Conditions: Crohn Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 388
Healthy volunteers: no

Brief summary:
The purpose of the study is to assess the safety and efficacy of JNJ-64304500 in participants with moderately to severely active Crohn's disease.

Detailed description:

Arms:
arm 1: Participants will receive placebo Subcutaneously (SC) at Weeks 0, 2, 4, 6, 8, and 10. From Week 12 Placebo-treated participants who are in clinical response at Week 12 (\>=100-point reduction from baseline in Crohn's Disease Activity Index (CDAI) or CDAI \<150) will continue to receive placebo SC injections every 2 weeks from Week 12 through Week 22. Placebo -treated participants who are not in clinical response at Week 12 will receive JNJ-64304500 400 mg SC at Week 12 and then JNJ-64304500 200 mg every two weeks from Week 14 through Week 22. arm 2: Participants will receive JNJ-64304500 400 milligram (mg) SC at Week 0 then 200 mg SC every two weeks through Week 22. arm 3: Placebo SC at Weeks 0, 2, 4, and 8. From Week 12, placebo-treated participants who are in clinical response at Week 12 (\>=100-point reduction from baseline in CDAI or CDAI \<150) will continue to receive placebo at Weeks 12, 14, 16, and 20. Placebo -treated participants who are not in clinical response at Week 12 will receive JNJ-64304500 150 mg SC at Week 12 and then JNJ-64304500 75 mg at Weeks 14, 16, and 20. Participants who complete Part II 24 weeks assessment and may benefit from continued treatment in the opinion of the investigator are eligible to enter the Part II LTE in which they will continue to receive placebo up to 52 weeks (for a total of up to 72 weeks of placebo in Part II).

The study has been unblinded due to lack of sufficient efficacy of JNJ- 64304500. Participants receiving placebo during the LTE will stop receiving placebo. arm 4: JNJ-64304500 400 mg SC at Week 0 and 200 mg SC at Weeks 2, 4, 8, 12, 16, and 20. Participants who complete Part II 24 weeks assessment and may benefit from continued treatment in the opinion of the investigator are eligible to enter the Part II LTE in which they will continue to receive JNJ-64304500 high dose up to 52 weeks (for a total of up to 72 weeks of JNJ-64304500 in Part II).

The study has been unblinded due to lack of sufficient efficacy of JNJ-64304500. Participants receiving JNJ-64304500 during the LTE will stop receiving study drug and will have a final safety follow-up visit 16 weeks after the last dose of study drug. arm 5: JNJ-64304500 150 mg SC at Week 0 and 75 mg SC at Weeks 2, 4, 8, 12, 16, and 20. Participants who complete Part II 24 weeks assessment and may benefit from continued treatment in the opinion of the investigator are eligible to enter the Part II LTE in which they will continue to receive JNJ-64304500 middle dose up to 52 weeks (for a total of up to 72 weeks of JNJ-64304500 in Part II).

The study has been unblinded due to lack of sufficient efficacy of JNJ-64304500. Participants receiving JNJ-64304500 during the LTE will stop receiving study drug and will have a final safety follow-up visit 16 weeks after the last dose of study drug. arm 6: JNJ-64304500 50 mg SC at Week 0 and 25 mg SC at Weeks 2, 4, 8, 12, 16, and 20. Participants who complete Part II 24 weeks assessment and may benefit from continued treatment in the opinion of the investigator are eligible to enter the Part II LTE in which they will continue to receive JNJ-64304500 low dose up to 52 weeks (for a total of up to 72 weeks of JNJ-64304500 in Part II).

The study has been unblinded due to lack of sufficient efficacy of JNJ-64304500. Participants receiving JNJ-64304500 during the LTE will stop receiving study drug and will have a final safety follow-up visit 16 weeks after the last dose of study drug. arm 7: Participants will receive tiered doses of Ustekinumab 260 mg (weight \<=55 kg), Ustekinumab 390 mg (weight \>55 kg and \<=85 kg), Ustekinumab 520 mg (weight \>85 kg) intravenously at Week 0 followed by 90 mg subcutaneously at Weeks 8 and 16. Participants who complete Part II 24 weeks assessment and may benefit from continued treatment in the opinion of the investigator are eligible to enter the Part II LTE in which they will continue to receive Ustekinumab up to 52 weeks (for a total of up to 72 weeks of Ustekinumab in Part II).

The study has been unblinded due to lack of sufficient efficacy of JNJ-64304500. Participants receiving Ustekinumab during the LTE will stop receiving study drug and will have a final safety follow-up visit after the last dose of study drug. However, participants receiving Ustekinumab in countries where Ustekinumab is not commercially available or approved for adult Crohn's disease were continued to receive Ustekinumab in the LTE.

Interventions: intervention 1: JNJ-64304500 intervention 2: Placebo intervention 3: Ustekinumab
Intervention descriptions: intervention 1: Participants will receive JNJ-64304500 Subcutaneously. intervention 2: Participants will receive placebo Subcutaneously. intervention 3: Participants will receive ustekinumab as per the dosing regimen.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 4 June 2021
Janssen Research & Development*
Clinical Protocol
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Protocol to Evaluate the Safety and Efficacy of JNJ-64304500 in Subjects with Moderately 
to Severely Active Crohn’s Disease
TRIDENT
Protocol 64304500CRD2001; Phase 2b
AMENDMENT 7
JNJ-64304500
*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 Infectious Diseases BVBA; 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).
EudraCT NUMBER:
2016-000634-21
Status:
Approved
Date:
4 June 2021
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-117774163:9.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT02877134


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 57
TIME AND EVENTS SCHEDULE: PART I ................................................................................................ 65
TIME AND EVENTS SCHEDULE: PART II MAIN STUDY PHASE .......................................................... 69
TIME AND EVENTS SCHEDULE: PART II LONG-TERM EXTENSION................................................... 74
TIME AND EVENTS SCHEDULE: PART II LONG-TERM EXTENSION................................................... 76
ABBREVIATIONS ...................................................................................................................................... 77
1.
INTRODUCTION................................................................................................................................ 79
1.1.
Nonclinical Studies......................................................................................................................... 80
1.2.
Clinical Studies............................................................................................................................... 80
1.2.1.
Rheumatoid Arthritis ................................................................................................................... 80
1.2.2.
Crohn’s Disease ......................................................................................................................... 80
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 83
2.1.
Objectives and Endpoints .............................................................................................................. 83
2.1.1.
Objectives ................................................................................................................................... 83
2.1.2.
Endpoints.................................................................................................................................... 83
2.2.
Hypothesis ..................................................................................................................................... 85
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 85
3.1.
Overview of Study Design.............................................................................................................. 85
3.1.1.
Part I ........................................................................................................................................... 90
3.1.2.
Part II .......................................................................................................................................... 90
3.1.3.
Interim Analysis .......................................................................................................................... 91
3.1.4.
Part II Long-Term Extension....................................................................................................... 91
3.2.
Study Design Rationale.................................................................................................................. 93
3.2.1.
Choice of JNJ-64304500 Dose for Placebo Nonresponders...................................................... 93
3.2.2.
Efficacy Assessments................................................................................................................. 94
3.2.3.
Pharmacokinetic Assessments................................................................................................... 94
3.2.4.
Immunogenicity Assessments .................................................................................................... 94
3.2.5.
Pharmacodynamic Assessments ............................................................................................... 94
3.2.6.
DNA and Biomarker Collection................................................................................................... 95
3.2.7.
Control, Randomization, and Blinding ........................................................................................ 95
3.2.8.
Dose Selection............................................................................................................................ 96
3.2.8.1.
JNJ-64304500 ......................................................................................................................... 96
3.2.8.2.
Ustekinumab............................................................................................................................ 99
4.
SUBJECT POPULATION.................................................................................................................. 99
4.1.
Inclusion Criteria .......................................................................................................................... 100
4.2.
Exclusion Criteria ......................................................................................................................... 104
4.3.
Prohibitions and Restrictions ....................................................................................................... 107
5.
TREATMENT ALLOCATION AND BLINDING............................................................................... 108


