-I, and CGI-I at Day 85.
9.2.2.
Evaluations 
Evaluations throughout the study will encompass several categories:

My JAKE/My JAKE MMApp, including the ABI, ABI-S, and Daily Tracker, as well as
system components available only in My JAKE (Journal and Event Tracker, Therapy 
Tracker, and Medical/Development History), to be completed periodically as instructed.


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
The ABI-C, to be completed periodically by the PI or delegate as instructed.

The JAKE Sense Continuous Biosensor, with training and manuals to guide appropriate use.

The JAKE Task Battery with the JAKE Sense Periodic Biosensors.

Standard assessment instruments and rating scales for evaluating ASD core and related 
symptoms, functioning, clinicians’ global impressions of disease severity and improvement, 
and caregiver stress.

Caregivers’ and subjects’ global impressions (Caregiver GI-S, Caregiver Assessment of 
Treatment, Self GI-I).
9.2.2.1.
Caregiver Reporting Tool: Modules and Components
My JAKE and My JAKE MMApp are two applications containing the caregiver reporting tool 
that can be used by the caregiver during the study to enter information about the behavior and 
mood of the subjects. Caregivers will register and use either the first application of the reporting 
tool, My JAKE, or the second application of the tool, My JAKE MMApp, dependent upon the 
application which is operational at the time. If neither version is available, caregivers will record 
information on paper forms as described below.
My JAKE encompasses various modules for use by clinicians, caregivers, and the sponsor. My 
JAKE MMApp is for use by caregivers and the sponsor. Both applications are accessible through 
most modern web browsers (“My JAKE Web”), as well as mobile devices (“My JAKE Mobile”). 
My JAKE or My JAKE MMApp is used throughout the study. Specific instructions for certain 
modules are below.
Not all modules described are available for both My JAKE Web and My JAKE Mobile 
interfaces.
Some modules in My JAKE are not available in My JAKE MMApp nor on paper forms. Table 2
provides further information on available modules and features.
Table 2:
Caregiver Reporting Tool: Available Modules and Features
My JAKE
(1st application)
My JAKE MMApp
(2nd application)
Paper Forms
Secondary caregiver reporting a
X
ABI & ABI-S
X
X
X
Daily Tracker
X
X
X
Journal a & Events Tracker
X
Therapy Tracker a
X
Medical/Developmental History
X
Abbreviations: ABI=Autism Behavior Inventory; ABI-S: Autism Behavior Inventory-Short Form
a.
Completion is optional in My JAKE 
The same primary caregiver should complete all components of the caregiver reporting tool and 
standard scales throughout the study. Additional caregivers can complete My JAKE components 
as secondary users.


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It is understood that caregivers of independent, adult subjects may not be able to enter the same 
amount into the caregiver reporting tool as caregivers of subjects who live with them.
Site and institution personnel will not modify, adjust, troubleshoot, change or alter the hardware 
or software of the JAKE System unless instructed to do so by or under the supervision of the 
sponsor.
Caregivers using My JAKE should be instructed not to revoke site or sponsor’s access to My 
JAKE and Microsoft HealthVault without investigator approval to do so.
9.2.2.1.1.
ABI
The ABI is a series of approximately 65 questions related to the core and associated symptoms of 
ASD. Questions are answered on 1 of 2 possible dimensions, quality (how well a person carries 
out a particular behavior) or frequency (how often a particular behavior occurs).
The ABI was developed by review of existing instruments in consultation with experts in the 
field and testing in the target population. The current versions of the ABI, ABI-S, and Autism 
Behavior Inventory-Clinician interview (ABI-C) are a result of a statistical and clinical review 
process, and qualitative review and feedback from users, including cognitive interviewing.
The development of the ABI adhered to the following FDA guidelines, (1) Precise definition of 
the target construct, (2) The need for the new measure and how it will enhance the substantive 
knowledge base, (3) Initial pool of items was submitted to expert review,143 (4) Identification and 
justification for sampling strategy, (5) Used Exploratory Factor Analysis (EFA) to assess the 
underlying factor structure to refine item pool,30 (6) Description of covariance and correlation 
matrix, (7) Use of psychometric techniques during scale refinement that included Item 
Discrimination, Item Difficulty, Correlation if items were deleted, Differential Item Functioning 
(DIF): a Rasch Analysis approach. 
Validation of the ABI began in ASD-001, where in a small sample of around 25 parents and 
20 clinician ratings, good test-retest reliability was found. Correlation between the ABI and 
validated instruments measuring similar domains was also good, and there was divergence 
between scales which were not expected to correlate. Validation, including an assessment of 
sensitivity to change, continued in the ASD-002 study.
The full ABI will be completed by the primary caregiver at screening, Day 1 (predose), Week 4,
Week 8, and Week 12. It should be completed at the site and on the same day as it is begun. 
The ABI-S is a shorter version of the ABI with approximately 20 items. The caregiver will 
complete the ABI-S on Week 2 (site), Week 6 (home), and Week 10 (home) as outlined in the 
Time and Events Schedule.
Following a caregiver interview, the PI or delegate will complete the ABI-C on visits listed in 
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For each subject, the ABI and ABI-S should be completed by the same caregiver, and the ABI-C 
should be completed by the same site personnel, at all administrations.
ABI-C
The ABI-C covers the domains and subdomains of the ABI-S and is intended for completion by 
the clinician following an interview with the caregiver and observation or interview with the 
individual with ASD, as appropriate. The clinician is required to rate the severity of behaviors or 
level of impairment observed or described on a scale of 1 to 7, where 1 indicates no impairment 
of behavior and 7 indicates severe difficulties with an area of functioning. There are 14 items 
across each of the 5 domains. The ABI-C is completed on paper. See Attachment 3 for a 
representative example of this instrument.
9.2.2.1.2.
Daily Tracker
The caregivers are required to select 3 items to track on a daily basis. Following completion of 
the ABI at the screening visit, a clinician at the site will discuss possible items to track with the 
caregivers and help them with their selection. Caregivers will have the opportunity to change the 
behaviors they track at the baseline visit. After this point they are required to track the same 
behaviors for the duration of the study. After 6 pm each day, caregivers are required to report on 
these behaviors, as well as report on subjects’ overall type of day, using an 8-point scale, ranging 
from ‘troubling’ to ‘encouraging’. 
A Mood Report is completed after 6 pm each day. The report allows the caregiver an opportunity 
to report the subject’s state, in terms of valence and arousal levels. It is presented twice, 
requiring caregivers to: 1) report subject’s overall mood for that day and 2) report the subject’s 
most extreme mood for that day.
In addition, each morning the caregiver will be asked to report on how well the subject slept the 
previous night using the same 8-point scale used for behavior ratings.
9.2.2.1.3.
Journal and Event Trackers
This module will:

Allow ad hoc free-text entry by caregivers.

Provide an interface for tracking both events and journal entries (tantrum, stereotypy, social 
interaction, etc.) as they occur. Caregivers will also be able to track progress towards a 
particular target behavior that they have entered.

Keep track of items of interest, including sleep problems, seizures and diet on a daily basis.
Events can be reported on a daily basis throughout the study, either as they occur or at a later 
stage. The clinician at the site will discuss 1 or 2 specific behaviors which the caregiver will aim 
to track using the event trackers. The caregiver will be encouraged to record 3 instances of these 
behaviors, as they happen, each week. Use of the journal will be encouraged but is considered 
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In My JAKE, the Mood Report can be completed at any time through the Events Tracker, in 
addition to reporting within the Daily Tracker. 
9.2.2.1.4.
Therapy Tracker
This module will track the subject’s various medical appointments, treatments, and other 
therapies. It can also be used to set up and schedule study visits with the parent or caregiver. Use 
of the therapy tracker will be encouraged but is considered optional.
9.2.2.1.5.
Medical/Developmental History
This module is to be filled out by caregivers (with assistance, if needed) during the 
screening/on-boarding phase of the study. Certain sections, such as the developmental milestones 
may continue to be edited throughout the study.
If the Medical/Development History section is not completed by the caregiver, the site is 
responsible for ensuring completion of required fields in My JAKE.
9.2.2.2.
JAKE Sense
Biosensors will be evaluated and used as per the Time and Events Schedules and descriptions 
below.
9.2.2.2.1.
Continuous Biosensor
Continuous Biosensors can be worn over extended periods of time such as throughout the day or 
during sleep. The Continuous Biosensor will also be worn and assessed during study visits as 
with the Periodic Biosensors below. Description of the Continuous Biosensor and its use in this 
study is provided below.
The Continuous Biosensor is the ActiGraph GT9X Link Wristband. The ActiGraph Link is a 
wireless wristband biosensor that measures activity. This sensor should be worn continuously 
except when necessary to remove it for charging or other reasons.
The subject will be required to wear the Continuous Biosensor during every site visit so that data 
can be collected afterwards by study site personnel. 
ActiGraph Link is a recognized medical device in the United States - 510(k) number K040554 
Code: GWQ. While this device is being used in compliance with its intended use, it is not being 
used in such a way as to diagnose, treat, or prevent any disease, nor is its output being used in (or 
in support of) any regulatory filing (now or in the future).
9.2.2.2.2.
Periodic Biosensors
Periodic Biosensors will only be worn or used for a discrete period of assessment at a study visit. 
As opposed to the Continuous Biosensors, which will also be worn during normal daily 
activities, Periodic Biosensors will be assessed during the time that the subject is exposed to 
specific visual and auditory tasks or stimuli via a computer interface (the JAKE Task Battery; 


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see more complete description below). Periodic Biosensors and their description and use in the 
study are described below.
9.2.2.2.2.1.
Electroencephalogram (Brain Products ActiCHamp 32)

24-bit battery-supplied, active channel amplifier using the actiCAP active electrodes 

available with 32, 64, 96, 128 and 160 EEG channels

Intended 19 channels for measurement: Fp1, Fp2, F3, F4, F7, F8, Fz, C3, C4, Cz, T7, 
T8, P3, P4, P7, P8, Pz, O1, O2; reference electrode position on left mastoid bone

8 integrated AUX inputs can be used with a full range of biosignal sensors 
(eg, electrooculogram [EOG], electromyogram [EMG], ECG, respiration, acceleration, 
temperature, blood pulse, photo sensor, microphone, etc.)

A photo sensor will be connected to the first AUX input to detect visual stimuli changes 
(onset and duration)

high sampling rate (up to 100 KHz) and wide hardware bandwidth

simple plug and play concept to easily increase the number of channels (by adding modules
of 32 channels)
9.2.2.2.2.2.
Actiwave Cardio Single-Channel ECG
Heart rate data will be collected using the Actiwave Cardio Single-Channel Electrocardiogram 
(patch); (http://www.camntech.com/products/actiwave-cardio/actiwave-cardio-overview).
The 
Actiwave Cardio is a water-resistant ultra-miniature single channel ECG waveform recorder. It 
consists of 2 electrodes connected by a short lead which simply clip onto 2 standard ECG pads 
worn on the chest. It also contains a tri-axial accelerometer, the signal from which allows the 
user to determine resting body position. Adhesive, disposable electrodes are applied to the 
subject’s chest – the device is then clipped to the electrodes.
The Actiwave Cardio is a recognized medical device in the United States - 510(k) number 
K100266 Code: MWJ. While this device is being used in compliance with its intended use, it is 
not being used in such a way as to diagnose, treat, or prevent any disease, nor is its output being 
used in (or in support of) any regulatory filing (now or in the future).
NOTE: The Actiwave Cardio is used only for JAKE Sense Periodic Biosensor evaluation and is 
different from the 12-lead ECG used for drug safety assessments.
9.2.2.2.2.3.
Eye Tracker (Tobii X2-30)
The
Tobii X2-30 features include the following (http://www.tobii.com/de/eye-tracking-
research/global/products/hardware/tobii-x2-30-eye-tracker/): 
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9.2.2.2.2.4.
iMotions Biometric Research Platform: Emotient FACET 
Module
iMotions® Biometric Research Platform: Emotient™FACET Module (https://imotions.com/blog/
facial-expression-analysis/) will be used for affect detection via computer recognition of subject 
affect. Facial recognition will take place throughout the administration of the JAKE Task Battery
using a standard computer web camera.
In addition, 5 minutes of video intended to elicit facial expressions (e.g., ‘funny animals’) will be 
shown during the Task Battery. Subjects will also be asked to make faces to reflect core 
emotions: Happy, Sad, Surprise, Scared, Angry, Yucky (disgust).
9.2.2.3.
JAKE Task Battery: Tasks and Stimuli for use With Periodic 
Biosensors
Tasks and stimuli (the JAKE Task Battery) for use with Periodic Biosensors will comprise a 
battery of tests approximately 30 minutes in duration. All stimuli are presented using the 
software application platform iMotions® Biometric Research Platform (formerly known as 
Attention Tool). Subjects will use all Periodic Biosensors throughout all components of the Task 
Battery, though certain components are focused on specific sensors as indicated by the section 
headers. A subset of these sensors will interface directly with iMotions® Biometric Research 
Platform, while others will use their own proprietary software to operate. 
Additionally, subjects will continue wearing the Continuous Biosensor during administration of 
the Task Battery. Tasks and stimuli will be presented on a computer monitor and may require 
interaction as described below. The tasks are presented in 2 sets of approximately 13 minutes. 
Breaks are permitted between sets and as necessary within a set (though this is discouraged). 
Devices should continue to be worn during all breaks.
Images/video within a task will be counterbalanced for order between subjects.
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9.2.2.4.
Caregiver Reporting Tool: Data Processing 
The JAKE Data Pipeline is an internal set of tools designed specifically to handle data that is 
entered through My JAKE. While My JAKE will have access to all data contained within a 
subject’s Microsoft HealthVault account, only a subset of this information is collected and 
archived by the sponsor through the My JAKE Data Pipeline. 
My JAKE MMApp Data Processing incorporates an integrated set of tools designed specifically 
to handle data that is entered through My JAKE MMApp. The sponsor will have full access to all 
information entered through My JAKE MMApp. 
The sponsor will use the information collected through the My JAKE Data Pipeline and My 
JAKE MMApp to track study progress and outcomes and perform related study analysis. This 
information may contain limited personal “identifiers.” The information collected and archived 
may be shared with other members of the Johnson & Johnson family of companies, its 
contractors and consultants, and regulatory authorities such as FDA.
To ensure that access to protected health information (PHI) stored in Microsoft HealthVault is 
limited, high risk fields are filtered out during the My JAKE Data Pipeline data collection 
procedure. These fields include (but are not limited to) names, phone-numbers, street and email 
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addresses, dates (related to appointments or medical care), and descriptive free-text fields 
(journal entries, event descriptions). 
High-risk personally-identifiable fields required by My JAKE MMApp (such email address, 
dependent’s first name, etc.) are excluded from final study datasets.
9.2.2.5.
JAKE Sense Data Pipeline
The JAKE Sense Data Pipeline is an internal set of tools designed specifically to handle data 
collected by JAKE Sense. First, packages are archived to ensure traceability of derived analyses. 
Second, a series of utilities scans the packages to produce a series of extracted features in the 
form of flat .CSV-formatted files. Finally, the files are stored in a secured server file share (and 
combined with outputs from the My JAKE Data Pipeline) for the purpose of exploratory, POC
data mining.
The information collected and archived via the JAKE Sense Data Pipeline is subject to the same 
treatment and sharing policies as data collected and archived via the My JAKE Data Pipeline.
9.2.2.6.
Standard Instruments and Scales
The diagnosis of ASD will also be established or confirmed via standard instruments and scales. 
Subjects will be required to have a formal DSM-5 diagnosis of ASD using the ADOS-2. An 
ADOS-2 completed within 24 months prior to the screening visit is acceptable but the item 
responses must be available for entry into the study eCRF. Assessments will follow the Time and 
Events Schedule. All caregiver rating scales should be completed by the primary caregiver.
Preferably the same person should complete the scales throughout the study.
9.2.2.6.1.
Autism Diagnostic Observation Schedule™, Second Edition
The ADOS-2 is a validated scale that allows a reliable diagnosis of ASD across age, 
developmental level, and language skills. One of the 4 ADOS-2 modules should be selected 
according to the publisher’s manual. Module 4 should be scored according to the algorithm 
published in Hus et al, 2014.53
See Attachment 4 for a representative example of this instrument.
9.2.2.6.2.
Kaufman Brief Intelligence Test, Second Edition
The KBIT-2 is a 10-item questionnaire used to obtain a quick estimate of intelligence at 
screening in order both to help select subjects capable of performing the required tasks and for 
analysis of data. Three composite standard scores are calculated from the questionnaire.
See Attachment 5 for a representative example of this instrument.
9.2.2.6.3.
Zarit Burden Interview
The ZBI – short version is a scale of 22 items designed to assess the psychological burden 
experienced by a caregiver. Items ask how the caregiver feels and responses range from 0-4
(never to nearly always).


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See Attachment 6 for a representative example of this instrument.
9.2.2.6.4.
Social Responsiveness Scale 2™
The SRS-2 distinguishes autism spectrum conditions from other child psychiatric conditions by 
identifying the presence and extent of autistic social impairment. There are 5 subscales, 65 items. 
The SRS-2 comes in 3 versions- for preschool, school age, and adult. The PI will choose whether 
the school age or adult version is most appropriate for each subject using the instructions in the 
SRS-2 manuals.
See Attachment 7 for a representative example of this instrument.
9.2.2.6.5.
Child Adolescent Symptom Inventory Anxiety 
The CASI-Anx assesses symptoms of the following disorders: attention deficit hyperactivity 
disorder, oppositional defiant disorder, conduct disorder, generalized anxiety disorder, social 
phobia, separation anxiety disorder, disruptive mood dysregulation disorder, major depressive 
episode, manic episode, dysthymic disorder, schizophrenia, autistic/Asperger’s disorder, 
anorexia, and bulimia. One or 2 key symptoms of each of the following disorders are also 
included: obsessive-compulsive disorder, posttraumatic stress disorder, specific phobia, panic 
attack, motor tics, vocal tics, and substance use.
The Total Scale includes 173 items for parent version (teacher: 125).
This study will use only the 21-point anxiety scale (CASI-Anx) which was recommended as a 
possible outcome measure for autism.64 Responses will range from 0 (never) to 3 (very often).
See Attachment 8 for a representative example of this instrument.
9.2.2.6.6.
Repetitive Behavior Scale-Revised (parent)
The RBS-R is a 43-item report scale to indicate occurrence of repetitive behaviors and degree to 
which a behavior is a problem on a range between 0 (behavior does not occur) and 3 (behavior is 
a severe problem).
See Attachment 9 for a representative example of this instrument.
9.2.2.6.7.
Aberrant Behavior Checklist-Community
The ABC is a 58-item behavior rating scale used to measure behavior problems across 
5 subscales Irritability, Lethargy (Social Withdrawal), Stereotypy, Hyperactivity, Inappropriate 
Speech. Items are rated on a 4-point Likert scale (ranging from 0 [not at all a problem] to 
3 [the problem is severe in degree]), with higher scores indicating more severe problems.
See Attachment 10 for a representative example of this instrument.
9.2.2.6.8.
Clinical Global Impression-Severity and Improvement
The CGI-S scale assesses the severity of all illness. The CGI-S is a 7-point scale that requires the 
clinician to assess the severity of the subject’s illness at baseline and other visits. The CGI-I is a 


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single-item instrument that requires the clinician to assess the degree of improvement in the 
subject from the initiation of treatment using a 7-point scale. The time points for these 
assessments are included in the Time and Events Schedule.
See Attachment 11 for a representative example of each of these instruments. 
9.2.2.6.9.
Caregiver Global Impression of Severity
The Caregiver GI-S is a single-item instrument that asks caregivers to rate their overall 
impression of the severity of their child’s ASD symptoms at baseline and per the Time and 
Events Schedule. 
9.2.2.6.10.
Caregiver Assessment of Treatment
The Caregiver Assessment of Treatment is a 3-item questionnaire completed at the end of the 
treatment period. Caregivers rate their global impression of improvement in their child’s autism, 
whether there was improvement in specific symptoms, and their interest in having their child
continue the study medication.
See Attachment 14 for a representative example of this questionnaire.  
9.2.2.6.11.
Self-Assessment of Improvement
The subject will be asked to give his/her impression of overall improvement in ASD symptoms 
using a single-item instrument, the Self GI-I.
9.2.2.6.12.
Evaluation of JAKE
At the end of the treatment period caregivers will provide feedback on their experience with the 
JAKE system using a questionnaire. This is not a part of the evaluation of treatment, but may 
provide useful feedback for future use of the JAKE system. 
9.2.2.7.
JAKE Help/Manuals
JAKE will include robust help for sites and caregivers for all components of the system. My 
JAKE will display only the appropriate content to the logged in account (ie, help sections 
intended for site personnel are not accessible to subjects or caregivers). The help system will 
contain (but is not limited to) general information, troubleshooting steps, and instructional guides 
in the form of quick reference guides, training videos, or checklists for each JAKE System 
component. My JAKE MMApp will contain a reduced set of checklists appropriate for the 
caregiver. Study sites are expected to be proficient in using the help system and following all of 
the steps outlined in the instructional guides prior to enrolling subjects. Training will be 
conducted on the use of the help system, instructional guides, and their related components.
A hardcopy of the JAKE manual will be provided to clinical sites, and will be available online in 
My JAKE. Caregivers will be given a hardcopy of a Caregiver Guide, which will also be 
available online in both My JAKE and My JAKE MMApp. These documents and / or applicable 


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help sections may be updated during the trial. Any updates will be proactively communicated to 
sites. An interactive, site-only, on-line version of the full help manual will be available.
There will also be a toll-free helpline available for sites and caregivers. Callers will be instructed 
not to provide their name, call-back numbers, or any other identifiable information to protect 
subject and caregiver identity. The toll-free helpline is operated by employees and contractors of
the sponsor.
9.2.2.8.
National Database for Autism Research/Global Unique ID
Subjects will participate in NDAR data sharing. Prior to their first subject each PI must apply to 
NDAR (to obtain access to the GUID creation tool). During screening, the site will generate a 
GUID for each subject using PHI such as name, place of birth and date of birth. PHI is 18 classes 
of information defined by US law and regulation that can be used to identify an individual. The 
storage and transmittal of PHI is restricted by US regulation. This PHI does not leave the site and 
is not transmitted to the sponsor or to National Institutes of Health (NIH). The GUID cannot be 
used to recreate the PHI. The site will enter the GUID into the sponsor’s eCRF system.
There are 2 components to NDAR.
1. The sponsor may use the GUID to access data held by NDAR on individual subjects that has 
been shared with NDAR from other research projects and studies. Such data will be 
de-identified and will only be held in NDAR if the subject or legally appointed representative 
had granted consent in an Institutional Review Board (IRB) approved study for it to be sent 
to NDAR and shared with other researchers
2. Data from this study may be submitted to the NDAR using the GUID. NDAR is a computer 
system run by the National Institutes of Health that allows researchers studying autism to 
collect and share information with each other. With an easier way to share, researchers hope 
to learn new and important things about autism more quickly than before. 
Data obtained from and shared with NDAR will be that of subjects in this study. The sponsor 
will be able to obtain additional data on subjects in this study from NDAR and potentially use 
that data to learn more about autism and improve the JAKE System.
During and after the study, the sponsor may send information about subject’s health and 
behavior and any other data gathered in this study to NDAR. All data sent to NDAR will be 
provided through the JAKE Sense Data Pipeline and first de-identified in compliance with 
45 CFR 164.514(b)(1). Only the NDAR GUID will link data from different sources to unique 
subjects. Researchers nationwide can then file an application with the NIH to obtain access to 
study data for research purposes. Experts at the NIH with expertise in the protection of health 
and science information will review every request carefully to minimize risks to subjects’ 
privacy.
9.3.
Biomarker Evaluations
During the study, the following PD evaluations will be performed at the time points indicated in 
the Time and Events schedule: plasma concentrations of 
.
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Additionally, blood biomarkers related to autism (including but not limited to cytokines and 
miRNAs) will be investigated to allow for exploratory immunophenotyping and for an
exploratory PD evaluation. Biomarkers may be added or deleted based on scientific information 
or technical innovations under the condition that the total volume of blood collected will not be 
increased.
The biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between ASD and phenotypes and biomarkers.
For visits that include biomarker sample collection, subjects should be advised to follow a 
low-fat diet for at least 8 hours prior to their scheduled visit. Subjects should be advised to 
refrain from strenuous exercise and use of NSAID medications for 24 hours before their 
scheduled visit. This is because the use of NSAIDs may impact biomarker measurements, 
specifically via altering circulating and inducible cytokine levels. In addition, NSAIDs also have 
been reported to inhibit FAAH directly so there is a particular need in FAAH studies to restrict 
their use. Information regarding compliance with these restrictions should be recorded on the 
CRF or lab requisition form.
9.4.
Pharmacokinetics
9.4.1.
Evaluations 
Venous blood samples for analysis of JNJ-42165279 in plasma will be collected at the 
time points indicated in the Time and Events Schedule. 
Blood samples will be used to evaluate the plasma PK of JNJ-42165279. Samples collected for 
analyses of JNJ-42165279 plasma concentration may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study period or for the 
evaluation of relevant biomarkers. Genetic analyses will not be performed on these plasma 
samples. Subject confidentiality will be maintained.
The date and time of study drug administration in the clinic on Day 1, Week 2 and Week 12 
visits, and the day prior to the Week 2 and 12 visits (both morning and evening doses) must be 
accurately recorded. Subjects will be instructed to take the dose of study drug at the Week 2 and 
12 visits at the clinical site after collection of the first PK blood sample on those days.
9.4.2.
Analytical Procedures
Plasma will be analyzed to determine concentrations of JNJ-42165279 using a validated, 
specific, and sensitive liquid chromatography-tandem mass spectrometry method by or under the 
supervision of the sponsor. 
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. In addition, plasma samples may be stored for 
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9.4.3.
Pharmacokinetic Parameters
The oral clearance and apparent distribution volume of JNJ-42165279 are assumed to be 
logarithmically distributed. The intersubject variabilities (expressed as percent coefficient of 
variation) of these parameters are 35.9% and 18.1%, respectively, based on previously conducted
population analyses that used pooled PK data from studies with JNJ-42165279 in adults. 
Assuming a similar PK variability (ie, 35.9%) for subjects who are 13 to 18 years of age and a 
sample size of 15 subjects, the probability that the 95% confidence interval for the geometric 
mean of each PK parameter will fall within 71% to 140% of the true geometric mean is 80%.
The plasma concentration-time data of JNJ-42165279 will be analyzed using population PK 
modeling. Typical population values of basic PK parameters (eg, apparent clearance, apparent 
distribution volume) will be estimated together with the inter-individual variability. Effects of 
subject demographics, laboratory parameter values, and other covariates on the PK of 
JNJ-42165279 will be explored. The results of the population PK analyses may be reported 
separately.
9.5.
Pharmacogenomic (DNA) Evaluations
A pharmacogenomic blood sample will be collected from all eligible subjects. Deoxyribonucleic 
acid (DNA) samples will be analyzed for FAAH gene variants. Additional analyses may be 
conducted if it is hypothesized that this may help resolve issues with the clinical data. DNA
samples may also be used for the identification of genetic and/or epigenetic factors that may 
influence the PK, PD, efficacy, safety and/or tolerability of JNJ-42165279, and for exploratory 
genetic and/or epigenetic analyses, including of autism.
DNA samples will be used for research related to JNJ-42165279 or ASD. They may also be used 
to develop tests/assays related to JNJ-42165279 or ASD. Pharmacogenomic research may consist 
of the analysis of 1 or more candidate genes or of the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate) in relation to JNJ-42165279 or ASD 
clinical endpoints.
The pharmacogenomics data obtained from this study may also be included in an ongoing 
cross-study analysis to investigate the relationship between ASD and phenotypes and 
biomarkers.
9.6.
Safety Evaluations
During the study, regular safety assessments will be performed as listed in the Time and Events 
Schedule. These safety assessments include but are not limited to: vital signs, electrocardiogram 
(ECG), physical examination, adverse events, Columbia Suicide Severity Rating Scale 
(C-SSRS), Aberrant Behavior Checklist-Irritability Subscale (ABC-I), and clinical laboratory 
tests. 
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the case report form (CRF).


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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.
9.6.1.
Adverse Events
Adverse events will be reported by the subject (or when appropriate, by a caregiver, surrogate, or 
the subject's legally-acceptable representative) from the time informed consent is signed until 
completion of the subject’s last study-related procedure. Adverse events will be followed by the 
investigator as specified in Section 12, Adverse Event Reporting.
9.6.2.
Suicidality Evaluation
The C-SSRS and/or the ABC-I will be used in the evaluation of suicidality, as indicated below:

At screening, the investigator will determine if evaluation of suicidality using the C-SSRS is 
feasible for each subject. 

If feasible, both the C-SSRS and ABC-I should be performed at screening. 

If the investigator determines that the C-SSRS is not feasible at screening, only the ABC-I 
will be used at screening and throughout the study. 

If both were used at screening, then both should continue to be used throughout the study 
unless the investigator determines that it is no longer feasible to use the C-SSRS; in this
case, the ABC-I should be used alone for the remainder of the trial. 

The irritability subscale of the ABC (ie, ABC-I) will be collected at every visit except the 
second screening visit, either as part of the full ABC or alone. This is irrespective of whether 
the C-SSRS is performed.

Note: The full ABC includes the ABC-I subscale. Thus, administration of the ABC-I 
subscale alone is only needed when the full ABC is not performed.
The results of the C-SSRS and ABC-I should be reviewed by the investigator at each visit 
collected prior to the subject’s departure. If a suicide-related thought or behavior is identified at 
any time or if there are any other concerning findings or changes, a thorough evaluation will be 
performed by a study physician, and appropriate medical care will be provided.
9.6.2.1.
Columbia Suicide Severity Rating Scale
Consistent with regulatory guidance, any occurrence of suicide-related thoughts and behaviors 
will be assessed. An interview to assess the risk of suicidal ideation and behavior will be 
conducted at the time points listed in the Time and Events Schedule. 
The C-SSRS is a measure of the spectrum of suicidal ideation and behavior that was developed 
in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to 
assess severity and track suicidal events through any treatment.97 The C-SSRS is a clinical 
interview providing a summary of both ideation and behavior that can be administered during 
any evaluation or risk assessment to identify the occurrence and intensity of suicidal thoughts 
and suicidal behaviors. It can also be used during treatment to monitor for clinical worsening. 


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Both pediatric and adult versions of the C-SSRS are available and the investigator should use the 
appropriate version per C-SSRS instructions and training.
The Baseline/Screening version of the C-SSRS will be used at screening and the Since the Last 
Visit version will be used at all other visits.
See Attachment 12
and
Attachment 13
for representative examples of the C-SSRS 
(Baseline/Screening) and C-SSRS (Since Last Visit), respectively.
9.6.2.2.
Aberrant Behavior Checklist - Irritability Subscale
The ABC-I is a subscale of the ABC (described in Section 9.2.2.6.7) focusing on irritability, 
aggression and self-injurious behavior. As the C-SSRS may not be appropriate for all subjects in 
this study, the ABC-I may be used as a substitute as per instructions in Section 9.6.2, Suicidality 
Evaluation.
9.6.3.
Vital Signs
Sitting vital signs (body temperature, pulse/HR, blood pressure) will be collected at the time 
points indicated in the Time and Events Schedule.
9.6.4.
Electrocardiogram
Twelve-lead ECGs will be collected at the time points listed in the Time and Events Schedule.12
At all time points, triplicate ECGs are required. The individual ECG tracings should be obtained 
as closely as possible in succession, but no more than 2 minutes apart. The full set of triplicates 
should be completed in less than 4 minutes. It should be noted that the single-lead ECG used 
during the JAKE Task Battery is not used as a substitute for the 12-lead recorder.
During the study, the clinical investigator will review the ECG for immediate management and 
to mark abnormalities. A description of the overall assessment (ie, normal or abnormal plus 
reason) will be made and a copy of the trace will be placed with the source data. 
9.6.5.
Physical and Neurological Examination 
The study investigator or other authorized and appropriately qualified designee will perform the 
physical examination at screening, Week 12, and at final follow up.
Height will be measured at screening only. Body weight will be measured at screening, Day 1, 
and at other times as specified in the Time and Events schedule.
The neurological examination can be adapted as necessary but at screening should include 
mental status (orientation and memory); oculomotor motion and vision for cranial nerve testing; 
limb strength and abnormal movements for motor function; and tests of cerebellar function: gait, 
finger-to-nose, heel-to-shin, and rapid alternating movements. Tests of sensation (eg, pain, 
vibration, etc) should be included only if indicated by clinical history/symptoms. Neurological 
examinations subsequent to screening may be more abbreviated and directed for follow up of 
abnormalities.


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9.6.6.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis 
will be collected. The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the adverse event section of 
the CRF. The laboratory reports must be filed with the source documents. The following tests 
will be performed at a central laboratory appointed by the sponsor:

Hematology Panel 
-hemoglobin
- platelet count
-hematocrit
- mean corpuscular volume
- red blood cell (RBC) count
- mean corpuscular hemoglobin
- white blood cell (WBC) count with differential
- mean corpuscular hemoglobin 
concentration

Coagulation
-prothrombin time
- International normalized ratio (INR)
-activated partial thromboplastin time (aPPT)

Serum Chemistry Panel 

Urinalysis 
Dipstick
Flow Cytometry
-specific gravity
-RBC
-pH
-WBC
-glucose
-epithelial cells
-protein
-blood
-ketones
Sediment 
-bilirubin
-crystals
-urobilinogen
-casts
-nitrite
-bacteria
-leukocyte esterase
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
- phosphate
-glucose
-albumin
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)
-total and direct bilirubin
-magnesium


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Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen will be 
determined using a dipstick. RBC, WBC, epithelial cells, crystals, casts, and bacteria will be 
measured using flow cytometry. If there is discordance between the dipstick results and the flow 
cytometric results, the sediment will be examined microscopically.

Urine Drug Screen: opiates (including methadone), cocaine, amphetamines, cannabinoids, 
barbiturates, benzodiazepines, phencyclidine, and MDMA. 

Serology (HBsAg, anti-HCV, HIV, and thyroid-stimulating hormone [TSH]).

Pregnancy tests: 

In all women, a serum β-hCG will be performed at screening. 

In WOCBP; a urine pregnancy test will be performed at all other timepoints beginning 
on Day 1. 

If the urine pregnancy test is positive, a serum β-hCG test will be performed.
The use of local laboratories is allowed in cases where initiation of treatment or safety follow up 
is time-critical and the central laboratory results are not expected to be available before the need 
to begin dosing or if actions need to be taken for safety reasons (samples will be taken in parallel 
for the central laboratory).
10.
SUBJECT COMPLETION / WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed the ABI at 
Week 12 (Day 85) of the double-blind phase. Subjects who prematurely discontinue study 
treatment for any reason before completion of the double-blind phase will not be considered to 
have completed the study.
10.2.
Discontinuation of Study Treatment and Withdrawal from Study
A subject's study treatment should be discontinued and the subject withdrawn from the study if:

The blind is broken at the site

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

A subject experiences a severe adverse event or SAE while receiving treatment, that is 
considered at least possibly related to study drug, after discussion with and agreement of the 
medical monitor

Liver function test criteria (any of following):

ALT or AST >5xULN 

ALT or AST >3xULN and (Total Bilirubin Level [TBL] >2xULN or INR >1.5) 

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 


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
Noncompliance with study drug (ie, less than 80% compliance) during the blinded treatment 
phase

Serious violation of protocol procedures after discussion with and agreement of the medical 
monitor

A subject becomes pregnant

Lost to follow up

Withdrawal of consent
If a subject is lost to follow up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study before the end of the double-blind treatment phase, ET/EW 
and posttreatment follow up assessments should be obtained.
If the decision to discontinue treatment or withdraw from the study is made at a study visit, that 
visit may be converted into the EW visit. The follow up visit should take place afterwards as per 
the Time and Events Schedule.
If the decision to discontinue treatment or withdraw from the study is made in-between study 
visits, the subject should return to the site as soon as possible for an EW visit. The follow up visit 
should take place afterwards as per the Time and Events Schedule.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the ICF.
11.
STATISTICAL METHODS
Statistical analyses will be conducted by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy, safety, 
tolerability, PD and PK data is outlined below. Specific details will be provided in the Statistical 
Analysis Plan (SAP).
11.1.
Subject Information
The primary efficacy and safety analysis sets are defined below.

Intent-to-treat (ITT-BID): all subjects enrolled under BID dosing who receive at least 1 dose 
of study medication and have both a baseline and a postdose efficacy evaluation.


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
Safety: all randomized subjects who receive at least 1 dose of study medication
11.2.
Sample Size Determination
The sample size for the study is based on all subjects who are enrolled under BID dosing. The 
assumption used in the determination of sample size was a treatment effect size of 0.63 for the 
difference between the JNJ-42165279 treatment group and placebo, calculated as the mean 
change in the primary endpoints from baseline to Day 85. To detect the treatment effect size of 
0.63 in any of the primary endpoints with a power of 90% at an overall 1-sided significance level 
of 0.10, 25 subjects in each group are required. When adjusted for a drop-out rate of 
approximately 15% of subjects, this will require 60 subjects (under BID dosing) to be randomly 
assigned to treatment in a 1:1 ratio (30 per group).
The treatment difference effect size is based on results of a previous meta-analysis  showing that
applied behavior analytic intervention leads to medium-to-large effects on a variety of scales for 
children with autism.136 Additionally, previous studies of selective serotonin reuptake inhibitors 
(SSRIs), antipsychotics and antiepileptic drugs (AEDs) were reviewed. The sample size 
calculation is based on simulated multivariate normal data with the additional assumption that 
there is a correlation of 0.75 between the ABI Social Communication and RRB domains and 
0.90 between each of the domains and the ABI Core Domain Score.
11.3.
Efficacy Analysis
11.3.1.
Primary Efficacy Endpoints
The primary efficacy analysis will be based on the ITT-BID analysis set. The primary efficacy 
endpoints are the changes from baseline to Day 85 in the ABI Core Domain Score, ABI Social 
Communication Domain Score, and ABI RRB Domain Score during the double-blind treatment 
phase. Each will be analyzed using a mixed effects model for repeated measures (MMRM). The 
model will include time, treatment, time-by-treatment interaction, age group (13-17 years and 
18-35 years, inclusive), and gender (male and female) as factors, and baseline score as a 
continuous covariate. An unstructured variance-covariance matrix will be used. In case of 
convergence problems, simpler variance-covariance structures such as Toeplitz or autoregressive
order 1 (AR[1]) will be considered.
The study will be deemed positive if any of the primary efficacy endpoints are statistically 
superior to placebo using a 1-sided 0.10 significance level.
Additional sensitivity analyses for the primary efficacy endpoints may be specified in the SAP.
Descriptive statistics for values and changes from baseline will be provided by treatment group 
at each time point during the double-blind phase. Descriptive statistics of the primary efficacy 
endpoints may be provided by subgroups; this will be specified in the SAP.