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5.1.
Treatment Allocation .................................................................................................................... 108
5.2.
Blinding ........................................................................................................................................ 108
6.
DOSAGE AND ADMINISTRATION ................................................................................................ 110
6.1.
Part I............................................................................................................................................. 110
6.2.
Part II............................................................................................................................................ 110
6.3.
Part II Long-term Extension ......................................................................................................... 111
7.
TREATMENT COMPLIANCE.......................................................................................................... 112
8.
PRESTUDY AND CONCOMITANT THERAPY .............................................................................. 113
8.1.
Concomitant Medications............................................................................................................. 113
8.1.1.
Corticosteroid Tapering ............................................................................................................ 114
8.2.
Prohibited Medications................................................................................................................. 114
9.
STUDY EVALUATIONS .................................................................................................................. 115
9.1.
Study Procedures......................................................................................................................... 115
9.1.1.
Overview................................................................................................................................... 115
9.1.2.
Screening Period ...................................................................................................................... 115
9.1.3.
Double-Blind Treatment Period ................................................................................................ 116
9.1.4.
Final Efficacy and Safety Follow-up Visit.................................................................................. 117
9.2.
Efficacy Evaluations..................................................................................................................... 117
9.2.1.
Crohn’s Disease Activity Index ................................................................................................. 117
9.2.2.
Bristol Stool Form Scale ........................................................................................................... 117
9.2.3.
Abdominal Pain Numerical Rating Scale.................................................................................. 118
9.2.4.
Patient’s Global Impression of Severity of Crohn’s Disease .................................................... 118
9.2.5.
Patient’s Global Impression of Change of Severity of Crohn’s Disease .................................. 118
9.2.6.
C-Reactive Protein.................................................................................................................... 118
9.2.7.
Fecal Lactoferrin and Calprotectin............................................................................................ 118
9.2.8.
Inflammatory Bowel Disease Questionnaire............................................................................. 119
9.2.9.
36-Item Short Form Health Survey........................................................................................... 119
9.2.10.
Fistula Assessment................................................................................................................... 119
9.2.11.
Endoscopic Endpoints .............................................................................................................. 119
9.2.12.
Histologic Assessment.............................................................................................................. 120
9.3.
Pharmacokinetics and Immunogenicity Evaluations.................................................................... 120
9.3.1.
Evaluations ............................................................................................................................... 120
9.3.2.
Serum Concentration................................................................................................................ 121
9.3.3.
Immunogenicity Assessments (Antibodies to Study Agent)..................................................... 121
9.4.
Biomarker and Other Pharmacodynamic Evaluations ................................................................. 121
9.4.1.
Serum-based Biomarkers......................................................................................................... 121
9.4.2.
Whole Blood-based Biomarkers ............................................................................................... 121
9.4.3.
Biopsy-based Biomarkers......................................................................................................... 122
9.4.4.
NKG2D Receptor Occupancy................................................................................................... 122
9.4.5.
Immunophenotyping ................................................................................................................. 122
9.5.
Pharmacogenomic (DNA) Evaluations ........................................................................................ 122
9.6.
Medical Resource Usage............................................................................................................. 122
9.7.
Safety Evaluations ....................................................................................................................... 122
9.8.
Sample Collection and Handling.................................................................................................. 126
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ......................................................................................................................... 126
10.1.
Completion ................................................................................................................................... 126
10.2.
Discontinuation of Study Treatment............................................................................................. 127
10.3.
Withdrawal From the Study.......................................................................................................... 129
10.4.
Withdrawal From the Use of Research Samples......................................................................... 129
10.5.
Withdrawal From Pharmacogenomic Research Only.................................................................. 130
11.
STATISTICAL METHODS............................................................................................................... 130


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11.1.
Sample Size Determination ......................................................................................................... 131
11.1.1.
Sample Size in Part I ................................................................................................................ 131
11.1.2.
Sample Size in Part II ............................................................................................................... 132
11.2.
Efficacy Analyses ......................................................................................................................... 133
11.2.1.
Part I ......................................................................................................................................... 133
11.2.1.1.
Primary Endpoint Analysis..................................................................................................... 133
11.2.1.2.
Other Efficacy Endpoint Analyses ......................................................................................... 134
11.2.2.
Part II ........................................................................................................................................ 135
11.2.2.1.
Primary Endpoint Analysis..................................................................................................... 135
11.2.2.2.
Major Secondary Endpoint Analyses .................................................................................... 136
11.2.2.3.
Other Efficacy Endpoint Analyses ......................................................................................... 137
11.3.
Pharmacokinetic Analyses........................................................................................................... 137
11.4.
Immunogenicity Analyses ............................................................................................................ 138
11.5.
Biomarker Analyses ..................................................................................................................... 138
11.6.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 138
11.7.
Pharmacogenomic Analyses ....................................................................................................... 138
11.8.
Medical Resource Utilization........................................................................................................ 139
11.9.
Safety Analyses ........................................................................................................................... 139
11.10.
Interim Analysis............................................................................................................................ 139
11.11.
Data Monitoring Committee ......................................................................................................... 140
12.
ADVERSE EVENT REPORTING .................................................................................................... 140
12.1.
Definitions .................................................................................................................................... 140
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 140
12.1.2.
Attribution Definitions................................................................................................................ 142
12.1.3.
Severity Criteria ........................................................................................................................ 142
12.1.3.1.
Severity Criteria: General Categorical Descriptors................................................................ 142
12.1.3.2.
Severity Criteria Based on National Cancer Institute Common Terminology Criteria 
for Adverse Events Toxicity Grade........................................................................................ 143
12.2.
Special Reporting Situations........................................................................................................ 143
12.3.
Procedures................................................................................................................................... 144
12.3.1.
All Adverse Events.................................................................................................................... 144
12.3.2.
Serious Adverse Events ........................................................................................................... 145
12.3.3.
Pregnancy................................................................................................................................. 145
12.3.4.
Events of Special Interest......................................................................................................... 146
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 146
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 146
13.1.
Procedures................................................................................................................................... 146
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 147
14.
STUDY DRUG INFORMATION....................................................................................................... 147
14.1.
Physical Description of Study Drugs............................................................................................ 147
14.2.
Packaging .................................................................................................................................... 147
14.3.
Labeling........................................................................................................................................ 147
14.4.
Preparation, Handling, and Storage............................................................................................. 147
14.5.
Drug Accountability ...................................................................................................................... 148
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 148
16.
ETHICAL ASPECTS ....................................................................................................................... 149
16.1.
Study-Specific Design Considerations......................................................................................... 149
16.2.
Regulatory Ethics Compliance..................................................................................................... 149
16.2.1.
Investigator Responsibilities ..................................................................................................... 149
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 149
16.2.3.
Informed Consent ..................................................................................................................... 151
16.2.4.
Privacy of Personal Data .......................................................................................................... 152
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 152