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11.3.2.
Secondary Efficacy Endpoints
Descriptive statistics for values and changes from baseline (where applicable) will be provided 
for all secondary efficacy measures by treatment group at each time point during the 
double-blind phase.
For the secondary efficacy endpoints, comparisons between JNJ-42165279 and placebo will be 
performed by means of an MMRM model as described for the primary efficacy endpoints.
Relationships between select biosensors and scales will be measured with the appropriate
correlation analyses. These relationships will be further defined in the SAP.
Descriptive statistics of actual values and changes from baseline (where applicable) by treatment 
group at each time point during the double-blind phase will be provided for key biosensor 
measures and standard scales.
11.4.
Biomarker and Pharmacogenomic Analysis
Baseline biomarker values (collected during screening) and changes from baseline to the time 
points specified in the Time and Events Schedule will be assessed. Biomarker values will be 
tabulated by treatment group over time points and summary statistics will be calculated. 
Associations between biomarkers and clinical endpoints will be explored. Correlations between 
values with efficacy and other clinical evaluations will be assessed.
Pharmacogenomic analyses may include candidate gene analyses or genome-wide association
analyses in relation to treatment response.
Results from biomarker and/or pharmacogenomic analyses may be presented in a separate report.
11.5.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis
An interim analysis will be conducted to evaluate the concentrations of JNJ-42165279 in plasma 
of adolescent subjects. The analysis would be performed after approximately 16 adolescent 
subjects (ie, 8 adolescent subjects randomized to active drug) have been randomized and 
participated in the PK sampling at the Week 2 visit. A procedure will be developed that 
maintains the double-blind. The interim analysis is intended to confirm that the observed JNJ-
42165279 mean concentrations in adolescent subjects fall below the upper limit of the 95% 
prediction intervals of mean JNJ-42165279 concentrations at corresponding time points 
predicted using allometric scaling.
The individual plasma JNJ-42165279 concentration-time values will be listed and summarized 
descriptively.
A population PK modeling of plasma concentrations of JNJ-42165279 will be undertaken, if 
warranted at the time of the interim analysis and after completion of the study.
CCI


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Where appropriate, the relationship between plasma concentrations of JNJ-42165279 and 
corresponding plasma concentrations of 
 will be plotted to evaluate the relationships 
graphically.
Population PK/PD analysis of biomarkers and/or efficacy markers may also be performed, and a 
suitable dose- and/or exposure-response model may be developed. If necessary or relevant for 
the analysis, Phase 1 data may be integrated to inform the model structure or key parameter 
values.
Details of the PK/PD analyses, if conducted, will be described in an analysis plan and results 
may be provided in a separate report.
11.6.
Safety Analysis
All randomized subjects who receive at least 1 dose of study medication will be included in the 
safety analysis set.
Adverse Events
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). All reported adverse events with onset during the double-blind treatment 
phase (ie, treatment-emergent adverse events [TEAEs], and adverse events that have worsened 
since baseline) will be included in the analysis. For each TEAE, the percentage of subjects who 
experience at least 1 occurrence of the given event will be summarized by treatment group and 
dose level. Serious adverse events will be summarized separately.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who withdraw due to an adverse event, or who experience a severe adverse 
event or a SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Markedly abnormal results 
(specified in the SAP) will be used in the summary of laboratory data. Descriptive statistics will 
be calculated for each laboratory analyte at baseline, and for observed values and changes from 
baseline at each scheduled time point.  
The number and percentage of subjects experiencing a laboratory result below or above
markedly abnormal ranges will be provided for each laboratory analyte by treatment group and 
dose level. 
Listings of subjects with any laboratory result outside the markedly abnormal ranges will be 
provided.
12-Lead ECG
Heart rate and ECG intervals (RR, PR, QRS and QT) as well as corrected QT intervals according 
to Fridericia’s formula (QTcF) from the 12-lead ECG will be summarized at baseline and at each 
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scheduled time point and for changes from baseline using descriptive statistics. Subjects with 
abnormal findings in ECG will be listed.
The number and percentage of subjects with QTcF value >450 msec (males only), >470 msec 
(females only), >480 msec (all subjects), or >500 msec (all subjects) will be summarized by 
treatment group, as will the number and percentage of subjects with a change from baseline in 
QTcF >30 or >60 msec.
Data listings of subjects with any potentially clinically important values (QTcF value >450
[males only], >470 [females only], >480, or >500 msec), or with a change from baseline in QTcF
>30 or >60 msec, will be provided.
Vital Signs
Descriptive statistics of pulse, blood pressure (systolic and diastolic), temperature, and body 
weight 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 provided.
Columbia Suicide Severity Rating Scale
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment 
group in incidence tables.
Aberrant Behavior Checklist-Irritability Subscale
Irritability, aggression, and self-injurious behavior based on the ABC-I will be summarized 
descriptively at each scheduled visit by treatment group.
11.7.
Data Monitoring Committee
An internal DMC, with 1 external expert, will be established to monitor data to ensure the 
continuing safety of the subjects enrolled in this study. The committee will meet at least once to 
review interim data. After the review, the DMC will make recommendations regarding the safety 
and continuation of the study. The details will be provided in a separate DMC charter.
The DMC will consist of at least 1 medical expert in the relevant therapeutic area and at least 
1 statistician. The DMC responsibilities, authorities, and procedures will be documented in its 
charter.
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 
(SOPs) 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 
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Participants should be aware that the comments, journal entries, and other information they may 
enter through My JAKE/My JAKE MMApp, or Microsoft HealthVault are not being actively 
reviewed for clinical purposes. Participants must inform the site immediately of any medical or 
psychiatric issues.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Unanticipated Study Device Effects (USDE) – UNITED STATES 
A USDE is defined as “A serious study effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
study brochure (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety or welfare of patients” 
(21 CFR 812.3[s]).
Unanticipated study device effects are considered a subset of SAEs in this study.
All study device effects will be collected per the same procedures as AEs.
Serious Adverse Event
A SAE 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.)


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
Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
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 JNJ-42165279, 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 Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.


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Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

For this study, safety events of interest/adverse events of special interest include diplopia, 
vision impairment, gait disturbance, and severe headache. These events will trigger a 
neurological examination and a narrative by the investigator.
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the SAE page of the CRF.


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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 30 days after the last 
dose of study drug, must be reported using the SAE Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All other events that meet the definition of a SAE will be reported as SAEs, regardless of 
whether they are protocol-specific assessments. Anticipated events will be recorded and reported 
as described in Attachment 15.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the intervention caused a 
serious anticipated event, they will submit a safety report in narrative format to the investigators 
(and the head of the investigational institute where required). The sponsor assumes responsibility 
for appropriate reporting of anticipated events to the regulatory authorities according to 
requirements of the countries in which the studies are conducted. The investigator (or sponsor 
where required) must report SUSARs to the appropriate Independent Ethics Committee
(IEC)/IRB that approved the protocol unless otherwise required and documented by the 
IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded. Participating 
investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number


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
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 SAEs 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 SAEs will be transmitted to the sponsor using the SAE 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 SAE should be made by facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE. 
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 SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered SAEs. Any adverse event that results in a prolongation of the originally 
planned hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the subject for (part of) the 
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The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a SAE.
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.
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 on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The JNJ-42165279 solid dosage formulation will be supplied as 25-mg tablets. 
The JNJ-42165279 placebo will be supplied as tablets, matching visually to the active tablets. 
JNJ-42165279/placebo will be manufactured and provided under the responsibility of the 
sponsor. 
Refer to the Investigator's Brochure for a list of excipients.
Packaging
The study drug will be packaged in individual subject kits. Each kit will consist of 1 bottle 
containing 33 tablets.
All JNJ-42165279/placebo solid formulation study drug will be dispensed in child-resistant 
packaging.
14.2.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.3.
Preparation, Handling, and Storage
All study medication at the clinical site will be stored in a secure area with restricted access.
The JNJ-42165279 and placebo solid dosage formulation must be stored at controlled 
temperatures, as indicated on the product specific labeling.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
14.4.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects, or their legally acceptable representatives, where applicable, must 
be instructed to return all original containers, whether empty or containing study drug. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.


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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 drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with, but not limited to, the following supplies:

Investigator’s Brochure for JNJ-42165279

Pharmacy manual/study site investigational product manual

Laboratory kits and manual

IVRS/IWRS Manual

Electronic data capture (eDC) Manual

Sample ICFs

JAKE System quick start guides

Biosensors

EEG (and associated peripherals)

Eye Tracker

Wristbands
o
Actigraph GT9X Link (and associated peripherals)

Actiwave Cardio Single-Channel ECG (and associated peripherals)

Caregiver, clinician, and subject scales

ADOS-2

CASI-Anx

ZBI

RBS-R

SRS-2

KBIT-2

ABC

CGI-S and CGI-I


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
C-SSRS

ABI-C

Caregiver GI-S

Caregiver Assessment of Treatment

Evaluation of JAKE

Self GI-I

Paper versions of ABI, ABI-S, and Daily Tracker 

Computer equipment

JAKE Sense Workbench PC 

External monitor (for use with JAKE Sense Workbench PC and Task Battery)

Laptop docking station / port replicator (for use with JAKE Sense Workbench PC and 
Task Battery)

USB mouse (for use with JAKE Sense Workbench PC and Task Battery)

High definition web camera (for use with JSW PC and Task Battery)

Secured Apple iPad(s) to be used for the caregiver reporting tool registration and task 
completion during site visits

Verizon Jetpack (or similar 4G mobile hotspot) to permit Internet connectivity for the 
JSW PC and iPad(s)

Cart (if needed by investigator, for use with JAKE Sense Workbench PC and Task 
Battery)
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. 
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize
participation in research. For each subject, his or her parent(s) (preferably both parents, if 
available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has 
been fully explained and before the performance of any study-related assessments. Assent must 
be obtained from children (minors) capable of understanding the nature of the study, typically 


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subjects 7 years of age and older, depending on the institutional policies. For the purposes of this 
study, all references to subjects who have provided consent (and assent as applicable) refers to 
the subjects and his or her parent(s) or the subject's legal guardian(s) or legally acceptable
representative(s) who have provided consent according to this process. Minors who assent to a 
study and later withdraw that assent should not be maintained in the study against their will, even 
if their parent(s) still want them to participate.
The majority of subjects with ASD have normal intelligence and are expected to be able to give 
consent (adults) or assent (children). Those participants who are not competent to give consent 
should have their legally authorized representative give consent as per local regulations.
The treatment duration in this study of subjects with ASD is supported by the available 
toxicology and clinical data (see Investigator’s Brochure). A safety signal of reversible mild 
elevation of liver transaminases was identified in the Phase 1 multiple dose study, occurring in 
subjects exposed to more than 4 days dosing with 100 mg. To mitigate the risk to subjects 
participating in this trial, a dose of 25 mg BID (total daily dose of 50 mg) was selected that 
should allow for testing of the pharmacology of the compound. All subjects will be screened and 
those with evidence of pre-existing liver dysfunction will not be enrolled, clinical safety labs will 
be collected as per the Time and Events Schedule and available for ongoing monitoring by the 
investigator and sponsor, and ‘stopping rules’ have been developed for stopping treatment in the 
event that subjects have elevated liver function analytes.
A placebo arm is warranted and necessary to allow for an accurate assessment of the safety and 
tolerability of the study drug. Treatment with placebo dosing is not equivalent to non-treatment. 
All medication treatment will occur within the context of carefully supervised and supportive 
care. Only investigators experienced in the treatment of ASD will participate in the trial and can 
provide expert guidance on the alternatives for treatment if subjects elect to discontinue the study 
prior to the last visit or after the completion of the study.
Only experienced and medically-qualified study site personnel are allowed to perform safety 
assessments.
The total blood volume to be collected will not exceed 200 mL, which is considered to be safe 
and acceptable even for the youngest participants in this study in comparison to a Red Cross 
blood donation.
No treatments for ASD are required to be discontinued for this study. The inability to change or 
add new treatments during the study will not cause potential harm as there are no approved 
treatments for the core symptoms of ASD.
Females will be enrolled in this study only if they are of non-childbearing potential or agree to use 
highly effective contraception. Pregnancy testing will be performed at screening and throughout 
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16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
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


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
If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC about the 
study completion [(if applicable, the notification will be submitted through the head of 
investigational institution)].
16.2.3.
Informed Consent and Assent Form
Each subject (or a legally acceptable representative) 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) and assent form 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 (or their legally acceptable representatives) 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 


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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 (or legally acceptable 
representative), is authorizing such access, includes permission to obtain information about his or 
her survival status. 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, and 
subsequent disease-related treatments, if needed. The physician may also recontact the subject 
for the purpose of obtaining consent to collect information about his or her survival status.
The subject (or legally acceptable representative) 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 either the subject's (or his or her legally 
acceptable representative's) personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
If the subject (or legally acceptable representative) 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 (or legally acceptable representative) is obtained.
Children (minors) or subjects who are unable to comprehend the information provided can be 
enrolled only after obtaining consent of a legally acceptable representative. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, typically 
subjects 7 years of age and older, depending on the institutional policies. Written assent should 
be obtained from subjects who are able to write. A separate assent form written in language the 
subject can understand should be developed for adolescents. After having obtained the assent, a 
copy of the assent form must be given to the subject, and to the subject's parent or if applicable 
legally acceptable representative.
The person who will be performing the caregiver study responsibilities (parent, legally 
acceptable representative, or other) must sign a caregiver consent form indicating that he or she 
understands and is willing and able to adhere to the caregiver’s responsibilities in the study.
When prior consent of the subject is not possible (and the subject's legally acceptable 
representative is not available), enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-
being of the subject and to ensure compliance with applicable regulatory requirements. The 


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subject (or legally acceptable representative) must be informed about the study as soon as 
possible and give consent to continue.
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 (or his or her legally acceptable representative, 
if applicable) 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 biomarker, DNA, and PK 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.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand JNJ-42165279, to 
understand ASD or other psychiatric disorders, to understand differential drug responders, and to 
develop tests/assays related to JNJ-42165279 and ASD. The research may begin at any time 
during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2, Discontinuation of Study Treatment and Withdrawal 
from Study [Withdrawal from the Use of Samples in Future Research]).


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16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the PI

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.


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
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the PI, 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, if needed, month and year of birth.
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 


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protocol; record of all adverse events and follow up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Instruments and scales described in Section 9.2.2.6, Standard Instruments and Scales, will be 
recorded on paper forms and will be considered source data. If paper forms are used for the Daily 
Tracker, ABI, or ABI-S, the paper forms will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
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 CRF 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 CRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. Data must be entered 


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into CRFs in English. Study site personnel must complete the CRF as soon as possible after a 
subject visit, and the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the CRF (if applicable) and complete the query. 
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, direct 
transmission of clinical laboratory and ECG data from a central laboratory into the sponsor's data 
base. Written instructions will be provided for collection, handling, storage, and shipment of 
samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. 
The sponsor will review CRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.


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Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the CRF are known to the sponsor and study-site 
personnel and are accessible for verification by the sponsor study-site contact. If electronic 
records are maintained at the study site, the method of verification must be discussed with the 
study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last study assessment 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 assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.


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17.9.2.
Study Termination
The sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding JNJ-42165279 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 exploratory biomarker 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 JNJ-42165279, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 


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information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or 
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.


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ATTACHMENTS
Attachment 1: Contraceptive and Barrier Guidance and Collection of Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

Infertile due to medical condition
No menses for 12 months and permanently infertile due to an underlying medical condition. 
Documentation of a workup conclusively diagnostic of permanent infertility due to primary 
ovarian insufficiency will be required.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral 
tubal occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) 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 the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of ≤1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.


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
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectables

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

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.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of >1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a) 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.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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Attachment 2: Examples of Prohibited Cytochrome P450 (CYP) 3A4 Inhibitors and Inducers
Note: This is not a comprehensive list of all moderate and strong CYP3A4 inhibitors and inducers. 
Inducers
Inhibitors
Carbamazepine
Amiodarone
Dexamethasone
Clarithromycin
Nevirapine
Clotrimazole
Phenobarbital
Conivaptan
Phenytoin
Delavirdine
Primidone
Diltiazem
Rifabutin/rifampicin
Erythromycin
St. John’s Wort
Fluconazole
Fluvoxamine
Grapefruit
Indinavir
Isoniazid
Itraconazole
Ketoconazole
Miconazole
Nefazodone
Nelfinavir
Nifedipine
Norfloxacin
Omeprazole
Propoxyphene
Quinine
Ritonavir
Saquinavir
Seville oranges
Telaprevir
Troleandomycin
Verapamil
Zafirlukast


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Attachment 15:
Anticipated Events
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events:

anxiety

depression

self-injurious behavior

disruptive/challenging behavior  
Reporting of Anticipated Events
These events will be captured on the eCRF and in the database, and will be reported to the 
sponsor as described in Section 12.3.1, All Adverse Events. 
Any event that meets SAE criteria will be reported to the sponsor within the appropriate timeline 
as described in Section 12.3.2, Serious Adverse Events. These anticipated events are exempt 
from expedited reporting as individual single cases to Health Authorities. However, if based on 
an aggregate review, it is determined that an anticipated event is possibly related to study drug, 
the sponsor will report these events in an expedited manner.


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Attachment 16:
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, 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 guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of participants and site staff. 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.
Scheduled visits that cannot be conducted in person at the study site will be performed to the 
extent possible remotely/virtually or delayed until such time that on-site visits can be resumed. 
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 via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor.
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.  
Modifications made to the study conduct as a result of the COVID-19 pandemic should be 
summarized in the clinical study report.


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Continuation of Study Intervention

Any issue with continuation and/or provision of study intervention should be discussed with 
the sponsor and should be well documented.
Study Visits:

Whenever possible, subjects and caregivers should come to the clinic for their study visits in 
order to conduct assessments which can only be performed in-person (eg, select safety 
assessments, ADOS-2, KBIT-2, JAKE Task Battery, sample collection). Every study visit 
except Screening Visit 2 includes some assessments that can only be performed in-person.

Screening Visit 2 can be conducted 1) completely in-clinic, 2) completely remotely using 
telemedicine, or 3) a combination of in-clinic and remote collection via telemedicine.
Telemedicine:

Telemedicine (via phone or video conversation) conducted by qualified site personnel may 
be used for procedures that do not require in-person interaction, if needed, to reduce the 
duration of exposure between clinical staff and subjects/caregivers or if an in-clinic visit is 
not possible. Assessments that are collected by interview/questioning of subjects or 
caregivers, as well as patient- and caregiver-reported outcomes, may be collected by 
telemedicine. This can be done by using telemedicine at the clinical site (eg, in separate 
rooms) or at home. Telemedicine used within the clinic will not be considered remote data 
collection.
Laboratory Assessments:

Samples should be collected at the clinical site and shipped to a central laboratory whenever 
possible. The use of an authorized/certified local laboratory is allowed if this is not possible. 
A copy of the local laboratory report should be reviewed by the investigator and filed with 
the source documents, along with reference ranges.
Informed Consent:

Consenting and re-consenting of participants for the measures taken (including also remote 
consenting by phone or video consultation) will be performed as applicable and according to 
local guidance for informed consent applicable during the COVID-19 pandemic. The process 
is to be documented in the source documents.
Monitoring:

In case on-site monitoring visits are not possible, monitoring visits and activities may be 
conducted remotely (in accordance with site and local requirements). Additional on-site 
monitoring visits may be needed in the future to catch up on source data verification.
Site Audits:

During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct 
impact/engagement from the investigator and study site personnel may be waived in order to 
comply with national, local, and/or organizational social distancing restrictions. Additional 
quality assurance activities such as remote audits or focused review of study related 
documents may take place with limited impact/engagement if possible.