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16.2.6.
Country Selection ..................................................................................................................... 153
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 153
17.1.
Protocol Amendments.................................................................................................................. 153
17.2.
Regulatory Documentation .......................................................................................................... 153
17.2.1.
Regulatory Approval/Notification .............................................................................................. 153
17.2.2.
Required Prestudy Documentation........................................................................................... 153
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 154
17.4.
Source Documentation................................................................................................................. 155
17.5.
Case Report Form Completion .................................................................................................... 155
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 156
17.7.
Record Retention ......................................................................................................................... 156
17.8.
Monitoring .................................................................................................................................... 157
17.9.
Study Completion/Termination..................................................................................................... 158
17.9.1.
Study Completion/End of Study................................................................................................ 158
17.9.2.
Study Termination..................................................................................................................... 158
17.10.
On-Site Audits .............................................................................................................................. 158
17.11.
Use of Information and Publication.............................................................................................. 158
REFERENCES.......................................................................................................................................... 161
ATTACHMENTS....................................................................................................................................... 162
INVESTIGATOR AGREEMENT ............................................................................................................... 175
LIST OF ATTACHMENTS
Attachment 1:
Definition of Inadequate Initial Response, Loss of Response, or Intolerance 
to TNF-Antagonist Therapies (Infliximab, Adalimumab, or Certolizumab 
Pegol) or Vedolizumab ............................................................................................. 162
Attachment 2:
Definitions of Inadequate Response to or Intolerance of Corticosteroids or 
AZA/6-MP/MTX and Corticosteroid Dependence..................................................... 167
Attachment 3:
Tuberculin Skin Testing............................................................................................ 169
Attachment 4:
Crohn’s Disease Activity Index................................................................................. 170
Attachment 5:
Liver Safety Monitoring and Assessment................................................................. 171
Attachment 6:
Anticipated Events.................................................................................................... 174


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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule, Part I ............................................................................................ 65
Table 2:
Time and Events Schedule, Part II ........................................................................................... 69
Table 3: 
Time and Events Schedule, Long-term Extension Before Unblinding for JNJ-
64304500, Ustekinumab, and Placebo and After Unblinding for JNJ-64304500j.................... 74
Table 4: 
Time and Events Schedule, Long-term Extension Phase After Unblinding for 
Ustekinumab Subjects in Countries Where Ustekinumab Is Not Commercially 
Available ................................................................................................................................... 76
Table 5:
Predicted median serum JNJ-64304500 concentrations and NKG2D receptor 
occupancy after administration of the selected dose regimens of JNJ-64304500 ................... 97
Table 6:
Power to detect a treatment difference and sample size combinations at an overall 
Type 1 error of 0.05 (2-sided) for Part I .................................................................................. 132
Table 7:
Power to detect a treatment difference and sample size combinations at an overall 
Type 1 error of 0.05 (2-sided) for Part II ................................................................................. 133
FIGURES
Figure 1:
Schematic representation of 64304500CRD2001.................................................................... 86
Figure 2:
Schematic Overview of Part I of Study 64304500CRD2001 .................................................... 88
Figure 3:
Schematic Overview of the 64304500CRD2001 Part II (Including the Long-term 
Extension) ................................................................................................................................. 89


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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
17 March 2016
Amendment 1
14 June 2016
Amendment UK-1
22 September 2016 (superseded by Amendment 2)
Amendment 2
09 November 2016
Amendment 3
12 December 2017
Amendment 4
24 April 2018
Amendment 5
17 January 2019
Amendment 6
04 February 2020
Amendment 7
04 June 2021
Amendments below are listed beginning with the most recent amendment. The changes to the protocol are 
indicated with an underline.
Amendment 7 (04 June 2021)
The overall reason for the amendment: The study has been unblinded due to lack of sufficient efficacy of 
JNJ-64304500 based on the Part II Week 12 analysis. The unblinding occurred after all Part II subjects completed 
their Week 24 assessments. Subjects who were receiving JNJ-64304500 or placebo in the Part II long-term 
extension (LTE) were discontinued. Subjects receiving ustekinumab in countries where ustekinumab is not
commercially available were continued in the LTE. To reduce the burden of the ustekinumab subjects who continue 
in the LTE, the laboratory assessments (including PK and immunogenicity) have been removed, and the 16-week 
safety follow-up has been removed due to the well-known safety profile of ustekinumab. 
Applicable 
Section(s)
Description of Change(s)
Rationale: To update details around the subject unblinding in Part II of the study and the subsequent conduct of the 
LTE.
Synopsis; 
3.1.4, Part II Long-
Term Extension; 
6.3, Part II Long-
Term Extension
Subjects will continue to receive the same treatment regimen during the Part II LTE that 
they were receiving between Week 12 and Week 20 in the main study phase of Part II 
(placebo, high, middle, low dose JNJ-64304500 or ustekinumab). To maintain the study
blind, all patients, investigators, and sites will remain blinded to treatment allocation 
during the Part II LTE until the last subject in the Part II main study phase has completed 
the Week 24 assessments and the Sponsor unblinds the study the Week 24 data analysis 
has been completed.
The timing of the Week 24 data analysis is dependent upon the timing and completion of 
Part II enrollment. Whether an individual subject will receive his/her treatment allocation 
during the Part II LTE will depend upon his/her Part II enrollment date. Therefore, a 
portion of subjects will complete the entire Part II LTE in a blinded fashion before study 
unblinding, while other subjects could be unblinded to treatment allocation during their 
participation in the Part II LTE.
On 15 March 2021, sites were informed that due to lack of sufficient efficacy of 
JNJ-64304500, subjects who were receiving JNJ-64304500 or placebo in the LTE were 
discontinued, subjects receiving ustekinumab in countries where ustekinumab is not 
commercially available were continued in the LTE. 
Any subject who withdraws from the Part II LTE prior to study unblinding will return for a 
final safety follow-up visit 16 weeks after the last dose of study drug. For subjects who 


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Applicable 
Section(s)
Description of Change(s)
remain in the Part II LTE at the time of study unblinding, continuation of study drug 
during the Part II LTE will be dependent upon treatment allocation, as follows:

JNJ-64304500: Subjects receiving JNJ-64304500 during the LTE will stop receiving 
study drug and will have a final safety follow-up visit 16 weeks after the last dose of 
study drug. continue to receive the same dose of JNJ-64304500 administered during 
the Part II main study phase. Subjects will continue to receive study drug q4w, 
although any additional placebo injections used to maintain the study blind during the 
blinded phase of the Part II LTE will be discontinued after study unblinding. 
Following the last scheduled dose of study drug at Week 72, a final safety follow-up 
visit will be performed at approximately Week 88. For subjects who discontinue study 
participation prior to Week 72, a final safety follow-up visit will be performed 16 
weeks after the last dose of study drug.
Rationale: The 16-week safety follow-up has been removed due to the well-known safety profile of ustekinumab.
Synopsis; 
3.1.4 Part II Long-
Term Extension;
6.3 Part II Long-term 
Extension
If a subject continues on ustekinumab in countries where commercial ustekinumab is not 
available or approved for adult Crohn’s disease, ustekinumab will continue to be provided 
to subjects through Week 72, followed by a final safety follow-up visit 16 weeks after the 
last dose of ustekinumab.
Rationale: To reduce the burden of the ustekinumab subjects who continue in the LTE, the laboratory assessments 
(including PK and immunogenicity) have been removed.
Synopsis;
3.1.4 Part II Long-
Term Extension;
6.3 Part II Long-term 
Extension
All subjects in the Part II LTE (before unblinding for JNJ-64304500, ustekinumab, and 
placebo and after unblinding for JNJ-64304500) will be assessed according to the Time & 
Events Schedule (Table 3, Table 4), which includes assessments, adverse events (AEs), 
laboratory analyses, and PK and immunogenicity samples. Ustekinumab subjects in the 
Part II LTE (after unblinding for ustekinumab subjects in countries where ustekinumab is 
not commercially available) will be assessed according to the Time & Events Schedule 
(Table ), which includes assessments and AEs.
Rationale: To update details around the subject unblinding in Part II of the study and the subsequent conduct of the 
LTE.
Section 5.2 Blinding
At the time of the interim analysis lock for Part I, a limited number of sponsor personnel 
will become unblinded to treatment assignment. At the time of the Week 12 DBL for Part I 
and the Week 12 DBL for Part II, the sponsor, except for site monitors, who have 
interactions with the investigative sites, will become unblinded to treatment assignment. 
Identification of sponsor personnel who will have access to subject-level data for the 
interim analysis lock for Part I will be documented before the unblinding. The study blind 
will be maintained for investigators, site personnel, subjects, and site monitors until the 
last subject in Part II has completed the Week 24 assessments and the Sponsor unblinds the 
study until the Week 24 analyses have been completed for Part II. This measure will 
mitigate the potential bias in the remaining investigator and subject assessments.


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Applicable 
Section(s)
Description of Change(s)
Rationale: To reduce the burden of the ustekinumab subjects who continue in the LTE, the laboratory assessments 
(including PK and immunogenicity) have been removed.
Section 9.1.1 
Overview
The Time and Events Schedules summarize the frequency and timing of efficacy, PK, 
immunogenicity, PD, pharmacogenomic, medical resource utilization, and safety 
measurements applicable to this study (Table 1, Table 2, Table 3, Table 4). The Time and 
Events Schedules for the LTE after unblinding for ustekinumab subjects in countries 
where ustekinumab is not commercially available (Table 4) includes safety assessments.
Rationale: The 16-week safety follow-up has been removed due to the well-known safety profile of ustekinumab.
10.1 Completion
The final safety follow-up visit will occur approximately 16 weeks after last study agent 
administration for all subjects who received JNJ-64304500 or ustekinumab. Following the 
study unblinding, any remaining ustekinumab subjects in the LTE (in countries were 
ustekinumab is not commercially available) will not have a final safety visit due to the 
well-known safety profile of ustekinumab. If the investigator decides that the patient 
should continue ustekinumab treatment after completing the Part II LTE, the investigator 
or the subject’s treating physician is responsible for providing the subject with commercial 
ustekinumab, which should be administered according to the approved dosing regimen in 
each country. Refer to Section 3.1.4, Part II Long-Term Extension, for details regarding 
the ustekinumab follow-up visit.
Rationale: The 16-week safety follow-up has been removed due to the well-known safety profile of ustekinumab.
Section 9.1.4 Final 
Efficacy and Safety 
Follow-up Visit
Subjects in the Part II LTE should complete the final safety follow-up visit approximately 
16 weeks after receiving the last dose of study drug (Table 3; Table 4). Subjects in the Part 
II LTE on ustekinumab after unblinding will not require a safety follow-up visit.
Rationale: To update details around the subject unblinding in Part II of the study and the subsequent conduct of the 
LTE.
Table 4, Time and 
Events Schedule, 
Long-term Extension 
Phase After 
Unblinding for 
Ustekinumab Subjects 
in Countries Where 
Ustekinumab is Not 
Commercially 
Available
Every 16 Weeks column was removed. 
Final safety follow-up column was removed.
Clinical laboratory assessments rows (hematology and chemistry) were removed. 
Pharmacokinetics/Immunogenicity rows (Study agent serum concentration, assessment for 
antibody to study agent) were removed.
Footnote h was removed: Serum concentration of study agent and antibodies to study agent 
will be evaluated. One venous blood sample of sufficient volume should be collected (at 
visits where study intervention will be administered, blood samples should be collected 
prior to study intervention administration). Each serum sample will be divided into 3 
aliquots (1 each for serum concentration of study agent, antibodies to study agent and a 
back-up).
Footnote i was removed: Pharmacokinetic and immunogenicity samples will be obtained 
only at the specified timepoints and when SAEs are reported by study subjects.
Footnote j was modified and updated to footnote h: Visits every 8 weeks may include 
scheduled visits at Weeks 32, 40, 48, 56, 64, and 72, depending on when unblinding 
occurs. The final safety assessment should be performed at the final dosing visit.
Footnote k was removed: Visits every 16 weeks may include scheduled visits at Weeks 40, 
56, and 72, depending on when unblinding occurs.


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Applicable 
Section(s)
Description of Change(s)
Rationale: Minor errors were noted. 
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 6 (04 February 2020)
The overall reason for the amendment: To adjust the maximum proportions of Bio-NF subjects enrolled in 
Part II.
Applicable Section(s)
Description of Change(s)
Rationale: The maximum proportion of Bio-NF subjects will be adjusted to 60% (from 50%), which will allow for 
additional enrollment flexibility, based upon observed enrollment patterns in Part II. The maximum proportion of 
Bio-IR subjects will remain at 60%. The proposed change should pose no risk to statistical power for Part II, as the 
power is based on overall population.
3.1, Overview of 
Study Design
The following subsection was revised: 
It is anticipated that approximately 370 to 420 subjects will be randomized overall across 
Part I and Part II:

Part I will study the safety and efficacy of a high dose regimen of JNJ-64304500 
compared with placebo and will enroll a minimum of 120 subjects and a maximum of 
170 subjects (Bio-IR and Bio-NF).