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COVID-19-Related Documentation:

Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study 
should be documented with the prefix “COVID-19-related” in the case report form (CRF). 
Other relevant study data elements impacted by the pandemic should also be documented/ 
labeled as “COVID-19-related” in CRFs and/or other study systems, as directed by sponsor 
guidance.
Data Analyses:

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study 
data and any additional data analyses will be outlined in study SAP(s). 
Known or suspected COVID-19-positive patients:
Screening:

Patients should be excluded from study participation if they or their study-designated 
caregiver 1) are known or reported to have a positive test for COVID-19, or 2)  are 
suspected to have COVID-19 by the investigator based on symptoms, or 3) have had 
recent exposure to someone who is known to be COVID-19 positive, and have not yet 
successfully completed a period of self-isolation per local and federal guidelines.

Subjects may be eligible to rescreen at Investigator discretion provided that local and 
federal guidelines are followed for self-isolation and symptom resolution (if 
applicable) prior to the rescreening and if the subject has not already met the 
rescreening limit (only one rescreen permitted by protocol).
During Study Conduct:

If a subject has tested positive for COVID-19, the investigator should contact the 
sponsor’s responsible medical officer to discuss whether the subject can continue in the 
study and plans for study intervention and follow-up. It may be possible to continue study 
participation if the subject is asymptomatic or mildly symptomatic provided that:

current local and federal guidelines can be followed without significant impact to 
scheduled visits or procedures (including guidelines pertaining to the recommended 
self-isolation period).

the subject/caregiver can obtain the study drug from the clinic and can remain 
adherent to the restrictions outlined in Section 8.1 Prestudy and Concomitant 
Therapy.

the subject is believed to be able to resume in-clinic visits without significant visit 
delay to complete assessments that are not easily replicated by telemedicine.

the subject’s COVID-19 symptoms, if present, are judged to be unlikely to impact 
data integrity.

If the study-designated caregiver has tested positive for COVID-19, the decision whether 
to continue subject participation in the study should be discussed with the sponsor’s 
responsible medical officer.



SAP_001.pdf: 
1
Approved, Date: 22 November 2022
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study 
Investigating the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and 
Adult Subjects with Autism Spectrum Disorder
Protocol 42165279AUT2001; Phase 2a
JNJ-42165279
Status:
Approved
Date:
22 November 2022
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-192581164
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03664232


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Statistical Analysis Plan 42165279AUT2001
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Approved, Date: 22 November 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 5
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 12
2.1.
Visit Windows................................................................................................................................. 12
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 14
2.3.
Analysis Sets.................................................................................................................................. 14
2.3.1.
All Randomized Analysis Set...................................................................................................... 14
2.3.2.
Efficacy Analysis Set .................................................................................................................. 15
2.3.2.1.
FAS-BID Analysis Set.............................................................................................................. 15
2.3.2.2.
FAS Analysis Set..................................................................................................................... 15
2.3.2.3.
Modified FAS-BID Analysis Set............................................................................................... 15
2.3.3.
Safety Analysis Set..................................................................................................................... 15
2.3.4.
Pharmacokinetics Analysis Set .................................................................................................. 15
2.4.
Study Reference Start and End Dates........................................................................................... 15
2.5.
Analysis Phases............................................................................................................................. 15
2.5.1.
Start and End Dates of Analysis Phases.................................................................................... 15
2.6.
Study Day and Relative Day .......................................................................................................... 16
2.7.
Baseline and End Point.................................................................................................................. 16
2.8.
Imputation Rules for Missing Adverse Event (AE) Date of Onset/Resolution ............................... 16
2.9.
Imputation Rules for Determining Prior or Concomitant Medication and other ASD 
Therapy When Missing Dates........................................................................................................ 17
2.9.1.
Prior Medications or other ASD Therapy.................................................................................... 17
2.9.2.
Concomitant Medications or other ASD Therapy Taken During the Double-blind Phase.......... 18
2.9.3.
Concomitant Medications or other ASD Therapy Taken During the Follow-up Phase .............. 19
2.10.
Definition of Subgroups.................................................................................................................. 20
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 20
4.
SUBJECT INFORMATION................................................................................................................ 20
4.1.
Demographics and Baseline Characteristics ................................................................................. 20
4.2.
Disposition Information................................................................................................................... 21
4.3.
Treatment Compliance................................................................................................................... 21
4.4.
Extent of Exposure......................................................................................................................... 22
4.5.
Protocol Deviations ........................................................................................................................ 22
4.6.
Prior and Concomitant Medications and ASD Therapy ................................................................. 22
5.
EFFICACY ......................................................................................................................................... 23
5.1.
Analysis Specifications................................................................................................................... 25
5.1.1.
Level of Significance................................................................................................................... 25
5.1.2.
Data Handling Rules................................................................................................................... 26
5.2.
Primary Efficacy Endpoints ............................................................................................................ 26
5.2.1.
Definition..................................................................................................................................... 26
5.2.2.
Estimand..................................................................................................................................... 29
5.2.3.
Analysis Methods........................................................................................................................ 30
5.3.
Secondary Endpoints..................................................................................................................... 31


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5.3.1.
Aberrant Behavior Checklist (ABC) ............................................................................................ 31
5.3.1.1.
Definition.................................................................................................................................. 31
5.3.1.2.
Analysis Methods .................................................................................................................... 32
5.3.2.
Autism Behavior Inventory-Short Form (ABI-S).......................................................................... 33
5.3.2.1.
Definition.................................................................................................................................. 33
5.3.2.2.
Analysis Methods .................................................................................................................... 35
5.3.3.
Autism Behavior Inventory-Clinician interview (ABI-C) .............................................................. 35
5.3.3.1.
Definition.................................................................................................................................. 35
5.3.3.2.
Analysis Methods .................................................................................................................... 36
5.3.4.
Clinical Global Impression–Severity (CGI-S).............................................................................. 36
5.3.4.1.
Definition.................................................................................................................................. 36
5.3.4.2.
Analysis Methods .................................................................................................................... 37
5.3.5.
Clinical Global Impression – Improvement (CGI-I)..................................................................... 37
5.3.5.1.
Definition.................................................................................................................................. 37
5.3.5.2.
Analysis ................................................................................................................................... 37
5.3.6.
Repetitive Behavior Scale – Revised (RBS-R)........................................................................... 37
5.3.6.1.
Definition.................................................................................................................................. 37
5.3.6.2.
Analysis Methods .................................................................................................................... 38
5.3.7.
Zarit Burden Interview (ZBI) ....................................................................................................... 39
5.3.7.1.
Definition.................................................................................................................................. 39
5.3.7.2.
Analysis Methods .................................................................................................................... 39
5.3.8.
Child Adolescent Symptom Inventory – Anxiety (CASI-Anx) ..................................................... 39
5.3.8.1.
Definition.................................................................................................................................. 39
5.3.8.2.
Analysis Methods .................................................................................................................... 40
5.3.9.
Social Responsiveness Scale 2 (SRS-2) ................................................................................... 40
5.3.9.1.
Definition.................................................................................................................................. 40
5.3.9.2.
Analysis Methods .................................................................................................................... 41
5.3.10.
Caregiver Global Impression of Severity (Caregiver GI-S) ........................................................ 41
5.3.10.1.
Definition.................................................................................................................................. 41
5.3.10.2.
Analysis Methods .................................................................................................................... 41
5.3.11.
Caregiver Assessment of Treatment.......................................................................................... 42
5.3.11.1.
Definition.................................................................................................................................. 42
5.3.11.2.
Analysis Methods .................................................................................................................... 42
5.3.12.
Self Global Impression of Improvement (Self GI-I)..................................................................... 42
5.3.12.1.
Definition.................................................................................................................................. 42
5.3.12.2.
Analysis Methods .................................................................................................................... 42
5.4.
Janssen Autism Knowledge Engine (JAKE) .................................................................................. 43
5.4.1.
Evaluation of JAKE..................................................................................................................... 43
5.4.1.1.
Definition.................................................................................................................................. 43
5.4.1.2.
Analysis ................................................................................................................................... 43
5.4.2.
My JAKE ..................................................................................................................................... 43
5.4.2.1.
Daily Tracker............................................................................................................................ 44
5.4.2.1.1.
Definition .............................................................................................................................. 44
5.4.2.1.2.
Analysis Methods ................................................................................................................. 44
5.4.2.2.
Mood Report............................................................................................................................ 45
5.4.2.2.1.
Definition .............................................................................................................................. 45
5.4.2.2.2.
Analysis Methods ................................................................................................................. 46
5.4.3.
JAKE Sense................................................................................................................................ 46
5.4.3.1.
Continuous Biosensor ............................................................................................................. 46
5.4.3.1.1.
Definition .............................................................................................................................. 46
5.4.3.1.2.
Analysis Methods ................................................................................................................. 47
5.4.3.2.
Periodic Biosensors................................................................................................................. 48
5.4.3.2.1.
Definition .............................................................................................................................. 50
5.4.3.2.2.
Analysis Methods ................................................................................................................. 52
6.
SAFETY............................................................................................................................................. 53
6.1.
Adverse Events .............................................................................................................................. 53
6.2.
Clinical Laboratory Tests................................................................................................................ 54


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6.3.
Vital Signs and Physical Examination Findings ............................................................................. 55
6.4.
Electrocardiogram.......................................................................................................................... 55
6.5.
Other Safety Parameters ............................................................................................................... 57
6.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 57
6.5.2.
Aberrant Behavior Checklist-Irritability Subscale (ABC-I) .......................................................... 57
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 58
8.
BLOOD / PLASMA BASED BIOMARKERS .................................................................................... 59
REFERENCES............................................................................................................................................ 61
ATTACHMENTS......................................................................................................................................... 61
ATTACHMENT 1 SRS-2 SCORING INSTRUCTIONS .............................................................................. 62
ATTACHMENT 2 CRITERIA FOR TREATMENT-EMERGENT MARKEDLY ABNORMAL 
LABORATORY VALUES .................................................................................................................. 81


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Approved, Date: 22 November 2022
VERSION HISTORY
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
22 Jan 2021
Not Applicable
Initial release
Amendment 1
Xx Nov 2022
Fixed formatting errors
Section 1.5: Clarified how QD or BID 
treatment groups are assigned
Section 2.1: Minor edits to the analysis 
windows
Section 2.3.2.3: Added a modified FAS-
BID analysis set
Section 5.2.3: Added a sensitivity 
analysis using the modified FAS-BID 
analysis set.
Section 5.3.2.1: Corrections made to 
ABI-S item table
Section 5.3.4.2: Removed frequency of 
change from baseline in CGI-S. Added 
MMRM analysis
Section 5.3.5: Added MMRM analysis
Section 5.3.9.1: Clarification made to 
SRS-2 scoring
Section 5.3.10.2: Removed frequency 
of change from baseline in Caregiver 
GI-S. Added MMRM analysis
Section 5.4.2.1.2: Corrections made to 
analysis of Daily Tracker features.
Section 5.4.2.2.2: Corrections made to 
analysis of Mood Report features.
Section 5.4.3.1.2: Corrections made to 
analysis of Actigraph features.
Section 6.5.2: Added definition and 
analysis for the Aberrant Behavior 
Inventory-Irritability Scale 
Section 7: Added summary analysis for 
Pharmacokinetics results.
Section 8:Added correlation analyses 
for plasma concentrations of 
 and 
efficacy measures.
Made the analysis plan consistent
with the protocol objectives and 
reflect the change in dose 
regimen from Protocol 
Amendment 5.
CCI


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ABBREVIATIONS
ABC
Aberrant Behavior Checklist 
ABC-I
Aberrant Behavior Checklist-Irritability Subscale
ABI
Autism Behavior Inventory (Caregiver, full version)
ABI-C
Autism Behavior Inventory-Clinician interview
ABI–S
Autism Behavior Inventory-Short Form 
ADOS-2
Autism Diagnostic Observation Schedule, Second edition
ASD
Autism Spectrum Disorder
AE
adverse event
AEA
N-arachidonoylethanolamine
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AR[1]
autoregressive order 1
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
Caregiver GI-S
Caregiver Global Impression of Severity
CASI-Anx
Child Adolescent Symptom Inventory – Anxiety
CGI-I
Clinical Global Impression–Improvement
CGI-S
Clinical Global Impression–Severity
CI
confidence interval
CRF
case report form
CSS
Calibrated severity score
C-SSRS
Columbia Suicide Severity Rating Scale
DB
Double blind
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EEG
electroencephalogram
ERP
event-related potential
FAA
fatty acid amide
FAAH
fatty acid amide hydrolase
FACET
Facial Expression Analysis
FAS
full analysis set
F/U
Follow-up
HAI
high autism interest
IWRS
interactive web response system
JAKE
Janssen Autism Knowledge Engine
K-BIT
Kaufman Brief Intelligence Test
LAI
low autism interest
LS 
least squares
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed effects model for repeated measures
OEA
N-oleoylethanolamide
PEA
N-palmitoylethanolamide
PI
principal investigator
PK
pharmacokinetic(s)
RBS-R
Repetitive Behavior Scale – Revised
RRB
Repetitive/Restrictive Behavior
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
Self GI-I
Self Global Impression of Improvement
SRS-2
Social Responsiveness Scale 2
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
ULN
upper limit of normal


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US
United States
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
ZBI
Zarit Burden Interview
DEFINITIONS OF TERMS
Autism Behavior Inventory
(or “ABI”) - A module of My JAKE; a series of 62 questions related 
to the core and associated symptoms of ASD
Autism Behavior Inventory-Short
(or “ABI-S”) - A shorter version of the ABI with 24 questions
Autism Behavior Inventory-Clinician
(or “ABI-C”) - A14-item version of the ABI to be completed by the 
clinician following an interview
Continuous Biosensor(s)
A wearable wrist-based biosensor worn over extended periods of 
time throughout the day and during sleep
JAKE
Janssen Autism Knowledge Engine. Refers generally to the set of 
tools and technologies developed by Janssen Research & 
Development, LLC, for the purpose of tracking outcomes and 
enabling research of new treatments in autism spectrum disorders.
JAKE Sense
A component of the JAKE System; all biosensors (Continuous and 
Periodic) used by the JAKE System. JAKE Sense (and its hosted 
biosensors) are used solely for exploratory, proof-of-concept 
research.
JAKE Sense Data Pipeline
(or “JSDP”) - a component of the JAKE System; the JAKE Sense 
Data Pipeline refers to all feature extraction methods, processes, and 
procedures, as well as the study data archive for maintaining 
traceability of all JAKE Sense datasets. Data collected and archived 
via the JSDP may contain limited personal identifiers. This data is 
available only to employees and contractors of Janssen Research & 
Development, and its affiliates. 
My JAKE Data Pipeline
(or “JDP”) - a component of the JAKE System; the My JAKE Data 
Pipeline refers to all feature extraction methods, processes, and 
procedures, as well as the study data archive for maintaining 
traceability of all My JAKE datasets. Data collected and archived via 
the JDP may contain limited personal identifiers. This data is 
available only to employees and contractors of Janssen Research & 
Development, and its affiliates.
My JAKE
A component of the JAKE System; the web and mobile based 
platform used by caregivers and study participants to interact with 
the JAKE System
JAKE System
The core elements of JAKE: My JAKE, JAKE Sense, My JAKE 
Data Pipeline, and JAKE Sense Data Pipeline.
JAKE Task Battery
(or “Task Battery”) - A set of challenge tasks and stimuli, 
approximately 30 minutes in length, used in conjunction with 
Periodic Biosensors
Mentis
An internally-used project codename used to label activities and 
research studies related to JAKE
Periodic Biosensors
A set of wearable and stationary biosensors used during a discrete 
period of assessment at a study visit; representative devices include 
EEG, ECG, eye tracking, and video


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for Study 42165279AUT2001.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of JNJ-42165279 compared with 
placebo in the improvement of symptoms of Autism Spectrum Disorder (ASD) during 12 weeks 
of treatment on the following parameters: 

Autism Behavior Inventory (ABI) Core Domain Score (Social Communication and 
Repetitive/Restrictive Behavior [RRB]).

ABI Social Communication Domain Score.

ABI RRB Domain Score.
Secondary Objectives

To assess the safety and tolerability of JNJ-42165279 compared to placebo.

To assess the effect of JNJ-42165279 compared with placebo on the following parameters in 
subjects with ASD:

ABI Mood & Anxiety, Challenging Behavior, Self-Regulation domains.

Aberrant Behavior Checklist (ABC), Autism Behavior Inventory-Short Form (ABI-S), 
Autism Behavior Inventory-Clinician interview (ABI-C), Clinical Global Impression-
Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), Repetitive Behavior 
Scale-Revised (RBS-R), Zarit Burden Interview (ZBI), Child Adolescent Symptom 
Inventory-Anxiety (CASI-Anx), Social Responsiveness Scale 2 (SRS-2), Caregiver 
Global Impression of Severity (Caregiver GI-S), Caregiver Assessment of Treatment, and 
Self Global Impression of Improvement (Self GI-I) scales.

To correlate changes in the ABI with changes in biosensors, Janssen Autism Knowledge 
Engine (JAKE®) components and standard scales (ABC, CGI-S, RBS-R, ZBI, CASI-Anx, and 
SRS-2).

To compare the performance of the ABI with that of the ABC.

To compare the effect of JNJ-42165279 to placebo using the JAKE Task Battery biosensor 
data.

To assess the pharmacokinetics (PK) of JNJ-42165279 in subjects with ASD using a 
population PK approach, and explore its relationship with efficacy and safety parameters 
where appropriate.

To evaluate the relationship between plasma concentrations of 
and efficacy. 
Exploratory Objectives
The exploratory objectives are:
CCI


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1.2.
Trial Design
This is a randomized, multi-center, double-blind, placebo-controlled, parallel group, outpatient 
study assessing the efficacy, safety, and tolerability of JNJ-42165279 during 12 weeks of treatment 
in adolescent and adult subjects with ASD. 
Approximately 80 adolescent and adult subjects (between 13 and 35 years of age, inclusive) will 
be randomized in a 1:1 ratio to receive double-blind treatment of either JNJ-42165279 or placebo. 
The randomization will be stratified by gender and age (13 - 17 years and 18 – 35 years). Subjects 
enrolled prior to Protocol Amendment 5 were randomized to receive once daily dosing of placebo 
or 25 mg JNJ-42165279 throughout the treatment period. All other subjects will receive twice 
daily (BID) dosing of placebo or 25 mg JNJ-42165279 (total daily dose of 50 mg).
Study procedures include safety and efficacy evaluations and blood sample collections for 
pharmacogenomic assessment, pharmacokinetics, and biomarkers of treatment activity. 
This study consists of a 26-day eligibility screening period, a 12-week double-blind treatment 
period and a follow up examination (to occur 14 days [±1 week] after last dose of study drug). The 
study duration for each subject will be approximately 4 months.
The study design scheme is described in Figure 1.
CCI




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The study will be deemed positive if any of the primary efficacy endpoints are statistically superior 
to placebo using a 1-sided 0.10 significance level.
1.4.
Sample Size Justification
The sample size for the study is based on all subjects who are enrolled under BID dosing. The 
assumption used in the determination of sample size was a treatment effect size of 0.63 for the 
difference between the JNJ-42165279 treatment group and placebo, calculated as the mean change 
in the primary endpoints from baseline to Day 85. To detect the treatment effect size of 0.63 in 
any of the primary endpoints with a power of 90% at an overall 1-sided significance level of 0.10, 
25 subjects in each group are required. When adjusted for a drop-out rate of approximately 15% 
of subjects, this will require 60 subjects to be randomly assigned to treatment in a 1:1 ratio (30 per 
group).
The treatment difference effect size is based on results of a previous meta-analysis showing that
applied behavior analysis interventions lead to medium-to-large effects in a variety of symptomatic 
rating scales for children with autism (Virues-Ortega 2010). Additionally, previous studies of 
selective serotonin reuptake inhibitors (SSRIs), antipsychotics and antiepileptic drugs were 
reviewed. The sample size calculation is based on simulated multivariate normal data with the 
additional assumption that there is a correlation of 0.75 between the ABI Social Communication 
and Restrictive Behavior domains and 0.90 between each of the domains and the ABI Core Domain 
score.
1.5.
Randomization and Blinding
Randomization 
Central randomization will be implemented in this study. At the start of the double-blind phase, 
subjects will be randomly assigned to 1 of 2 treatment groups (JNJ-42165279 or placebo) based 
on the computer-generated randomization schedule prepared before the study by, or under the 
supervision of the sponsor. The randomization will be balanced by using randomly permuted 
blocks and will be stratified by gender (male and female) and age at time of first consent (13-17 
years and 18-35 years), with an allocation ratio of 1:1 to placebo and JNJ-42165279. 
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
Subjects will be assigned to either QD or BID treatment groups programmatically by comparing 
the randomization date to the issue date of the protocol the subject consented to at study 
enrollment.