Part II will study the safety and efficacy of multiple-dose regimens of JNJ-64304500 
compared with placebo, with ustekinumab (STELARA®) as a reference arm. Part II 
will enroll approximately 250 subjects (the maximum proportion of either Bio-NF or 
Bio-IR subjects will be 60%).
3.1.2, Part II
The last sentence in the first paragraph was revised:
In Part II, 250 additional Bio-IR or Bio-NF subjects will be randomly assigned to receive 
placebo or 1 of 3 dose levels of JNJ-64304500 or ustekinumab in a ratio of 1:1:1:1:1 using 
permuted block randomization, stratified by baseline CDAI score (≤300 or >300), SNP-
positive status (yes or no), and Bio-IR status (yes or no). The maximum proportion of 
either Bio-NF or Bio-IR subjects will be 60%.


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Applicable Section(s)
Description of Change(s)
Rationale:  Footnotes in the Time and Events Schedules for the Part II Long-term Extension were revised to clarify 
that PK and immunogenicity samples will be collected at the timepoints shown in the schedules; PK and 
immunogenicity samples collected at Week 24 are part of the main study, not part of the LTE. 
Table 3, Time and 
Events Schedule, 
Long-term Extension 
Before Unblinding for 
JNJ-64304500, 
Ustekinumab, and 
Placebo and After 
Unblinding for JNJ 
64304500j
Footnote k was revised:
k.
Pharmacokinetic and immunogenicity samples will be obtained only at the specified 
timepoints and when SAEs are reported by study subjects.
Table 4, Time and 
Events Schedule, 
Long-term Extension 
Phase After 
Unblinding in 
Countries Where 
Ustekinumab is Not 
Commercially 
Available
Footnote i was revised:
i.
Pharmacokinetic and immunogenicity samples will be obtained only at the specified 
timepoints and when SAEs are reported by study subjects.
Rationale:  The specified time period for treatment with apheresis as an exclusion criterion (5h) was inadvertently 
omitted in Protocol Amendment 5 and has been reinstated.
4.2, Exclusion 
Criteria
5. Has received any of the following prescribed medications or therapies within the 
specified period:
…
h. Treatment with apheresis (eg, Adacolumn apheresis) <3 weeks before baseline.
Rationale: Minor errors were corrected. 
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 5 (17 January 2019)
The overall reason for the amendment: The 3 main reasons for updating this protocol were to reduce the sample 
size for Part II from 275 to 250 subjects, change the primary endpoint timing for Part II from Week 8 to Week 12,
based on the results from the previous Part I Week 12 analysis, and add a Part II long-term extension (LTE) to 
provide longer term study drug access to eligible subjects for up to 52 weeks. Additionally, the exclusion and 
discontinuation criteria have been refined for clarification.
Applicable Section(s)
Description of Change(s)


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Rationale: A 52-week LTE is being added to Part II to provide longer-term study drug access to eligible subjects 
who are benefitting from therapy, and to obtain longer-term safety data for JNJ-64304500.
Synopsis; Section 
1.2.2, Crohn’s 
Disease;
Section 3.1, Overview 
of Study Design;
Section 3.2, Study 
Design Rationale
The following sentence was added:
A long-term extension (LTE) for Part II of the study was added to the protocol as part of 
Protocol Amendment 5. After Protocol Amendment 5 is implemented, subjects who 
complete Part II Week 24 assessments and who may benefit from continued treatment in 
the opinion of the investigator, are eligible to enter the Part II LTE to receive up to 
52 weeks of additional treatment. Subjects who have completed Week 24 assessments 
prior to the implementation of Protocol Amendment 5 will not be eligible to enroll in the
Part II LTE.
The following sentence was added:
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24
assessments and who may benefit from continued treatment in the opinion of the 
investigator, are eligible to enter the Part II LTE to receive up to 52 weeks of additional 
treatment. Subjects who have completed Week 24 prior to the implementation of Protocol 
Amendment 5 will not be eligible to enroll in the Part II LTE.
Synopsis, Overview 
of Study Design
The 2nd paragraph was revised:
The duration of the study will be 38 weeks in Part I and 36 weeks in Part II for subjects 
who do not enter the Part II LTE. The study duration includes study agent administration 
visits and a final efficacy and safety follow-up visit. Eligible subjects will only participate 
in Part I or Part II of the study.
The following was added as the 3rd paragraph:
After Protocol Amendment 5 is implemented, subjects who complete Part II of the study 
through Week 24 and who may benefit from continued treatment in the opinion of the 
investigator, will be eligible to enter the Part II LTE to receive up to 52 weeks of 
additional treatment.
Synopsis, Dosage and 
Administration, 
Long-term Extension; 
Section 6.3, Part II
Long-term Extension
The following content was added:
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments, and who may benefit from continued treatment in the opinion of the 
investigator, are eligible to enter the Part II LTE. In the Part II LTE, each subject will be 
eligible to receive up to 52 weeks of additional study drug (for a total of up to 72 weeks of 
study drug in Part II). The first dose of study drug within the Part II LTE will be 
administered after the Week 24 assessments have been completed. The dose may be 
administered on the same day as the Week 24 assessments, or may be administered on a 
later date, as long as the dose is administered within the Week 24 visit window.
Subjects will continue to receive the same treatment regimen during the Part II LTE that 
they were receiving between Week 12 and Week 20 in the main study phase of Part II 
(placebo, high, middle, low dose JNJ-64304500 or ustekinumab). To maintain the study 
blind, all patients, investigators, and sites will remain blinded to treatment allocation 
during the Part II LTE until the last subject in the Part II main study phase has completed 
the Week 24 assessments and the Week 24 data analysis has been completed.
The timing of the Week 24 data analysis is dependent upon the timing and completion of 
Part II enrollment. An individual subject’s unblinding during the Part II LTE will depend 
upon his/her Part II enrollment date. Therefore, a portion of subjects will complete the 
entire Part II LTE in a blinded fashion before study unblinding, while other subjects could 


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be unblinded to treatment allocation during their participation in the Part II LTE.
Any subject who withdraws from the Part II LTE prior to study unblinding will return for a 
final safety follow-up visit 16 weeks after the last dose of study drug. For subjects that 
remain in the Part II LTE at the time of study unblinding, continuation of study drug 
during the Part II LTE will be dependent upon treatment allocation as follows:

JNJ-64304500: 
Subjects 
will 
continue 
to 
receive 
the 
same 
dose 
of 
JNJ-64304500 administered during the Part II main study phase. Subjects will 
continue to receive study drug q4w, although any additional placebo injections used to 
maintain the study blind during the blinded phase of the Part II LTE will be 
discontinued after study unblinding. Following the last scheduled dose of study drug 
at Week 72, a final safety follow-up visit will be performed at approximately Week 
88. For subjects who discontinue study participation prior to Week 72, a final safety 
follow-up visit will be performed 16 weeks after the last dose of study drug.

Placebo: Subjects receiving placebo who remain in the Part II LTE at the time of 
study unblinding will have their final safety follow-up visit subsequent to unblinding 
and will be discontinued from the study. No further follow-up visits will be 
performed.

Ustekinumab: Subjects receiving ustekinumab will continue to receive it during the 
Part II LTE until unblinding occurs. After unblinding, based on the treating 
physician’s clinical judgment, subjects may receive ustekinumab in a manner 
dependent on the country in which they are located:

If a subject is not continuing on ustekinumab after unblinding, the subject will 
need to return for a final safety follow-up visit that will be performed 16 weeks 
after the final dose of study ustekinumab.

If a subject continues on ustekinumab in a country where commercial 
ustekinumab is available and approved for the treatment of adult Crohn’s 
disease, the treating physician is responsible for providing the subject with 
commercial ustekinumab, which should be administered according to the 
approved dosing regimen in each country. The final safety follow-up visit 
should be performed after unblinding but before receiving the first dose of 
commercial ustekinumab.

If a subject continues on ustekinumab in countries where commercial 
ustekinumab is not available or approved for adult Crohn’s disease, 
ustekinumab will continue to be provided to subjects through Week 72, 
followed by a final safety follow-up visit 16 weeks after the last dose of 
ustekinumab.
For eligible Part II subjects, participation in the Part II LTE is entirely voluntary. Eligible 
subjects who do not wish to enter the Part II LTE will complete the Part II Week 24 safety 
and efficacy assessments, followed by the final efficacy and safety assessments at 
Week 36.
During the Part II LTE, all concomitant medications, including Crohn’s disease-specific 
medications (except for the prohibited medications listed in Section 8.2) may be 
administered at the discretion of the investigator.
All subjects in the Part II LTE will be assessed according to the Time & Events Schedule 
(Table 3, Table 4), which includes assessments, adverse events (AEs), laboratory analyses, 


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and PK and immunogenicity samples.
Synopsis, Efficacy 
Evaluations; Section 
3.1, Overview of 
Study Design; Section 
3.2.2, Efficacy 
Assessments
The following sentence was added:
Efficacy evaluations will not be performed during the Part II LTE.
Table 2, Time and 
Events Schedule: Part 
II Main Study Phase
Urine pregnancy test removed from Table 2 (Time and Events Schedule: Part II Main 
Study Phase) and added to Table 3 (Part II Long-term extension).
Footnotes b, c, d, and v updated:
b.
Visit windows should be ±4 days for each visit up to and including Week 12; 
from Week 16 to end of study, visit window should be ± 7 days.
c.
Subjects who terminate study participation should complete an early termination 
visit. If a subject completed assessments at Week 24 and terminated after 
Week 24, the only assessments that should be performed at the early termination 
visit are those planned for the final efficacy and safety follow-up visit. Subjects 
who discontinue study agent administration before Week 12 (but have not 
terminated study participation) should complete the Week 12 assessments and 
return for a final efficacy and safety follow-up visit approximately 16 weeks 
after their last study agent administration. Subjects who discontinue study agent 
administration after Week 12 (but have not terminated study participation) 
should complete the Week 24 assessments and return for a final efficacy and 
safety follow-up visit approximately 16 weeks after their last study agent 
administration.
d.
Subjects should complete a final efficacy and safety follow-up visit 
approximately 16 weeks after their last study agent administration. For subjects 
who complete all visits and are not enrolling in the Part II LTE, this will occur at 
Week 36.
v.
At all visits when study intervention will be administered, 1 blood sample should 
be collected prior to study intervention administration for evaluation of serum 
concentrations and/or antibodies to the study interventions. For the IV infusion 
related visit (Week 0), the SC study intervention should be administered first, 
followed by IV infusion; another blood draw should be taken approximately 
60 minutes after completion of the infusion for serum concentration 
measurement.
Footnote f added to Table 2.
Table 3, Time and 
Events Schedule: Part 
II Long-Term 
Extension
Time and Events Schedule: Time and Events Schedule, Long-term Extension Before 
Unblinding for JNJ-64304500, Ustekinumab, and Placebo and After Unblinding for 
JNJ-64304500 was added. 
Table 4, Time and 
Events Schedule: Part 
II Long-Term 
Extension
Time and Events Schedule: Long-term Extension Phase After Unblinding in Countries 
Where Ustekinumab is Not Commercially Available was added.


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Section 3.1, Overview 
of Study Design
The following sentence was added to the eleventh paragraph:
After Protocol Amendment 5 is implemented, all subjects who complete Part II of the 
study through Week 24, and who may benefit from continued treatment in the opinion of 
the investigator, are eligible to enter the Part II LTE and continue to receive treatment for 
up to 52 weeks (Week 24 to Week 72), as described in Section 3.1.4. A schematic 
representation of the Part II LTE is shown in Figure 3.
Section 3.1, Overview 
of Study Design
Figure 1, Schematic representation of 64304500CRD2001 was updated to include the 
Part II LTE.
Section 3.1, Overview 
of Study Design
Figure 3, Schematic Overview of the 64304500CRD2001 Part II (Including the Long-term 
Extension) was added.
Section 3.1.4, Long-
Term Extension
The following content was added:
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments, and who may benefit from continued treatment in the opinion of the 
investigator, are eligible to enter the Part II LTE. In the Part II LTE, each subject will be 
eligible to receive up to 52 weeks of additional study drug (for a total of up to 72 weeks of 
study drug in Part II). The first dose of study drug within the Part II LTE will be 
administered after the Week 24 assessments have been completed. The dose may be 
administered on the same day as the Week 24 assessments, or may be administered on a 
later date, as long as the dose is administered within the Week 24 visit window.
Subjects will continue to receive the same treatment regimen during the Part II LTE that 
they were receiving between Week 12 and Week 20 in the main study phase of Part II 
(placebo, high, middle, low dose JNJ-64304500 or ustekinumab). To maintain the study 
blind, all patients, investigators, and sites will remain blinded to treatment allocation 
during the Part II LTE until the last subject in the Part II main study phase has completed 
the Week 24 assessments and the Week 24 data analysis has been completed.
The timing of the Week 24 data analysis is dependent upon the timing and completion of 
Part II enrollment. Whether an individual subject will receive his/her treatment allocation 
during the Part II LTE will depend upon his/her Part II enrollment date. Therefore, a 
portion of subjects will complete the entire Part II LTE in a blinded fashion before study 
unblinding, while other subjects could be unblinded to treatment allocation during their 
participation in the Part II LTE.
Any subject who withdraws from the Part II LTE prior to study unblinding will return for a 
final safety follow-up visit 16 weeks after the last dose of study drug. For subjects that 
remain in the Part II LTE at the time of study unblinding, continuation of study drug 
during the Part II LTE will be dependent upon treatment allocation as follows:

JNJ-64304500: Subjects will continue to receive the same dose of JNJ-64304500 
administered during the Part II main study phase. Subjects will continue to receive 
study drug q4w, although any additional placebo injections used to maintain the study 
blind during the blinded phase of the Part II LTE will be discontinued after study 
unblinding. Following the last scheduled dose of study drug at Week 72, a final safety 
follow-up visit will be performed at approximately Week 88. For subjects who 
discontinue study participation prior to Week 72, a final safety follow-up visit will be 
performed 16 weeks after the last dose of study drug.

Placebo: Subjects receiving placebo who remain in the Part II LTE at the time of 


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study unblinding will have their final safety follow-up visit subsequent to unblinding 
and will be discontinued from the study. No further follow-up visits will be 
performed.