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Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject for reasons related to the subject’s safety.
Data that may potentially unblind the treatment assignment (eg, study medication plasma 
concentrations, plasma biomarkers) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making special 
provisions, such as segregating the data in question from view by the investigators, clinical team, 
or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all subjects have completed the 
study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the treatment 
by contacting the IWRS. While the responsibility to break the intervention code in emergency 
situations resides solely with the investigator, it is recommended that the investigator contact the 
sponsor or its designee if possible to discuss the particular situation, before breaking the blind. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, 
and reason for the unblinding must be documented in the appropriate section of the case report 
form (CRF), and in the source document. The documentation received from the IWRS indicating 
the code break must be retained with the subject's source documents in a secure manner. 
Subjects who have had their treatment assignment unblinded should continue to return for required 
follow up evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim data review by the Data Monitoring Committee 
(DMC) is specified, the randomization codes and, if required, the translation of randomization 
codes into treatment and control groups will be disclosed to those authorized and only for those 
subjects included in the interim review.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is Study Day 1. If a subject has 2 or more actual visits in one visit 
window, the visit closest to the target day will be used as the protocol visit for that visit window.
The other additional visit(s) will not be used in the summaries or analyses but they can be used for 
determination of clinically important end points. If 2 actual visits are equidistant from the target 
day within a visit window, the later visit is used.


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All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the end point. Listed below 
(Table 1) are the visit windows and the target days for each visit defined in the protocol.
The My JAKE Daily Tracker and Mood Report, along with the JAKE Sense Continuous 
Biosensor, will not be windowed since these are intended to be collected on a daily or continuous
basis.
Table 1: Visit Windows
Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
ABI, ABC
Screening
2
Screening
<1
-21 to -1
DB
3
Baseline
<=1
1
5
Day 29
2 to 43
29
6
Day 57
44 to 71
57
7
Day 85
72 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
ABI-S
DB
4
Day 15
2 to 29
15
--
Day 43
30 to 57
43
--
Day 71
58 to end of DB
71
DB final visit
End Point (DB)
2 to end of DB
ABI-C, JAKE 
Sense Periodic 
Biosensors
DB
3
Baseline
<=1
1
5
Day 29
2 to 57
29
7
Day 85
58 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
CASI-Anx, RBS-R, 
SRS-2
Screening
2
Screening
<1
-21 to -1
DB
3
Baseline
<=1
1
5
Day 29
2 to 57
29
7
Day 85
58 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
ZBI
DB
3
Baseline
<=1
1
7
Day 85
2 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
Caregiver GI-S, 
CGI-S
DB
3
Baseline
<=1
1
5
Day 29
2 to 43
29
6
Day 57
44 to 71
57
7
Day 85
72 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
CGI-I
DB
5
Day 29
2 to 43
29
6
Day 57
44 to 71
57
7
Day 85
72 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
Caregiver 
Assessment of 
Treatment, 
Evaluation of 
JAKE, Self GI-I
DB
7
Day 85
2 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
C-SSRS
Screening
1
Screening
<1
-30 to -3
DB
3
Baseline
<=1
1
4
Day 15
2 to 22
15
5
Day 29
23 to 43
29
6
Day 57
44 to 71
57
7
Day 85
72 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB


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Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point (Day)
F/U
8
Follow-up
End of DB + 1 to 
end of F/U
99
ABC-I
Screening
1
Screening (1)
<1
-30 to -3
2
Screening (2)
<1
-21 to -1
DB
3
Baseline
<=1
1
4
Day 15
2 to 22
15
F/U
8
Follow-up
End of DB + 1 to 
end of F/U
99
Vital signs
Screening
1
Screening
<1
-30 to -3
DB
3
Baseline
<=1
1
4
Day 15
2 to 22
15
5
Day 29
23 to 43
29
6
Day 57
44 to 71
57
7
Day 85
72 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
F/U
8
Follow-up
End of DB + 1 to 
end of F/U
99
Body weight
Screening
1
Screening
<1
-30 to -3
DB
3
Baseline
<=1
1
5
Day 29
2 to 57
29
7
Day 85
58 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
F/U
8
Follow-up
End of DB + 1 to 
end of F/U
99
Height
DB
1
Baseline
<=1
-30 to -3
Clinical laboratory 
assessment
DB
1
Baseline
<=1
-30 to -3
4
Day 15
2 to 22
15
5
Day 29
23 to 43
29
6
Day 57
44 to 71
57
7
Day 85
72 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
ECG
DB
1
Baseline
<=1
-30 to -3
7
Day 85
2 to end of DB
85
DB final visit
End Point (DB)
2 to end of DB
F/U
8
Follow-up
End of DB + 1 to 
end of F/U
99
*Relative to Study Day 1. DB=double-blind. F/U=Follow-up
2.2.
Pooling Algorithm for Analysis Centers
All subjects will be enrolled at sites in the United States (US).  No pooling of sites will be carried 
out.
2.3.
Analysis Sets
2.3.1.
All Randomized Analysis Set
The all randomized analysis set includes all subjects who were randomized in the study (ie, 
subjects who reported a randomization date or were assigned a randomization number) regardless 
of whether treatment was received. This analysis set will be used for summarizing the overall study 
completion/withdrawal information.


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2.3.2.
Efficacy Analysis Set
2.3.2.1.
FAS-BID Analysis Set
The full analysis set (FAS-BID) includes all randomized subjects who received at least 1 dose of 
study agent at the BID dose and have both a baseline and at least 1 postbaseline efficacy 
assessment.  This analysis set will be used for all efficacy analyses.
2.3.2.2.
FAS Analysis Set 
The FAS analysis set includes all randomized subjects who received at least 1 dose of study agent 
at either dose and have both a baseline and at least 1 postbaseline efficacy assessment.  This 
analysis set will be used for summaries of efficacy data and efficacy sensitivity analyses.
2.3.2.3.
Modified FAS-BID Analysis Set 
The modified FAS-BID analysis set includes subjects who meet the same criteria for the FAS-BID 
analysis set described above but excludes subjects who were non-compliant with study medication. 
Non-compliance will be determined from PK samples at the Day 85/Early Withdrawal Visit with 
< 1 ng/ml detected.
2.3.3.
Safety Analysis Set
The safety analysis set includes all randomized subjects who received at least 1 dose of study 
agent.  This analysis set will be used for all safety analyses.
2.3.4.
Pharmacokinetics Analysis Set
The PK analysis set is defined as subjects who received at least 1 dose of study agent and have at 
least 1 valid blood sample drawn for PK analysis.
2.4.
Study Reference Start and End Dates
The overall reference start date for the study is defined as the date of the first dose of study agent 
(the date is missing for screened subjects who did not receive a dose of study agent). The overall 
reference end date for the study is the end of trial date including the last follow-up visit.
2.5.
Analysis Phases
There are 3 analysis phases defined in this study: Screening, Double-blind, and Posttreatment 
(Follow-up). Each analysis phase has its own analysis reference start date.
2.5.1.
Start and End Dates of Analysis Phases
Screening
The analysis reference start date of the screening phase is the date informed consent is obtained.  
The analysis reference end date of the screening phase ends 1 day prior to the date of the first dose 
of study drug in the double-blind treatment phase.  The screening phase end date is left missing 
for those subjects who did not receive study drug.  Note, however, that for Height, Clinical 


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Laboratory Assessments, and ECG, the results taken at Screening will be used as the baseline, 
given that there is not a scheduled assessment on Day 1 (see Table 1).
Double-Blind Treatment Phase
The analysis reference start date of the double-blind phase is the date of the first study agent 
administration. The analysis reference end date of the double-blind phase (except for Adverse 
Events and Concomitant Medications) is the maximum of the date of the last visit in the double-
blind phase and the date of early treatment termination.  For Adverse Events and Concomitant 
Medications, the analysis reference end date of the double-blind phase is the date of the last dose 
of study drug plus 6 days. For randomized subjects who did not receive any medication in the 
double-blind phase, both analysis reference start and end dates are missing for the double-blind 
analysis phase.
Posttreatment (Follow-up) Phase
Start and end dates for the follow-up phase are only defined for subjects who continued into the 
follow-up phase. The start date of the follow-up phase is the day after the double-blind end date.
The follow-up phase end date is the last follow-up visit date. 
2.6.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study agent administration. All efficacy and 
safety assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'.
2.7.
Baseline and End Point
Baseline is defined as the last observation prior to the start of the first study agent administration.  
Baseline is defined for each parameter/assessment.
End point is defined as the last available postbaseline result within the double-blind treatment 
phase and is referred to as ‘End Point (DB)’. Unscheduled visit results are included in this 
definition and will be considered as the end point value if the unscheduled visit result is the last 
postbaseline result available within the double-blind treatment phase.
2.8.
Imputation Rules for Missing Adverse Event (AE) Date of Onset/Resolution
Partial AE onset dates will be imputed as follows:

If the onset date of an AE is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of the study agent start


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
The day of study agent start, if the month/year of the onset of AE is the same as 
month/year of the study agent start date and month/year of the AE resolution date is 
different

The day of study agent start or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the study agent start date and 
month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:

January 1 of the year of onset, as long as this date is on or after the study agent start date

Month and day of the study agent start date, if this date is the same year that the AE 
occurred

Last day of the year if the year of the AE onset is prior to the year of the study agent start 
date,

The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an AE is missing day only, it will be set to the earliest of the last day 
of the month of occurrence of resolution or the day of the date of death, if the death occurred 
in that month.

If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.

Completely missing resolution dates will not be imputed.
2.9.
Imputation Rules for Determining Prior or Concomitant Medication and 
other ASD Therapy When Missing Dates
2.9.1.
Prior Medications or other ASD Therapy
Prior medications or therapy are those taken by subjects before the start of dosing of first study 
agent. Medications will be classified as prior if the medication start date is complete and prior to 
the date of first dose of study agent or the medication end date is complete and prior to the date of 
first dose of study agent.
If the medication start day is missing, and the month and year of the medication start date are not 
missing, then if:

The month and year of the start date of medication is earlier than the month and year of the 
initial study agent administration; or

The case report form (CRF) indicates the medication was taken prior (prior medication 
flag=Yes) and the month and year of the start date of medication is the same as the month and 
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then the medication will be considered prior. 
If the medication start month and day are missing, and the year of the medication start date is not 
missing, then if:

The year of the start date of medication is earlier than the year of the initial study agent 
administration; or 

The CRF indicates the medication was taken prior when the year of the start date of medication 
is the same as the year of the initial study agent administration
then it will also be considered prior.
If the medication start date is completely missing, and the CRF indicates it was taken prior, it will 
also be considered prior.
2.9.2.
Concomitant Medications or other ASD Therapy Taken During the 
Double-blind Phase
Concomitant medications taken during the double-blind phase are those that started on the same 
day as the first dose or after the start of dosing or those continuing from predose (prior medication 
flag=Yes) and the CRF indicates the medication is ongoing or the medication stop date is on or 
after the first dose of study agent. Medications that start on or after the date of the last dose of 
study agent plus 7 days are not considered concomitant medications taken during the double-blind 
phase, but will be included as concomitant medications taken during the follow-up phase (see 
Section 2.5.1). 
If the medication start date is missing the day, but the medication month and year are complete, 
then if the month and year of the medication start date are on or prior to the month and year of the 
last dose of study agent plus 6 days and: 

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study agent administration, or

The stop date month and year (day is missing) of the medication is on or after the initial study 
agent administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study agent administration 
then the medication is classified as concomitant during the double-blind phase.
If the medication start date is missing the month and day, but the year is complete, then if the year 
of the start date is the same as or prior to the year of the last dose of study agent plus 6 days and: 

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or


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
The stop date of the medication is on or after the initial study agent administration, or

The stop date month and year (day is missing) of the medication is on or after the initial study 
agent administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study agent administration 
then the medication is classified as concomitant during the double-blind phase.
If the medication start date is completely missing then if: 

The CRF indicates that the medication is ongoing, or 

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study agent administration, or

The stop date month and year (day is missing) of the medication is on or after the initial study 
agent administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study agent administration
then the medication is classified as concomitant during the double-blind phase.
2.9.3.
Concomitant Medications or other ASD Therapy Taken During the 
Follow-up Phase
Follow-up medications are those medications that started on or after the last dose of study agent 
plus 7 days, or that started prior to the last dose of study agent plus 7 days, but continue on or after 
the last dose of study agent plus 7 days. 
If the medication start date is complete and the medication started on or after the last dose of study 
agent plus 7 days, then the medication is classified as concomitant during the follow-up phase.
If the medication start date is complete and the medication started prior to the last dose of study 
agent plus 7 days or the medication start date is a partial date (missing day or missing month and 
day) or the medication start date is completely missing, then if: 

The CRF indicates that the medication is ongoing, or 

The stop date of the medication is missing, or 

The stop date of the medication is on or after the last dose of study agent plus 7 days, or

The stop date month and year (day is missing) of the medication is on or after the last dose of 
study agent plus 7 days, or

The stop date year (day and month are missing) of the medication is on or after the last dose 
of study agent plus 7 days
then the medication is classified as concomitant during the follow-up phase.


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2.10.
Definition of Subgroups
Descriptive statistics will be provided for the primary efficacy endpoints by the following 
subgroups:
Subgroup
Definition
IQ (based on K-BIT IQ 
composite standard score)
<85 
85 to 115
≥116
Autism Severity (based on 
ABI Core Domain score)
<0.91
≥0.91 to <1.44
≥1.44
Age Group
13 - 17 years
18 - 35 years
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An internal DMC, with 1 external expert, will be established to monitor data to ensure the 
continuing safety of the subjects enrolled in this study. The committee will meet at least once to 
review interim data. After the review, the DMC will make recommendations regarding the safety 
and continuation of the study. The details will be provided in a separate DMC charter and DMC 
SAP.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by treatment group and 
dose and overall. In addition, the distribution of subjects by site ID will be presented.
4.1.
Demographics and Baseline Characteristics
Table 2 presents a list of the demographic variables that will be summarized by treatment group
and dose and overall for the FAS analysis set.
Table 2: Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body mass index (BMI) (kg/m2)
Categorical Variables
Age (13-17 years, 18-35 years)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (male, female)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'


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Since only month and year will be collected on the CRF for date of birth, age will be calculated 
assuming the day of the date of birth is the first day of the month (ie, day = 1).  Age at the time of 
informed consent will be calculated out to 1 decimal place.
Table 3 presents a list of the baseline disease characteristics variables that will be summarized by 
treatment group and dose and overall for the FAS analysis set.  
Table 3: Baseline Disease Characteristics
Continuous Variables
Summary Type
Kaufman Brief Intelligence Test (K-BIT) verbal standard score
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
K-BIT nonverbal standard score
K-BIT IQ composite standard score
Autism Diagnostic Observation Schedule, Second edition (ADOS-2) total 
score and CSS total score
Categorical Variables
Frequency distribution with the 
number and percentage of 
participants in each category.
ASD therapy ongoing (Yes/No)
Neurodevelopmental conditions (Yes/No)
Listings of the demographic and baseline characteristics, as well as medical history and 
neurodevelopmental conditions, will be provided.
4.2.
Disposition Information
Screened subjects and reason for screen failures will be summarized overall.
The number of subjects in the following disposition categories will be summarized throughout the 
study by treatment group and dose and overall:

Subjects randomized

Subjects receiving study agent

Subjects completing the study

Subjects who terminated study prematurely

Reasons for termination of study
Listings of subjects will be provided for the following categories:

Subjects who terminated study prematurely

Subjects who were unblinded during the study period

Subjects who were randomized yet did not receive study agent.
4.3.
Treatment Compliance
Study agent compliance will be calculated as follows:
Study agent compliance (%) = 100 x number of days taking study medication at planned dose/total 
treatment duration (including days off study agent)


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The total treatment duration will be based on the date of the last dose recorded in the CRF.
Descriptive statistics on the percent (%) compliance will be summarized by treatment group for 
the safety analysis set.  In addition, percent compliance will be categorized as <60%, 60%-<80%, 
80%-≤100%, and the number and percentage of subjects in each category will be summarized.
4.4.
Extent of Exposure
Total duration of exposure (including days off study agent) is defined as (date of last dose of study 
agent – date of first dose of study agent) +1.
Total dose days of exposure is defined as the total number of days that study agent was 
administered to the subject (excluding days of study agent interruption).
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for total duration of 
exposure (including days off study agent) and for total dose days of exposure (excluding days off 
study agent) will be presented by treatment group and dose for the safety analysis set. 
A listing of study drug administration will be provided.
4.5.
Protocol Deviations
Subjects with major protocol deviations will be summarized by category for the full analysis set.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
In addition, protocol deviations related to COVID-19 including missing visits and remote visits 
due to COVID will be summarized; corresponding listing will be provided.
4.6.
Prior and Concomitant Medications and ASD Therapy
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study agent. Concomitant medications are defined as any therapy 
used on or after the same day as the first dose of study agent, including those that started before 
and continue after the first dose of study agent.
Prior medications will be summarized by treatment group and standardized medication name for 
the safety analysis set.  The proportion of subjects who receive each prior medication will be 
summarized as well as the proportion of subjects who receive at least one prior medication. 
Summaries of concomitant medications will be presented by treatment group and standardized 
medication name for the safety analysis set, for those medications used during the double-blind 


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phase and for those used during the follow-up phase separately.  Definitions for concomitant 
medications used during the double-blind phase and those used during the follow-up phase are 
provided in Section 2.9.2 and 2.9.3, respectively. The proportion of subjects who receive each 
concomitant medication will be summarized as well as the proportion of subjects who receive at 
least one concomitant medication.  
A by-subject listing of all prior and concomitant medications will also be provided.
5.
EFFICACY
The efficacy variables for the primary endpoint ABI, as well as the ABI- Short form and ABI-
Clinician, and other standard scales used in this study are listed in Table 4.
Table 4:
Efficacy Variables for ABI and Standard Scales
Efficacy Variable
Endpoint
ABI

Change from baseline to Day 85 in the ABI Core Domain score 
(Social Communication and Restrictive Behavior)
Primary

Change from baseline to Day 85 in the ABI Social 
Communication Domain score
Primary

Change from baseline to Day 85 in the ABI Restrictive 
Behavior Domain score
Primary

Change from baseline to Day 85 in the ABI Mood & Anxiety 
Domain score
Secondary

Change from baseline to Day 85 in the ABI Challenging 
Behavior Domain score
Secondary

Change from baseline to Day 85 in the ABI Self-regulation 
Domain score
Secondary

Change from baseline to Day 85 in the ABI Reciprocity 
Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Non-verbal 
Communication Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Verbal 
Communication Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Resistance to 
Change Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Stereotypical 
Behavior Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Hypersensitivity 
Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Impulsivity 
Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Irritability 
Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Hyperactivity 
Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Anxiety 
Subdomain score
Secondary

Change from baseline to Day 85 in the ABI Agression 
Subdomain score
Secondary


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Table 4:
Efficacy Variables for ABI and Standard Scales
Efficacy Variable
Endpoint
ABC

Change from baseline to Day 85 in ABC Irritability subscale 
score
Secondary

Change from baseline to Day 85 in ABC Lethargy/Social 
Withdrawal subscale score
Secondary

Change from baseline to Day 85 in ABC Stereotypic Behavior 
subscale score
Secondary

Change from baseline to Day 85 in ABC Hyperactivity/ 
Noncompliance subscale score
Secondary

Change from baseline to Day 85 in ABC Inappropriate Speech 
subscale score
Secondary
ABI-S

Change from baseline to Day 85 in the ABI-S Core Domain 
score (Social Communication and Restrictive Behavior)
Secondary

Change from baseline to Day 85 in the ABI-S Social 
Communication Domain score
Secondary

Change from baseline to Day 85 in the ABI-S Restrictive 
Behavior Domain score
Secondary

Change from baseline to Day 85 in the ABI-S Mood & Anxiety 
Domain score
Secondary

Change from baseline to Day 85 in the ABI-S Challenging 
Behavior Domain score
Secondary

Change from baseline to Day 85 in the ABI-S Self-regulation 
Domain score
Secondary
ABI-C

Change from baseline to Day 85 in the ABI-C Core Domain 
score (Social Communication and Restrictive Behavior)
Secondary

Change from baseline to Day 85 in the ABI-C Social 
Communication Domain score
Secondary

Change from baseline to Day 85 in the ABI-C Restrictive 
Behavior Domain score
Secondary

Change from baseline to Day 85 in the ABI-C Mood & Anxiety 
Domain score
Secondary

Change from baseline to Day 85 in the ABI-C Challenging 
Behavior Domain score
Secondary

Change from baseline to Day 85 in the ABI-C Self-regulation 
Domain score
Secondary
CGI-S

Change from baseline to Day 85 in CGI-S
Secondary
CGI-I

Improvement at Day 85 in CGI-I
Secondary
RBS-R

Change from baseline to Day 85 in the Overall score
Secondary

Change from baseline to Day 85 in the Stereotyped Behavior
subscale score
Secondary

Change from baseline to Day 85 in the Self-injurious Behavior
subscale score
Secondary

Change from baseline to Day 85 in the Compulsive Behavior
subscale score, 
Secondary

Change from baseline to Day 85 in the Ritualistic Behavior 
subscale score
Secondary

Change from baseline to Day 85 in the Sameness Behavior 
subscale score
Secondary


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Table 4:
Efficacy Variables for ABI and Standard Scales
Efficacy Variable
Endpoint

Change from baseline to Day 85 in the Restricted Behavior
subscale score
Secondary
ZBI

Change from baseline to Day 85 in ZBI global score
Secondary
CASI-Anx

Change from baseline to Day 85 in CASI-Anx Symptom 
Severity score
Secondary
SRS-2

Change from baseline to Day 85 in SRS-2 total score T-score
Secondary

Change from baseline to Day 85 in SRS-2 Social Awareness
subscale T-score
Secondary

Change from baseline to Day 85 in SRS-2 Social Cognition
subscale T-score
Secondary

Change from baseline to Day 85 in SRS-2 Social 
Communication subscale T-score
Secondary

Change from baseline to Day 85 in SRS-2 Social Motivation
subscale T-score
Secondary

Change from baseline to Day 85 in SRS-2 Restricted Interests 
and Repetitive Behavior subscale T-score
Secondary

Change from baseline to Day 85 in SRS-2 Social 
Communication and Interaction subscale T-score
Secondary
Caregiver GI-S

Change from baseline to Day 85 in Caregiver GI-S
Secondary
Caregiver Assessment of 
Treatment

Responses to each of the questions at Day 85
Secondary
Self GI-I

Value at Day 85 in Self GI-I
Secondary
The efficacy variables based on the JAKE System are listed in Table 5.
Table 5:
Efficacy Variables Based on the JAKE System
Efficacy Variable
Endpoint
My JAKE
JAKE Sense

Various features from the Periodic Biosensors (see Section 
5.4.3.2)
Secondary
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The primary efficacy endpoints will be evaluated at a 1-sided significance level of 0.10 based on
the mixed effects model for repeated measures (MMRM) analysis.  For all other analyses of the 
primary efficacy endpoints and for all other efficacy endpoints, nominal 1-sided p-values will be 
CCI


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presented, for signal finding purposes.  Two-sided 80% confidence intervals will be presented.  No 
adjustments for multiplicity will be made.
5.1.2.
Data Handling Rules
Imputation of missing individual item scores will apply to each of the standard scales according to 
the methods described in their manuals.
5.2.
Primary Efficacy Endpoints
5.2.1.
Definition
The primary efficacy endpoints are the changes from baseline to Day 85 in the ABI Core Domain 
score, ABI Social Communication Domain score, and ABI Restrictive Behavior Domain score.  
The ABI is a series of 62 questions related to the core and associated symptoms of ASD and is 
completed by the caregiver at screening, baseline, Day 29, Day 57, and Day 85. It has 5 domains: 
Social Communication, Restrictive Behavior, Mood & Anxiety, Self-regulation, and Challenging 
Behavior.  Questions are answered on 1 of 2 possible dimensions, quality (how well a person 
carries out a particular behavior) or frequency (how often a particular behavior occurs).  The 
response options for items rated on the Quality dimension include: “Not at all”, “With support”, 
“With some reminders”, and “Without help”, along with an option of “I don’t know.”  The 
response options for items rated on the Frequency dimension include: “Never”, “Sometimes”, 
“Often”, and “Very often”, along with an option of “I don’t know.”
For the ABI, the following dimensions are used:

Items 1-13 are assessed using Quality dimension

Items 14-62 are assessed using the Frequency dimension
The steps below outline the steps needed to calculate the ABI domain and subdomain scores.
Score Individual Items
The individual items in the ABI should be scored based on the following algorithm.
For items assessed on the Quality dimension, scores are given as follows:
Not at all = 3
With support = 2
With some reminders = 1
Without help = 0
For all items assessed on the Frequency dimension, with the exception of ABI items 14, 15, 16, 
17, and 18, scores are given as follows:
Never = 0
Sometimes = 1
Often = 2


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Very often = 3
For ABI items 14, 15, 16, 17, and 18, scores are given as follows:
Never = 3
Sometimes = 2
Often = 1
Very often = 0
Calculate ABI Domain Scores
The items from the ABI that are included in each domain and subdomain for the ABI are shown 
in Table 6.  In addition, an ABI Core Domain score is created from the items in the ABI Social
Communication and ABI Restrictive Behavior Domains. In order to calculate a score for a given 
domain or subdomain, at least 50% of items must be non-missing and not “I don’t know”.  The 
domain and subdomain scores are calculated as the average of the non-missing items (ie, sum of 
all non-missing items divided by the number of non-missing items).  If more than 50% of items 
for a given domain or subdomain are missing or “I don’t know”, then no score for that domain or 
subdomain is calculated.
For all domains and subdomains, scores range from 0 to 3 with higher scores indicating more 
severe symptoms of ASD.  Negative changes in ABI domain and subdomain scores indicate 
improvement.
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5.2.2.
Estimand
The primary estimands, the main clinical quantities of interest to be estimated in the study, are
defined by the following 5 components:
Treatment:

Experimental: JNJ-42165279 dose of 50mg

Control: Placebo
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Population: subjects with a diagnosis of ASD, as defined through appropriate inclusion/exclusion 
criteria to reflect the targeted patient population;
Variable: changes from baseline to Day 85 in the ABI Core Domain score, ABI Social 
Communication Domain score, and ABI Restrictive Behavior Domain score had all subjects 
remained on randomized treatment;
Intercurrent event: captured through the variable definition;
Population-level Summary Measure: the difference in variable least squares (LS) means
between placebo and JNJ-42165279. 
The primary analysis will be based on the FAS-BID analysis set and the ABI scores collected 
during the double-blind phase.
5.2.3.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for the ABI 
Core Domain score, ABI Social Communication Domain score, and ABI Restrictive Behavior 
Domain score by treatment group and dose.
Each of the primary efficacy endpoints (changes from baseline to Day 85 in the ABI Core Domain 
score, ABI Social Communication Domain score, and ABI Restrictive Behavior Domain score)
will be analyzed using an MMRM, with time (scheduled Day), treatment (placebo, JNJ-
42165279), time-by-treatment interaction, age group as randomized (13-17 years, 18-35 years), 
and gender (male, female) as factors, and baseline score as a continuous covariate. An unstructured 
variance-covariance matrix will be used. In case of convergence problems, alternative variance-
covariance structures will be tried in the following order, with the first structure that converges 
being used in the analysis:  heterogeneous Toeplitz, standard Toeplitz, and autoregressive order 1 
(AR[1]) with separate subject random effect.  The Kenward-Roger method will be used for 
approximating the denominator degrees of freedom. The treatment effects will be estimated using 
LS means. A point estimate and 80% confidence interval for the treatment difference, along with 
the associated p-value will be provided.
The MMRM, as described above, will also be used to analyze all other post baseline time points
for the ABI Core Domain score, ABI Social Communication Domain score, and ABI Restrictive 
Behavior Domain score. 
Point estimates and 80% confidence intervals for the treatment 
differences at each time point will be provided, along with 1-sided p-values.
Descriptive statistics of the actual values and changes from baseline at each scheduled time point 
and end point will be presented for the other ABI domain scores (ABI Mood & Anxiety, ABI Self-
regulation, and ABI Challenging Behavior) and the ABI subdomain scores by treatment group and 
dose.  The other ABI domain scores (ABI Mood & Anxiety, ABI Self-regulation, and ABI 
Challenging Behavior) will be analyzed using the MMRM as described above.  Point estimates 


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and 80% confidence intervals for the treatment differences at each time point will be provided, 
along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the ABI 
domain scores.
ANCOVA
To assess the sensitivity of the results of the MMRM analysis of the primary endpoints, an analysis 
of covariance (ANCOVA) model for the change from baseline to end point in ABI Core Domain 
score, ABI Social Communication Domain score, and ABI Restrictive Behavior Domain score
will be carried out.  The ANCOVA model will include factors for treatment (placebo, JNJ-
42165279), age group as randomized (13-17 years, 18-35 years), and gender (male, female) as 
factors, and baseline score as a continuous covariate.  In addition, the same ANCOVA model will 
also be performed on observed case data at Day 85.  The estimates of treatment differences based 
on the LS means and 80% CIs will be provided for each model, along with the 1-sided p-values.
Sensitivity
To take into consideration all subjects enrolled prior to the dose regimen change from once daily 
to BID, the MMRM analyses described above will also be conducted for the full analysis set for 
the ABI Domain Scores.
In addition, the MMRM analyses described above will be conducted for the modified FAS-BID 
analysis set for all 6 ABI Domain Scores. 
5.3.
Secondary Endpoints
5.3.1.
Aberrant Behavior Checklist (ABC)
5.3.1.1.
Definition
The ABC is a 58-item behavior rating scale used to measure behavior problems across 5 subscales: 
Irritability, Lethargy/Social Withdrawal, Stereotypic Behavior, Hyperactivity/Noncompliance, 
and Inappropriate Speech. Items are rated on a 4-point Likert scale (ranging from 0 [not at all a 
problem] to 3 [the problem is severe in degree]), with higher scores indicating more severe 
problems.
The items related to each subscale are given below.
Irritability items: 2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, 57
Lethargy/Social Withdrawal items: 3, 5, 12, 16, 20, 23, 26, 30, 32, 37, 40, 42, 43, 53, 55, 58
Stereotypic Behavior items: 6, 11, 17, 27, 35, 45, 49
Hyperactivity/Noncompliance items: 1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 51, 54, 56


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Inappropriate Speech items: 9, 22, 33, 46
To score the ABC, the individual items for each subscale are simply summed to their respective 
totals.  Thus, the scale renders five subscale scores.  The Irritability subscale score ranges from 0 
to 45; the Lethargy/Social Withdrawal subscale score ranges from 0 to 48; the Stereotypic 
Behavior subscale score ranges from 0 to 21; the Hyperactivity/Noncompliance subscale score 
ranges from 0 to 48; and the Inappropriate Speech subscale score ranges from 0 to 12.  The use of 
a total of the five subscales is inappropriate and should not be considered.
The recommended maximum amount of missing data that can be tolerated varies by subscale.  The 
upper limits (ie, number of missing items tolerated for each subscale before discarding the data for 
the subscale) are as follows:  Irritability (15-item scale): 3 items, Lethargy/Social Withdrawal (16-
item scale): 3 items, Stereotypic Behavior (7-item scale): 2 items, Hyperactivity/Noncompliance 
(16-item scale): 3 items, and Inappropriate Speech (4-item scale): 1 item.  If more items than the 
stated upper limit are missing for a subscale, the subscale score will not be calculated.   
If the amount of missing data is within the upper limits described above, the subscale score will 
be prorated as follows: (a) Take the total number of items on the subscale and divide this be the 
number of completed items.  (b) Multiply that number by the total score for that subscale. (c) This 
becomes the new total score for this subscale for the given subject.
For all ABC subscales, higher scores indicate more severe problems.  Negative changes in ABC 
subscale scores indicate improvement.
5.3.1.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for each of the 
5 ABC subscales by treatment group and dose.
The change from baseline to Days 15 (Irritability subscale only), 29, 57, and 85 in each of the 5 
ABC subscale scores will be analyzed using the same MMRM as described in Section 5.2.3 for 
the primary efficacy endpoint, with the continuous covariate for baseline ABI domain score
changed to the respective baseline ABC subscale score.  Point estimates and 80% confidence 
intervals for the treatment differences at each time point will be provided, along with 1-sided p-
values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the ABC 
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5.3.2.
Autism Behavior Inventory-Short Form (ABI-S)
5.3.2.1.
Definition
The ABI-S is a shorter version of the ABI with 24 questions that is completed by the caregiver on 
Week 2, Week 6, and Week 10.  The baseline ABI-S score will be calculated from the full version 
of the ABI completed at Day 1.
Each item is assessed on 1 of 2 dimensions that target the quality or frequency of the given behavior
as described in 5.2.1.
For the ABI-S (and the corresponding items from the ABI), the following dimensions are used:

Items 1-3 are assessed using Quality dimension

Items 4-24 are assessed using the Frequency dimension
The steps below outline the steps needed to calculate the ABI-S domain scores.
Score Individual Items
The individual items in the ABI-S should be scored based on the following algorithm.
For items assessed on the Quality dimension, scores are given as follows:
Not at all = 3
With support = 2
With some reminders = 1
Without help = 0
For all items assessed on the Frequency dimension, with the exception of ABI-S items 4 and 5 
(corresponding ABI items 17 and 18), scores are given as follows:
Never = 0
Sometimes = 1
Often = 2
Very often = 3
For ABI-S items 4 and 5 (corresponding ABI items 17 and 18), scores are given as follows:
Never = 3
Sometimes = 2
Often = 1
Very often = 0
Calculate ABI-S Domain Scores
The items from the ABI-S and the ABI that are included in each domain for the ABI-S are shown 
in Table 7.  In addition, an ABI-S Core Domain score is created from the items in the Social 


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Communication and Restrictive Behavior Domains. In order to calculate a score for a given 
domain, at least 50% of items must be non-missing and not “I don’t know”.  The domain score is 
calculated as the average of the non-missing items (ie, sum of all non-missing items divided by 
the number of non-missing items).  If more than 50% of items for a given domain are missing or 
“I don’t know”, then no score for that domain is calculated.
For all domains and subdomains, scores range from 0 to 3 with higher scores indicating more 
severe symptoms of ASD.  Negative changes in ABI-S domain and subdomain scores indicate 
improvement
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5.3.2.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for each of the 
5 ABI-S domains by treatment group and dose.    
The change from baseline to Days 15, 43 and 71 in each of the 5 ABI-S domain scores will be 
analyzed using the same MMRM as described in Section 5.2.3 for the primary efficacy endpoint, 
with the continuous covariate for baseline ABI domain score changed to the respective baseline 
ABI-S domain score.  Point estimates and 80% confidence intervals for the treatment differences 
at each time point will be provided, along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the ABI-S 
domain scores.
5.3.3.
Autism Behavior Inventory-Clinician interview (ABI-C)
5.3.3.1.
Definition
The ABI-C covers the domains of the ABI and is intended for completion by the clinician 
following an interview with the caregiver and observation or interview with the individual with 
ASD, as appropriate. The clinician is required to rate the severity of behaviors or level of 
impairment observed or described on a scale of 1 to 7, where 1 indicates no impairment of behavior 
and 7 indicates very severe difficulties with an area of functioning. There are 14 items across the 
5 domains of Social Communication, Restrictive Behavior, Mood & Anxiety, Self-regulation and
Challenging Behavior.  
The items from the ABI-C that are included in each domain are shown in Table 8.  In addition, an 
ABI-C Core Domain score is created from the items in the ABI-C Social Communication and 
Restrictive Behavior Domains. In order to calculate a score for a given domain, at least 50% of 
items must be non-missing.  The domain score is calculated as the average of the non-missing 
items (ie, sum of all non-missing items divided by the number of non-missing items).  If more than 
50% of items for a given domain are missing, then no score for that domain is calculated.
For all domains, scores range from 0 to 7 with higher scores indicating more severe symptoms of 
ASD.  Negative changes in ABI-C domain and subdomain scores indicate improvement
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Table 8:ABI-C Domains
Domain
ABI-C Items
Social Communication (3 items; 2 items must be non-missing to 
calculate)
1. Social attention
2. Turn taking in social interaction
3. Non-verbal communication
Restrictive Behavior (5 items; 3 items must be non-missing to calculate)
4. Resistance to change
5. Restricted interests
6. Stereotypical behaviors
7. Self-harm
8. Hypersensitivity
Mood & Anxiety (2 items; 1 item must be non-missing to calculate)
9. Anxiety
10. Sleep
Self-regulation (2 items; 1 item must be non-missing to calculate)
11. Impulsivity
12. Hyperactivity
Challenging Behavior (2 items; 1 item must be non-missing to 
calculate)
13. Aggression
14. Temper tantrums
Core Domain (includes all items from the Social Communication and 
Restrictive Behavior Domains; 8 items; 4 items must be non-missing to 
calculate)
1, 2, 3, 4, 5, 6, 7, 8 (ie, items 1-8)
5.3.3.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for each of the 
5 ABI-C domains by treatment group and dose.
The change from baseline to Days 29 and 85 in each of the 5 ABI-C domain scores will be analyzed 
using the same MMRM as described in Section 5.2.3 for the primary efficacy endpoint, with the 
continuous covariate for baseline ABI domain score changed to the respective baseline ABI-C
domain score.  Point estimates and 80% confidence intervals for the treatment differences at each 
time point will be provided, along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the ABI-C 
domain scores.
5.3.4.
Clinical Global Impression–Severity (CGI-S)
5.3.4.1.
Definition
The CGI-S scale assesses the severity of all illness. The CGI-S is a 7-point scale that requires the 
clinician to assess the severity of the subject’s illness from 1 to 7, with higher scores indicating 
more severe illness.