Ustekinumab: Subjects receiving ustekinumab will continue to receive it during the 
Part II LTE until unblinding occurs. After unblinding, based on the treating 
physician’s clinical judgment, subjects may receive ustekinumab in a manner 
dependent on the country in which they are located:
o
If a subject is not continuing on ustekinumab after unblinding, the subject 
will need to return for a final safety follow-up visit that will be performed 16 
weeks after the final dose of study ustekinumab.
o
If a subject continues on ustekinumab in a country where commercial 
ustekinumab is available and approved for adult Crohn’s disease, the treating 
physician is responsible for providing the subject with commercial 
ustekinumab, which should be administered according to the approved 
dosing regimen in each country. The final safety follow-up visit should be 
performed after unblinding but before receiving the first dose of commercial 
ustekinumab.
o
If a subject continues on ustekinumab in countries where commercial 
ustekinumab is not available or approved for adult Crohn’s disease, 
ustekinumab will continue to be provided to subjects through Week 72, 
followed by a final safety follow-up visit 16 weeks after the last dose of 
study drug.
For eligible Part II subjects, participation in the Part II LTE is entirely voluntary. Eligible 
subjects who do not wish to enter the Part II LTE will complete the Part II Week 24 safety 
and efficacy assessments, followed by the final efficacy and safety assessments at 
Week 36.
During the Part II LTE, all concomitant medications, including Crohn’s disease-specific 
medications (except for the prohibited medications listed in Section 8.2) may be 
administered at the discretion of the investigator.
All subjects in the Part II LTE will be assessed according to the Time & Events Schedule 
(Table 3, Table 4), which includes assessments, AEs, laboratory analyses, and PK and 
immunogenicity samples.
Section 4.2, 
Exclusion Criteria
The following content was added to the end of this section:
Long-term Extension Phase
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments and who may benefit from continued treatment in the opinion of the 
investigator, are eligible to enter the Part II LTE to receive up to 52 weeks of additional 
treatment. Subjects must be excluded from LTE if they have developed Crohn’s disease 
complications which may be anticipated to require surgery in the next 12 months, if they 
have clinical evidence of a serious infection at Week 24, or if they intend to participate in 
any other study using an investigational agent or procedure during participation in the 
LTE. Investigators who have questions regarding subject eligibility for the LTE should 


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contact the sponsor.
Section 5.2, Blinding
The third bullet point was added:

Final DBL for Part I: Occurs when all Part I subjects have completed their final 
efficacy and safety visit or have terminated their study participation before the final 
efficacy and safety visit.
The fourth bullet point was revised:

Week 12 DBL for Part II (final DBL for Part I occurs at the same time): Occurs 
when all Part II subjects have completed their Week 12 visit or have terminated their 
study participation before Week 12.
The sixth bullet point was revised:

Final DBL for Part II: Occurs when all Part II subjects who entered the Part II LTE
have completed their final safety visit in the Part II LTE or have terminated their 
study participation before the final safety visit in the Part II LTE.
The 3rd paragraph was revised:
At the time of the interim analysis lock for Part I, a limited number of sponsor personnel 
will become unblinded to treatment assignment. At the time of the Week 12 DBL for Part I 
and the Week 12 DBL for Part II, the sponsor, except for site monitors, who have 
interactions with the investigative sites, will become unblinded to treatment assignment. 
Identification of sponsor personnel who will have access to subject-level data for the 
interim analysis lock for Part I will be documented before the unblinding. The study blind 
will be maintained for investigators, site personnel, subjects, and sponsor site monitors 
until the final Week 24 analyses have been completed for all subjects in Part I and Part II. 
This measure will mitigate the potential bias in the remaining investigator and subject 
assessments.
Section 8.1,
Concomitant 
Medications
The following paragraph was added as the sixth paragraph in the section:
Subjects participating in the Part II LTE may continue receiving concomitant medications 
they were receiving at the time of Part II Week 24, including aminosalicylates, 
immunomodulatory agents (including 6-MP/AZA, MTX),
enteral therapy,
and 
corticosteroids. During the Part II LTE, these medications may be initiated, discontinued, 
or dose adjusted at the investigator’s discretion.
Section 8.1.1, 
Corticosteroid 
Tapering
The following sentence was added as the 3rd paragraph:
During the Part II LTE, corticosteroids may be initiated, discontinued, or dose adjusted at 
the investigator’s discretion
Section 8.2,
Prohibited 
Medications
The first sentence in the section was revised:
Randomized subjects must not initiate any of the following prohibited medications at any 
time during Part I, Part II, or the Part II LTE:
Section 9.1.1,
Overview
Added reference to Table 3, Time and Events Schedule, Long-term Extension Before 
Unblinding for JNJ-64304500, Ustekinumab, and Placebo and After Unblinding for 
JNJ-64304500 and Table 4: Time and Events Schedule, Long-term Extension Phase After 
Unblinding in Countries Where Ustekinumab is Not Commercially Available.


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The last paragraph was updated:
The maximum amount of blood drawn from each subject in this study will be 
approximately 330 mL.
Section 9.1.3, 
Double-Blind 
Treatment Period
The last sentence in this section was revised:
Each subject must be instructed to complete the CDAI diary card daily during the study, 
except during the Part II LTE.
Section 9.1.4, Final 
Efficacy and Safety 
Follow-up Visit
This section was revised:
Subjects in Part I and Part II should complete the final efficacy and safety follow-up visit 
approximately 16 weeks after the last study agent administration (Table 1, Table 2). 
Subjects in Part II who are not continuing into the Part II LTE should complete the final 
efficacy and safety follow-up visit approximately 16 weeks after receiving the last dose of 
study drug (Table 2). Subjects in the Part II LTE should complete the final safety follow-
up visit approximately 16 weeks after receiving the last dose of study drug 
(Table 3, Table 4). Placebo subjects who remain in the Part II LTE at the time of study
unblinding will have their final safety follow-up visit subsequent to unblinding and will be 
discontinued from the study.
Section 10.1,
Completion
The original section was updated to become a subsection: Main Study Phase (Part I and 
Part II)
The bullet points in the Main Study Phase (Part I and Part II) section were revised:

Subjects who discontinue study agent in Part I before Week 8 should return for the 
Week 8 and Week 12 visit and a final efficacy and safety follow-up visit, which 
should occur 16 weeks after receiving the last dose of study drug.

Subjects who discontinue study agent at or after Week 8 in Part I should complete the 
Week 12 and Week 24 visit and a final efficacy and safety follow-up visit, which 
should occur 16 weeks after receiving the last dose of study drug.

Subjects who discontinue study agent in Part II before Week 12 should return for the 
Week 12 visit and a final efficacy and safety follow-up visit, which should occur 16 
weeks after receiving the last dose of study drug.