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5.3.4.2.
Analysis Methods
A frequency distribution of the CGI-S score at baseline, Day 29, Day 57, and Day 85 will be 
provided by treatment group and dose.  In addition, descriptive statistics (N, median, minimum, 
and maximum) of the actual values and the change from baseline will be presented by treatment 
group and dose for observed case data.  Hodges-Lehmann estimates and the corresponding 80% 
CI for the treatment differences in the FAS-BID analysis set will be provided for each time point.
In addition, the change from baseline in CGI-S score at each postbaseline timepoint will be 
analyzed using an MMRM model with baseline CGI-S score as a covariate.
Frequency distributions of the CGI-S score will be presented graphically using stacked bar charts 
for each time point.
5.3.5.
Clinical Global Impression – Improvement (CGI-I)
5.3.5.1.
Definition
The CGI-I is a 7-point scale to measure improvement in illness [(1=very much improved, 2=much 
improved, 3=minimally improved, 4=no change from baseline, 5=minimally worse, 6=much 
worse, 7=very much worse)].
5.3.5.2.
Analysis
Descriptive statistics of the actual values will be presented by treatment group and dose for 
observed case data.
A frequency distribution of the CGI-I score at Day 29, Day 57, and Day 85 will be provided by 
treatment group and dose.  In addition, descriptive statistics (N, median, minimum, and maximum) 
of the actual values will be presented by treatment group and dose for observed case data.  Hodges-
Lehmann estimates and the corresponding 80% CI for the treatment differences in the FAS-BID 
analysis set will be provided for each time point.
In addition, the CGI-I score at each postbaseline timepoint will be analyzed using an MMRM 
model with baseline CGI-S score as a covariate.
Frequency distributions of the CGI-I score will be presented graphically using stacked bar charts 
for each time point.
5.3.6.
Repetitive Behavior Scale – Revised (RBS-R)
5.3.6.1.
Definition
The RBS-R is a 43-item report scale to indicate occurrence of repetitive behaviors and degree to 
which a behavior is a problem on a range between 0 (behavior does not occur) and 3 (behavior is 
a severe problem).  There are 6 subscale scores: Stereotyped Behavior, Self-injurious Behavior, 
Compulsive Behavior, Ritualistic Behavior, Sameness Behavior, and Restricted Behavior.
The items related to each subscale are given below.


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Stereotyped Behavior: items 1 to 6
Self-injurious Behavior: items 7 through 14
Compulsive Behavior: items 15 through 22
Ritualistic Behavior: items 23 through 28
Sameness Behavior: items 29 through 39
Restricted Behavior: items 40 through 43
To score the RBS-R, the individual items for each subscale are summed to their respective totals. 
Thus, the scale renders six subscale scores.  If 2 or more items are missing within a subscale, no 
imputation will be performed, and the score will be left missing. Otherwise, the score will be 
calculated as the sum of the non-missing items multiplied by the ratio of the maximum number of 
items (i.e., 6 for Stereotyped Behavior) to the number of non-missing items.
The Stereotyped Behavior subscale score ranges from 0 to 18; the Self-injurious Behavior subscale 
score ranges from 0 to 24; the Compulsive Behavior subscale score ranges from 0 to 24; the 
Ritualistic Behavior subscale score ranges from 0 to 18; the Sameness Behavior subscale score 
ranges from 0 to 33; and the Restricted Behavior subscale score ranges from 0 to 12.  An overall 
score is also calculated as the sum of all 43 items and ranges from 0 to 129.  
For all subscales, as well as the overall score, higher scores indicate more severe problems.  
Negative changes in subscale and overall scores indicate improvement.
5.3.6.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for each of the 
6 RBS-R subscales and the overall score by treatment group and dose.
The change from baseline to Days 29 and 85 in each of the 6 RBS-R subscale scores and the overall 
score will be analyzed using the same MMRM as described in Section 5.2.3 for the primary 
efficacy endpoint, with the continuous covariate for baseline ABI domain score changed to the 
respective baseline RBS-R subscale or overall score.  Point estimates and 80% confidence intervals 
for the treatment differences at each time point will be provided, along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the RBS-
R subscale and overall scores.


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5.3.7.
Zarit Burden Interview (ZBI)
5.3.7.1.
Definition
The ZBI - short version is a scale of 22 items designed to assess the psychological burden 
experienced by a caregiver. Items ask how the caregiver feels and responses range from 0 (never) 
to 4 (nearly always).  The ZBI global score is the sum of all item scores and can range from 0 to 
88, with a higher score representing a higher burden.  A negative change in the ZBI global score 
indicates improvement.
If at least 16 items have been completed, a prorated score will be calculated as follows:

Sum the items that were answered.

Divide the sum by the number of items that were answered to yield the mean (average) 
response per item.

Multiply the mean response per item by 22 (the total items in the scale).
The ZBI global score will also be categorized into the following burden categories: Little or no 
burden (0-20), Mild to moderate burden (21-40), Moderate to severe burden (41-60), Severe 
burden (61-88).
5.3.7.2.
Analysis Methods
Descriptive statistics of the actual values at baseline and Day 85 and the change from baseline to 
Days 85 will be presented for the ZBI global score by treatment group and dose.
The change in ZBI global score from baseline to Day 85 will be analyzed using an ANCOVA 
model.  The ANCOVA model will include factors for treatment (placebo, JNJ-42165279), age 
group as randomized (13-17 years, 18-35 years), and gender (male, female) as factors, and baseline 
score as a continuous covariate.  The estimate of treatment difference based on the LS means and 
80% CIs will be provided, along with the 1-sided p-value.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for the ZBI global 
score.
A frequency distribution of the ZBI burden categories at baseline and Day 85 will be provided by 
treatment group and dose.
5.3.8.
Child Adolescent Symptom Inventory – Anxiety (CASI-Anx)
5.3.8.1.
Definition
The CASI assesses symptoms of the following disorders: attention deficit hyperactivity disorder, 
oppositional defiant disorder, conduct disorder, generalized anxiety disorder, social phobia, 
separation anxiety disorder, disruptive mood dysregulation disorder, major depressive episode, 


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manic episode, dysthymic disorder, schizophrenia, autistic/Asperger’s disorder, anorexia, and 
bulimia.
This study will use a 21-item anxiety scale (CASI-Anx) and responses range from 0 (never) to 3
(very often), with higher scores indicating more severe anxiety.
The Symptom Severity score is the sum of the response values for each item. If 2 or more items 
are missing, no imputation will be performed, and the score will be left missing. Otherwise, the 
score will be calculated as sum of the non-missing items multiplied by the ratio of the maximum 
number of items (i.e., 21) to the number of non-missing items.
The Symptom Severity score ranges from 0 to 63, with higher scores indicating more severe 
anxiety.  Negative changes in Symptom Severity scores indicate improvement.    
5.3.8.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for the CASI-
Anx Symptom Severity score by treatment group and dose.
The change from baseline to Days 29 and 85 in the CASI-Anx Symptom Severity score will be 
analyzed using the same MMRM as described in Section 5.2.3 for the primary efficacy endpoint, 
with the continuous covariate for baseline ABI domain score changed to the baseline CASI-Anx 
Symptom Severity score.  Point estimates and 80% confidence intervals for the treatment 
differences at each time point will be provided, along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time the CASI-Anx 
Symptom Severity score.
5.3.9.
Social Responsiveness Scale 2 (SRS-2)
5.3.9.1.
Definition
The SRS-2 is a 65-item scale that distinguishes autism spectrum conditions from other child 
psychiatric conditions by identifying the presence and extent of autistic social impairment.  The 
SRS-2 comes in 3 versions- for preschool, school age, and adult. The principal investigator (PI) 
will choose whether the school age or adult version is most appropriate for each subject in this 
study using the instructions in the SRS-2 manuals.
General scoring instructions for the scale are below.  The specific algorithm for each version of 
the form is given in Attachment 1.
Each of the 65 items has 4 possible responses: "Not True", "Sometimes True", "Often True", and 
"Almost Always True".  The scoring value for each item is 0 to 3 based on the appropriate Scoring 
Worksheet.  If a response to an item is missing, then the pre-defined median value for the item (0
or 1) is imputed.  The SRS-2 will not be scored if 7 or more item responses are missing.


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The total raw score is the sum of the item response values.  Tables for each form are provided to 
convert the total raw score to a standardized T-score.  For the School-Age Form, the conversion 
depends on the gender of the individual and whether the rater was a parent or teacher.  In this 
study, it will always be the parent (caregiver) as the rater.  The T-score can be categorized into one 
of four severity ranges to help interpret the results (Within normal limits, Mild, Moderate, Severe).
The SRS-2 also has 5 subscales: Social Awareness (Awr), Social Cognition (Cog), Social 
Communication (Com), Social Motivation (Mot), and Restricted Interests and Repetitive Behavior 
(RRB).  The raw score for each subscale is obtained by adding the response values from the 
Scoring Worksheet for the items associated with the subscale.  The sum of the subscales excluding 
the RRB raw score creates the Social Communication and Interaction (SCI) raw score.  The raw 
scores for each subscale can be converted to a T-score using the appropriate table for the form.
All analyses of the SRS-2 will use the derived T-scores.  For each of the subscale T-scores and the 
total score T-score, higher scores indicate more severe symptoms.  Negative changes in T-scores 
indicate improvement.    
5.3.9.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for each of the 
SRS-2 subscale T-scores and the total score T-score by treatment group.  In addition, a frequency 
distribution of the SRS-2 total score severity category at each scheduled time point and end point
will be provided by treatment group and dose.
The change from baseline to Days 29 and 85 in each of the subscale T-scores and the total score 
T-score will be analyzed using the same MMRM as described in Section 5.2.3 for the primary 
efficacy endpoint, with the continuous covariate for baseline ABI domain score changed to the 
respective baseline SRS-2 subscale or total T-score.  Point estimates and 80% confidence intervals 
for the treatment differences at each time point will be provided, along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the SRS-2
subscale T-scores and the total score T-score.
5.3.10.
Caregiver Global Impression of Severity (Caregiver GI-S)
5.3.10.1.
Definition
The Caregiver GI-S is a single-item instrument that asks caregivers to rate their overall impression 
of the severity of their child’s ASD symptoms.  The scale ranges from 1 (none) to 7 (severe), with 
higher scores indicating more severe symptoms.
5.3.10.2.
Analysis Methods
A frequency distribution of the Caregiver GI-S score at baseline, Day 29, Day 57, and Day 85 will 
be provided by treatment group and dose.  In addition, descriptive statistics (N, median, minimum, 
and maximum) of the actual values and the change from baseline will be presented by treatment 


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group and dose for observed case data.  Hodges-Lehmann estimates and the corresponding 80% 
CI for the treatment differences will be provided for each time point.
In addition, the change from baseline of the Caregiver GI-S score at each postbaseline timepoint 
will be analyzed using an MMRM model with baseline Caregiver GI-S score as a covariate.
Frequency distributions of the Caregiver GI-S score will be presented graphically using stacked 
bar charts for each time point.
5.3.11.
Caregiver Assessment of Treatment
5.3.11.1.
Definition
The Caregiver Assessment of Treatment is a 3-item questionnaire completed at the end of the 
treatment period. 

The first question asks caregivers to rate their overall impression of improvement in their 
child’s autism since starting the study medication, with 7 response options ranging from 1 
“Very much improved” to 7 “Very much worse” with higher scores indicating worsening of 
symptoms.

The second question asks caregivers whether there was improvement in 9 specific symptoms, 
with responses options of “Yes” or “No”.

The third question asks caregivers their interest in having their child continue the study 
medication.  There are 5 response options ranging from “Not at all interested” to “Extremely 
interested”.
5.3.11.2.
Analysis Methods
Frequency distributions of the responses for each of the questions will be provided by treatment 
group and dose.  In addition, descriptive statistics (N, median, minimum, and maximum) of the 
actual values of question 1 will be presented by treatment group and dose for observed case data.  
Hodges-Lehmann estimates and the corresponding 80% CI for the treatment differences in the 
FAS-BID analysis set will be provided
5.3.12.
Self Global Impression of Improvement (Self GI-I)
5.3.12.1.
Definition
At the end of the treatment period, the subject will be asked to give his/her impression of overall 
improvement in ASD symptoms using a single-item instrument, the Self GI-I.  The scale ranges 
from 1 (very much better) to 7 (very much worse), with higher scores indicating worsening of 
symptoms.
5.3.12.2.
Analysis Methods
A frequency distribution of the Self GI-I score will be provided by treatment group and dose.  In 
addition, descriptive statistics (N, median, minimum, and maximum) of the actual values will be 


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presented by treatment group and dose for observed case data.  Hodges-Lehmann estimates and 
the corresponding 80% CI for the treatment differences in the FAS-BID analysis set will be 
provided.
5.4.
Janssen Autism Knowledge Engine (JAKE)
The primary and secondary endpoints for this study are derived from caregiver or clinician-
reported measures.
In addition to standard outcome measures, this study utilizes JAKE to collect daily caregiver 
reports and continuous and periodic biosensor measures, which may be useful as clinical 
endpoints. Key representative features from the daily caregiver reports and the biosensors were 
selected for the CSR to examine treatment differences. The selection was based on reported 
findings in the literature and/or performance in previous non-interventional studies which have 
utilized JAKE. 
An addendum to the CSR, the Exploratory Biosensor Study Report, will contain both the key 
representative features and the larger set of features. This report will include the relationship of 
these features to other endpoints, in addition to analyses of the change over time and between 
treatment groups, with the purpose of developing a set of biosensor features and report measures 
which are sensitive to change.
In this SAP, only the analyses of the key representative features that will be included in the CSR 
are described.
5.4.1.
Evaluation of JAKE
5.4.1.1.
Definition
At the end of the treatment period, caregivers will provide feedback on their experience with the 
JAKE system using a questionnaire.  This is not a part of the evaluation of treatment, but may 
provide useful feedback for future use of the JAKE system.  

The question “How interested would you be in continuing to use the MY JAKE system?” 
has 5 response options ranging from “Not at all interested” to “Extremely interested”.  

The question “How easy or difficult was it to complete the following parts of My JAKE
during the study?” has 5 response options ranging from “Very difficult” to “Very easy” for 
4 JAKE components Daily Tracker, Mood Report, ABI, ABI-S
There are additional questions asking for free-form text responses which will not be analyzed.
5.4.1.2.
Analysis
Frequency distributions of the responses for each of the questions will be provided.
5.4.2.
My JAKE
My JAKE encompasses various modules for use by clinicians, caregivers and the sponsor.


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5.4.2.1.
Daily Tracker
Each day caregivers are asked to report on sleep quality in the morning and ‘overall type of day’ 
after 6 pm using an 8-point scale, ranging from 0 (‘troubling’) to 7 (‘encouraging’).  
In addition, the caregivers are required to select 3 items to track on a daily basis. These items are 
chosen from a subset of items presented, based on the caregiver’s response in the ABI. Following 
completion of the ABI at the screening visit, a clinician at the site will discuss possible items to 
track with the parents and help them with their selection. Parents will have opportunity to change 
the behaviors they track at the baseline visit. After this point they are required to track the same 
behaviors for the duration of the study. After 6 pm each day, caregivers are required to report on 
these behaviors, using an 8-point scale, ranging from 0 (‘troubling’) to 7 (‘encouraging’).
For analysis purposes, only data from primary caregivers will be used.
5.4.2.1.1.
Definition
The key representative features chosen to evaluate the daily tracker are given in Table 9:
Table 9: Key Representative Daily Tracker Features
Task
Feature
Direction that 
Indicates 
Improvement
(or two.sided if 
no hypothesis)
Derived 
in 
Analysis 
Datasets?
Daily Tracker
DAILY TRACKER | SLEEP TODAY
increase
DAILY TRACKER | TYPE OF DAY TODAY
increase
DAILY TRACKER | AVERAGE SLEEP RATING
increase
Yes
DAILY TRACKER | AVERAGE TYPE OF DAY
increase
Yes
For both the sleep quality and type of day, the actual daily values over time will be used in the 
analyses (ie, the features of “Sleep Today” and “Type of Day Today”).  In addition, the daily 
values for the seven days following the baseline visit, the seven days prior to the Day 29 visit, the 
seven days prior to the Day 57 visit, and the seven days prior to the Day 85 visit will be averaged 
(ie, “Average Sleep Rating” and “Average Type of Day”).  A minimum of three valid daily values 
are required to compute the given weekly average for each feature.
If a subject reports more than one response in a day, the last assessment will be used.
5.4.2.1.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline of the daily values over time will be presented by treatment group and dose
for “Sleep Today” and “Type of Day Today”.  Descriptive statistics of the average values at 
baseline, Day 29, Day 57, and Day 85 and the change from the baseline average to the average 
values at Days 29, 57, and 85 will also be presented by treatment group and dose for “Average 
Sleep Rating” and “Average Type of Day”.  


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For “Average Sleep Rating” and “Average Type of Day ”, the change from average baseline to 
each average postbaseline time point will be analyzed using the same MMRM as described in 
Section 5.2.3 for the primary efficacy endpoint, with the continuous covariate for baseline ABI 
domain score changed to the respective average baseline rating.  Point estimates and 80% 
confidence intervals for the treatment differences at each time point will be provided, along with 
1-sided p-values.  
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the averaged values over time for “Average Sleep 
Rating” and “Average Type of Day”.
5.4.2.2.
Mood Report
The ‘mood’ report allows the caregiver an opportunity to report the subject’s state, in terms of 
valence (mood) and arousal (activity) levels. This can be completed at any time through the event 
tracker. In addition, it is presented following the daily tracker completion in the evening, once for 
overall mood and once for most extreme mood, requiring parents to report: 1) subject’s overall 
mood for that day and 2) subject’s most extreme mood for that day.  For all analyses, only the 
values from the mood report (not values from the event tracker) will be used.  Valence and arousal 
levels range from -1 to +1.  
For analysis purposes, only data from primary caregivers will be used.
5.4.2.2.1.
Definition
The key representative features chosen to evaluate the mood report are given in Table 10:
Table 10: Key Representative Mood Report Features
Task
Feature
Direction that 
Indicates 
Improvement
(or two.sided if 
no hypothesis)
Derived 
in 
Analysis 
Datasets?
Mood Report
MOOD REPORT | OVERALL MOOD | VALENCE
increase
MOOD REPORT | OVERALL MOOD | AVERAGE VALENCE
increase
Yes
MOOD REPORT | OVERALL MOOD | AVERAGE POSITIVE 
VALENCE %
increase
Yes
For the “Overall Mood | Valence” feature, the actual daily values over time will be used in the 
analyses.  Since the daily percent positive valence will be either 0% or 100% for each subject, this 
feature will not be analyzed using the daily values. 
The daily values for the seven days following the baseline visit, the seven days prior to the Day 29
visit, the seven days prior to the Day 57 visit, and the seven days prior to the Day 85 visit will be 
averaged to compare the mood report features (ie, the features of “Overall Mood | Average 
Valence” and “Overall Mood | Average Positive Valence %”) to the standard scales performed at 
the clinic visits.  A minimum of three valid daily values are required to compute the given weekly 
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If a subject reports more than one response in a day, the last assessment will be used.
5.4.2.2.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline of the daily values over time will be presented by treatment group and dose
for the “Overall Mood | Valence” feature.  Descriptive statistics of the average values at baseline, 
Day 29, Day 57, and Day 85 and the change from the baseline average to the average values at 
Days 29, 57, and 85 will be presented by treatment group and dose for “Overall Mood | Average 
Valence” and “Overall Mood | Average Positive Valence %”.  
For the “Overall Mood | Average Valence” and “Overall Mood | Average Positive Valence %” 
features, the change from baseline to each average postbaseline time point will be analyzed using 
the same MMRM as described in Section 5.2.3 for the primary efficacy endpoint, with the 
continuous covariate for baseline ABI domain score changed to average baseline feature.  Point 
estimates and 80% confidence intervals for the treatment differences at each time point will be 
provided, along with 1-sided p-values.  
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the averaged values over time for “Overall Mood | 
Average Valence” and “Overall Mood | Average Positive Valence %”.
5.4.3.
JAKE Sense
5.4.3.1.
Continuous Biosensor
The Continuous Biosensor is the ActiGraph GT9X Link Wristband. The ActiGraph Link is a 
wireless wristband biosensor that measures activity.  This sensor should be worn continuously 
except when necessary to remove it for charging or other reasons.
5.4.3.1.1.
Definition
The key representative features chosen to evaluate the continuous biosensor are given in Table 11:
Table 11: Key Representative Daily Tracker Features
Task
Feature
Direction that 
Indicates 
Improvement
(or two.sided if 
no hypothesis)
Derived 
in 
Analysis 
Datasets?
ActiGraph 
Link
ACC | ADJUSTED SLEEP | ALL DAYS 
increase
Yes
ACC | AVERAGE ADJUSTED SLEEP | ALL DAYS | 7 DAYS
increase
Yes
ACC | SD ADJUSTED SLEEP | ALL DAYS | 7 DAYS
decrease
Yes
ACC | NUMBER AWAKENINGS | ALL DAYS
decrease
ACC | AVERAGE NUMBER AWAKENINGS | ALL DAYS | 
7 DAYS
decrease
Yes
ACC | SD NUMBER AWAKENINGS | ALL DAYS | 7 DAYS
decrease
Yes


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Adjusted sleep duration is calculated by subtracting the recommended sleep duration for the age 
group from actual sleep duration as measured by the actigraph ‘average sleep’ extracted feature.  
The recommended sleep duration by age group is listed below:
Age Group (years)
Recommended Sleep
6-13
600 min (10 hours)
14-17
540 min (9 hours)
18+
480 min (8 hours)
For both adjusted sleep and number awakenings, the actual nightly values over time will be used 
in the analyses (ie, the features of “Adjusted Sleep | All Days” and “Number Awakenings | All 
Days”). In addition, the nightly values for the seven nights following the baseline visit, the seven 
nights prior to the Day 29 visit, the seven nights prior to the Day 57 visit, and the seven nights
prior to the Day 85 visit will be averaged to compare the continuous biosensor features that are 
averages (ie, the features of “Average Adjusted Sleep | All Days | 7 Days” and “Average Number 
Awakenings | All Days | 7 Days”) to the standard scales performed at the clinic visits.  The 
corresponding SD of these 7-nightly averages for each subject will be computed for the features 
of “SD Adjusted Sleep | All Days | 7 Days” and “SD Number Awakenings | All Days | 7 Days”.  
A minimum of three valid nightly values are required to compute the given weekly average for 
each feature.
5.4.3.1.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline of the nightly values over time will be presented by treatment group and 
dose for “Adjusted Sleep | All Days” and “Number Awakenings | All Days”.  
Descriptive statistics of the average values at baseline, Day 29, Day 57, and Day 85 and the change 
from the baseline average to the average values at Days 29, 57, and 85 will also be presented by 
treatment group and dose for “Average Adjusted Sleep | All Days | 7 Days” and “Average Number 
Awakenings | All Days | 7 Days”.  
Likewise, descriptive statistics of the values at baseline, Day 29, Day 57, and Day 85 and the 
change from baseline to Day 29, Day 57, and Day 85 will be presented by treatment group and 
dose for “SD Adjusted Sleep | All Days | 7 Days” and “SD Number Awakenings | All Days | 7 
Days”.
For “Average Adjusted Sleep | All Days | 7 Days” and “Average Number Awakenings | All Days
| 7 Days”, the change from average baseline to each average postbaseline time point will be 
analyzed using the same MMRM as described in Section 5.2.3 for the primary efficacy endpoint, 
with the respective average baseline feature as a covariate.  Point estimates and 80% confidence 
intervals for the treatment differences at each time point will be provided, along with 1-sided p-
values.  Likewise, the change from baseline to each postbaseline time point will be analyzed using 
an MMRM for “SD Adjusted Sleep | All Days | 7 Days” and “SD Number Awakenings | All Days 
| 7 Days”.


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Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the averaged values over time for “Average 
Adjusted Sleep | All Days | 7 Days” and “Average Number Awakenings | All Days | 7 Days”.
5.4.3.2.
Periodic Biosensors
Periodic Biosensors will only be worn or used for a discrete period of assessment at a study visit.  
As opposed to the Continuous Biosensors, which will also be worn during normal daily activities, 
Periodic Biosensors will be assessed during the time that the subject is exposed to specific visual 
and auditory tasks or stimuli via a computer interface (the JAKE Task Battery).  
The JAKE Task Battery for use with Periodic Biosensors will comprise a battery of tests 
approximately 30 minutes in duration. The tasks and the associated biosensors are given below.
CCI


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Abbreviations: ECG=electrocardiogram, EEG=electroencephalogram, ERP=event-related potential, FACET=Facial 
Expression Analysis, HAI=high autism interest, LAI=low autism interest.
5.4.3.2.1.
Definition
The key representative biosensor features chosen to evaluate the periodic biosensors are given in 
Table 12:
Table 12: Key Representative Periodic Biosensor Features
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The recordings from the biosensors will be preprocessed by applying appropriate corrections and 
algorithms to classify the data. As part of the preprocessing, measurement values from the periodic 
biosensors that are +/- 5 standard deviations from the mean value for that parameter will be 
considered extreme outliers due to measurement error.  These outliers will be excluded from the 
analysis.
For the derived periodic biosensor features, the calculation is either dividing the result of one 
feature by another or subtracting one feature from another, as given in the feature name.
5.4.3.2.2.
Analysis Methods
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes from baseline at each scheduled time point and end point will be presented for each of the 
periodic biosensor features by treatment group and dose.    
The change from baseline to Days 29 and 85 in each of the periodic biosensor features will be 
analyzed using the same MMRM as described in Section 5.2.3 for the primary efficacy endpoint, 
with the continuous covariate for baseline ABI domain score changed to the respective baseline 
periodic biosensor feature score.  Point estimates and 80% confidence intervals for the treatment 
differences at each time point will be provided, along with 1-sided p-values.
Means (±standard error [SE]), mean changes (±SE) from baseline, and LS mean changes (±SE) 
from baseline will be presented graphically for the observed values over time for each of the 
periodic biosensor features.
In case of data deemed questionable due to issues during testing, analysis may be repeated on a 
subset of evaluable data.  Determination of what is considered evaluable will occur prior to 
database lock.
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6.
SAFETY
All safety analyses will be based on the safety analysis set based on actual treatment received, 
unless otherwise specified.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study agent through the day of last dose plus 6 days is considered to be treatment 
emergent. If the event occurs on the day of the initial administration of study agent, then the event 
will be assumed to be treatment emergent. If the event date is recorded as partial or completely 
missing, then the event will be considered to be treatment emergent unless it is known to be prior 
to the first administration of study agent based on partial onset date or resolution date. All reported 
treatment-emergent adverse events (TEAEs) will be included in the analysis.  For each AE, the 
number and percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment group and dose.
Summary tables will be provided for:

TEAEs

TEAEs occurring in ≥10% of subjects in either combined dose treatment group

Treatment-emergent serious AEs (SAEs)

TEAEs leading to discontinuation of study agent

TEAEs leading to termination of study participation

TEAEs by severity

TEAEs by relationship to study agent

TEAEs leading to dose interruption
For the summaries of TEAEs by severity/relationship to study drug, the observation with the most 
severe occurrence/closest relationship to study agent will be chosen if there is more than one 
incident of the same TEAE for the subject.
The incidence of TEAEs of special interest will be summarized by preferred term and treatment 
group and dose.  These include diplopia, vision impairment, gait disturbance, and severe headache.  
The preferred terms of the AEs to be included in the summary of TEAEs of special interest are 
marked as such on the AE CRF.
In addition to the summary tables, listings will be provided for subjects who:

Died


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
Had SAEs

Had AEs leading to discontinuation of study agent

Had AEs leading to termination of study participation
6.2.
Clinical Laboratory Tests
All clinical laboratory tests will be displayed for the subjects included in the safety analysis set.
Descriptive statistics will be presented for all chemistry, hematology, and urinalysis (pH and 
specific gravity) laboratory tests at scheduled time points.  In addition, change from baseline to all 
postbaseline time points will be summarized for chemistry, hematology, and urinalysis (pH and 
specific gravity) tests and displayed by treatment group and dose.  
The number and percentage of subjects with treatment-emergent postbaseline markedly abnormal 
values will be presented by treatment group and dose.  Clinical laboratory test values will be 
considered “treatment-emergent markedly abnormal” (TEMA) using the criteria defined by the 
sponsor listed in Attachment 2.  The identification of TEMA laboratory values is based on the 
postbaseline value being out of range while the baseline value is either missing or within the range 
given in Attachment 2. If postbaseline laboratory results are above the upper limit and the baseline 
value is below the lower limit, then the postbaseline abnormality will also be considered TEMA. 
The same applies to the postbaseline value being below the lower limit with the baseline value 
being above the upper limit.
The incidence of subjects with treatment-emergent alanine aminotransferase (ALT) values 
>3*upper limit of normal (ULN), ALT values >5*ULN, aspartate aminotransferase (AST) values 
>3*ULN, AST values >5*ULN, total bilirubin values >2*ULN, and INR values >1.5 will be 
presented for the double-blind phase. 
Additionally, incidence of treatment-emergent hepatic toxicity (suspected Hy’s Law (US Dept 
Health 2009) cases) defined as (ALT values >3*ULN or AST values > 3*ULN) AND total 
bilirubin values >2*ULN will be presented for the double-blind phase. Similar to the markedly 
abnormal analysis, only subjects with baseline (ALT values ≤3*ULN or AST values ≤3*ULN) 
(AND baseline total bilirubin values ≤2*ULN for hepatic toxicity) (or if baseline value is missing) 
will be eligible for these analyses.  
The incidence of subjects with (ALT values >3*ULN or AST values >3*ULN) AND (total 
bilirubin values >2*ULN or INR >1.5) will be presented for the double-blind phase.  As above, 
only subjects with baseline (ALT values ≤3*ULN or AST values ≤3*ULN) (AND baseline total 
bilirubin values ≤2*ULN or INR ≤1.5) (or if baseline value is missing) will be eligible for these 
analyses.
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6.3.
Vital Signs and Physical Examination Findings
Continuous vital sign parameters including temperature, weight, pulse, blood pressure (systolic 
and diastolic), and BMI will be summarized at each assessment time point. BMI will be calculated 
as weight (kg)/(height (m))2, at each time point that body weight is measured. The height 
measurement collected at screening will be used in the calculation. 
Change from baseline will be summarized for the treatment and follow-up periods. Descriptive 
statistics (mean, SD, median, minimum and maximum) will be presented. 
Incidence of treatment-emergent clinically important vital signs while on treatment, as defined in 
Table 13, will be summarized for subjects who had a baseline assessment and at least 1
postbaseline assessment for that vital sign.
Table 13: Clinically Important Vital Signs
Vital Sign
Criteria
Pulse
>120 bpm and with >30 bpm increase from baseline
<50 bpm and with >20 bpm decrease from baseline
Systolic blood pressure
>165 mm Hg and with >30 mm Hg increase from baseline
<90 mm Hg and with >30 mm Hg decrease from baseline
Diastolic blood pressure
>105 mm Hg and with >30 mm Hg increase from baseline
<50 mm Hg and with >20 mm Hg decrease from baseline
Temperature
>38oC and with ≥1oC increase from baseline
Weight
increase 10% from baseline
decrease 10% from baseline
A listing of subjects with treatment-emergent clinically important vital signs will be presented, 
along with a listing of all vital sign measurements.
In addition, listings will be provided for physical examination and neurological examination 
results.
6.4.
Electrocardiogram
All electrocardiogram (ECG) parameters will be displayed for the subjects included in the safety 
analysis set. No statistical testing will be performed.
Triplicate 12-lead electrocardiograms (ECGs) will be performed at the site and reviewed by the 
clinical investigator.  There will not be a central ECG reader. 
The ECG parameters that will be analyzed are heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc using Fridericia’s formula (QTcF) correction method:
Fridericia’s formula: QTcF (msec) = QT (msec) / RR1/3; if RR is missing, use QT (msec) * 
(HR(bpm)/60)1/3.




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6.5.
Other Safety Parameters
6.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS (Columbia Suicide Severity Rating Scale) is a low-burden measure of the spectrum 
of suicidal ideation and behavior to assess severity and track suicidal events through any treatment. 
It is a semi-structured clinician-administered questionnaire designed to solicit the occurrence, 
severity, and frequency of suicide-related ideation and behaviors during the assessment period.
Using the C-SSRS, potentially suicide-related events will be categorized using the following 
scores:
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no event that can be 
assessed on the basis of C-SSRS”).  Higher scores indicate greater severity.
A frequency distribution at each time point by treatment group and dose will be provided for the 
safety analysis set. Shifts from baseline to the maximum postbaseline score during the double-
blind phase will be summarized by treatment group and dose.
The maximum postbaseline score during the double-blind phase assigned for each subject will be 
summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal 
ideation (1-5), Suicidal behavior (6-10).  Shifts from baseline to the maximum category during the 
double-blind phase will be summarized by treatment group and dose.
A listing of all C-SSRS results will be provided.
6.5.2.
Aberrant Behavior Checklist-Irritability Subscale (ABC-I)
The Aberrant Behavior Checklist (ABC) is a 58-item behavior rating scale used to measure 
behavior problems across 5 subscales: Irritability, Lethargy (Social Withdrawal), Stereotypy, 
Hyperactivity, and Inappropriate Speech. Items are rated on a 4-point Likert scale (ranging from 
0 [not at all a problem] to 3 [the problem is severe in degree]), with higher scores indicating more 
severe problems.  The ABC-I is a subscale of the ABC focusing on irritability, aggression and self-
injurious behavior and consists of 15 items:
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If 2 or fewer items are missing, the missing items will be given a score of 0.  The ABC-I score will 
then be calculated by summing the scores of the 15 items and will range from 0 to 45.  If 3 or more 
items are missing, the ABC-I score will not be calculated.  
The ABC-I was collected at Screening Visit 1, Day 15 and at the follow-up visit.  The full ABC 
was collected at all other visits and the ABC-I subscale will be derived from the full scale.
Descriptive statistics for the ABC-I score will be presented at each time point by treatment group 
and dose for the safety analysis set.  In addition, descriptive statistics for the change from baseline 
for the ABC-I score will be presented.
A listing of all ABC-I results will be provided.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
PK analyses will be performed on the PK analysis set, defined as subjects who have received at 
least 1 dose of JNJ-42165279 and have at least 1 valid blood sample drawn for PK analysis.
Descriptive statistics (N, mean, SD, median, range and CV (%)) will be used to summarize JNJ-
42165279 concentrations at each sampling time point. Summary outputs will be provided by each 
combination of age group (adolescents or adults) and dosing (QD or BID).
Listed below (Table 15) are the visit windows and the target times for each visit defined in the 
protocol for blood sample collection for JNJ-42165279 and 
. Samples collected outside the 
intervals will be excluded from the summary outputs but included in a listing.
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Table 15: Visit Windows for Blood Sample Collection
Parameter
Analysis 
Phase
Scheduled 
Visit Number
Time Interval
(label on output)
Time Interval
(Time)*
Target Time 
Point (Time)
Blood sample 
collection for JNJ-
42165279
DB
3
Day 1: 0.5-1h
20 mins – 70 
mins postdose
45 mins postdose
4
Day 15: predose
>0 mins predose
predose
4
Day 15: 0.5-1h #
20 mins – 70 
mins postdose
45 mins postdose
4
Day 15: 2.0-2.5h
110 mins – 160 
mins postdose
135 mins 
postdose
7
Day 85/EW: predose
>0 mins predose
predose
7
Day 85/EW: 2.0-2.5h #
110 mins – 160 
mins postdose
135 mins 
postdose
Blood sample 
collection for 
Screening
1
Screening
DB
4
Day 15: predose
>0 mins predose
predose
4
Day 15: 0.5-1h #
20 mins – 70 
mins postdose
45 mins postdose
4
Day 15: 2.0-2.5h
110 mins – 160 
mins postdose
135 mins 
postdose
7
Day 85/EW: predose
>0 mins predose
predose
7
Day 85/EW: 2.0-2.5h #
110 mins – 160 
mins postdose
135 mins 
postdose
* Time interval and target time point are relative to each day dose time.
# Note that for subjects enrolled prior to protocol amendment 3, the collection time was 0.5-1.0h 
postdose.
Additional details of the population pharmacokinetic and concentration-effect analyses (if 
conducted) will be provided in a separate document.
8.
BLOOD / PLASMA BASED BIOMARKERS
The analyses of the plasma concentrations of 
will be based on the 
FAS analysis set.  The plasma concentrations are collected at screening, Day 15, and Day 85/early 
withdrawal.
Descriptive statistics (N, mean, SD, median, minimum and maximum) of the actual values and 
changes and percent changes from baseline for concentrations of 
 at each 
scheduled time point and end point will be provided by age group (adolescents or adults), treatment 
group and dose.
Samples collected outside the intervals listed in Table 15 will be excluded from the summary 
outputs but included in a listing.
Means (±standard error [SE]) and mean changes (±SE) from baseline will be presented graphically 
for the observed values over time for 
.
Exploratory biomarker and DNA sample analyses may be conducted to identify patient sub-types 
and/or predict response to treatments. Findings are reported separately to the clinical team.
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Other efficacy measures may be explored.
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REFERENCES
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER). [2009] Guidance for industry drug 
induced liver injury: premarketing clinical evaluation. Available: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf
Virues-Ortega J. Applied behavior analytic intervention for autism in early childhood: meta-analysis, meta-
regression and dose-response meta-analysis of multiple outcomes. Clin Psychol Rev. 2010: 30(4): 387-399.
ATTACHMENTS


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ATTACHMENT 2 CRITERIA FOR TREATMENT-EMERGENT MARKEDLY
ABNORMAL LABORATORY VALUES
Markedly Abnormal Limits
Laboratory Parameter
Low
High
Alanine aminotransferase (ALT) (SGPT) [U/L]
N/A
200
Albumin [g/L]
24
60
Alkaline phosphatase [U/L]
N/A
250
Aspartate aminotransferase (AST) (SGOT) [U/L]
N/A
250
Basophils [%]
N/A
6
Bicarbonate [mmol/L]
15.1
34.9
Bilirubin, total [mol/L]
N/A
51.3
Blood urea nitrogen [mmol/L]
N/A
17.9
Calcium [mmol/L]
1.5
3
Chloride [mmol/L]
94
112
Creatine kinase (U/L)
N/A
990
Creatinine [mol/L]
N/A
265.2
Eosinophils [%]
N/A
10
Erythrocytes (RBC) [x1012/L] -- female
3.0
5.5
                                                   -- male
3.0
6.4
Gamma glutamyl transferase [U/L]
N/A
300
Glucose [mmol/L]
2.2
16.7
Hemoglobin [g/L]
80
190
Hematocrit [fraction] -- female
0.28
0.50
                                   -- male
0.24
0.55
INR (unitless)
N/A
2
Lactate Dehydrogenase [U/L]
N/A
500
Leukocytes(WBC) [x109/L]
2.5
15.0
Lymphocytes [%]
10
60
Magnesium [mmol/L]
0.41 
2.02 
Monocytes [%]
N/A
20
Neutrophils, segmented [%]
30
90
(activated) Partial thromboplastin time [seconds]
N/A
70
Phosphate [mmol/L]
0.7
2.6
Platelet count [x109/L]
100
600
Potassium [mmol/L]
3.0
5.8
Protein, total [g/L]
50
N/A 
Sodium [mmol/L]
125
155
TSH [mIU/L]
<0.1
>5
Urate [mol/L]
89.2
594.8
Urine pH
N/A
8.0
Note: The same limits apply to both males and females unless gender is indicated; 
N/A = Not applicable.