Subjects who discontinue study agent at or after Week 12 in Part II should complete 
the Week 24 visit and a final efficacy and safety follow-up visit, which should occur 
16 weeks after receiving the last dose of study drug.
A new subsection was added:
Long-term Extension Phase
A subject will be considered to have completed the long-term extension phase of the study 
if he or she has completed the final safety follow-up visit in the Part II LTE.
The final safety follow-up visit will occur approximately 16 weeks after last study agent 
administration for all subjects who received JNJ-64304500 or ustekinumab. If the 
investigator decides that the patient should continue ustekinumab treatment after 
completing the Part II LTE, the investigator or the subject’s treating physician is 
responsible for providing the subject with commercial ustekinumab, which should be 
administered according to the approved dosing regimen in each country. Refer to 
Section 3.1.4, Part II Long-Term Extension, for details regarding the ustekinumab follow-


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up visit.
Subjects who received placebo will be considered to have completed the extension phase 
of the study if they complete 52 weeks of the Part II LTE and complete the final safety 
follow-up visit in the Part II LTE at before study unblinding or if they have been 
discontinued from the study prior to the final safety visit due to study unblinding. After 
unblinding of the Part II Week 24 data, subjects who received placebo during the Part II 
LTE will have their final safety follow-up visit at the time of study unblinding and will 
then be discontinued from the study. Subjects who prematurely discontinue study 
treatment for any reason, other than study unblinding, before completion of the study 
extension will not be considered to have completed the extension phase of the study.
Rationale: The assumptions for the sample size calculations in Part II have been refined based on observed efficacy 
data from the Part I Week 12 analysis. The sample size for Part II has been reduced from 275 to 250 (reduction of 
25 subjects, or 5 subjects per arm). 
Synopsis, Overview 
of Study Design
The first paragraph, 4th sentence revised:
An additional 250 subjects will be randomized in Part II.
Synopsis, Statistical 
Methods, Sample Size 
Determination
The first paragraph was revised:
Sample size calculations for Part I (Bio-IR subjects and Bio-NF subjects combined) were 
determined by the power to detect a significant difference in the change from baseline in 
the CDAI score at Week 8 between JNJ-64304500 and placebo using a 2-sample t-test. 
Sample size calculations for Part II (Bio-IR and Bio-NF subjects) were determined by the 
power to detect a dose-response signal for the change from baseline in the CDAI score at 
Week 12 (primary endpoint in Part II) using the Multiple Comparison Procedures with 
modeling techniques (MCP-Mod) method.
The third paragraph was revised:
For Part II, assuming the mean CDAI change from baseline at Week 12 is -111 in the JNJ-
64304500 group and -51 in the placebo group with a common SD of 102, 50 subjects per 
treatment group will provide a mean power of 85% to detect a dose-response signal based 
on 7 candidate dose-response models at an overall Type 1 error rate of 0.05.
Section 3.1, Overview 
of Study Design
The first sentence and the second bullet point of the seventh paragraph was revised:
It is anticipated that approximately 370-420 subjects will be randomized overall across 
Part I and Part II:

Part II will study the safety and efficacy of multiple-dose regimens of JNJ-64304500 
compared with placebo, with ustekinumab (STELARA®) as a reference arm. Part II 
will enroll approximately 250 subjects (Bio-NF subjects will be no more than 50% 
and Bio-IR subjects will be no more than 60%).
Section 3.1.2, Part II
The first sentence of the first paragraph was revised:
In Part II, 250 additional Bio-IR or Bio-NF subjects will be randomly assigned to receive 
placebo or 1 of 3 dose levels of JNJ-64304500 or ustekinumab in a ratio of 1:1:1:1:1 using 
permuted block randomization, stratified by baseline CDAI score (≤300 or >300), 
SNP-positive status (yes or no), and Bio-IR status (yes or no).


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Section 11.1, Sample 
Size Determination
This section was revised:
Sample size calculations for Part I and Part II were determined by the power to detect a 
significant difference in the change from baseline in the CDAI score at Week 8 (primary 
endpoint for Part I) between JNJ-64304500 and placebo using a 2-sample t-test. Sample 
size calculations for Part II were determined by the power to detect a dose-response signal 
for the change from baseline in CDAI at Week 12 (primary endpoint for Part II) using the 
Multiple Comparison Procedures with modeling techniques (MCP-Mod) method.
Section 11.1.1,
Sample Size in Part I
The title of Table 6 was revised to reflect the sample size of Part I.
Section 11.1.2,
Sample Size in Part II
The entire section was revised:
The assumptions for the sample size calculations in Part II were based on the Part I 
Week 12 analysis results. For Bio-IR subjects in Part I, the mean CDAI change from 
baseline at Week 12 was -30.9 (SD=85.15) and -77.4 (SD=103.68) for the placebo and 
JNJ-64304500 groups, respectively. For Bio-NF subjects in Part I, the mean CDAI change 
from baseline at Week 12 was -70.9 (SD=93.59) and -144.7 (SD=92.50) for the placebo 
and JNJ-64304500 groups, respectively.
For Part II, assuming the mean CDAI change from baseline at Week 12 is -111 in the 
JNJ-64304500 high dose group and -51 in the placebo group (these values are derived 
assuming a 1:1 ratio of Bio-IR and Bio-NF subjects) with a common SD of 102, 50 
subjects per treatment group will provide a mean power of 85% to detect a dose-response 
signal for the change from baseline in CDAI at Week 12 based on 7 candidate 
dose-response models (to be detailed in the SAP) at an overall Type 1 error rate of 0.05 
(2-sided). Fifty subjects per treatment group will also provide 83% power to detect a 
treatment difference between the JNJ-64304500 treatment group with the highest dose and 
the placebo treatment group for change from baseline in CDAI at Week 12 based on a 
2-sample t-test at a Type I error rate of 0.05 (2-sided; Table 7). This will result in a total 
sample size of 250 subjects in Part II (incorporating an additional 50 subjects for the 
ustekinumab treatment group).
Table 7 added to reflect the sample size in Part II.
Rationale: The timing for the primary endpoint and major secondary endpoints for Part II (except for the 
endoscopy endpoint) will be modified from Week 8 to Week 12, based on the results from the previous Part I Week 
12 analysis. This change will also align the timing of the primary endpoint and major secondary endpoints to the 
planned Week 12 Part II endoscopy endpoint. 
Synopsis, Primary 
Endpoints; Section 
2.1.2, Endpoints; 
Section 3.1, Overview 
of Study Design (9th
paragraph); Section 
11.2.2.1, Primary 
Endpoint Analyses
The primary endpoint was revised:
The primary endpoint for Part I and Part II is: Change from baseline in the CDAI score at 
Week 8.
The primary endpoint for Part II is: Change from baseline in the CDAI score at Week 12.


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Synopsis, Major 
Secondary Endpoints; 
Section 2.1.2, 
Endpoints; Section 
11.2.2.2, Major 
Secondary Endpoint 
Analyses
The major secondary endpoints were revised:

Clinical remission at Week 12 as measured by CDAI (CDAI <150).

Clinical response at Week 12 as measured by CDAI (≥100-point reduction from 
baseline in CDAI or CDAI <150).

Change in PRO-2 (the sum of the abdominal pain and stool frequency subscores of 
the CDAI score) from baseline at Week 12.

Clinical remission at Week 12 as measured by PRO-2 (PRO-2 <75).

Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from 
baseline in PRO-2 or PRO-2 <75).
Synopsis, Efficacy 
Analyses
The 4th paragraph was revised:
The primary endpoint for Part II is also the change from baseline in the CDAI score at 
Week 12. A unified strategy that combines Multiple Comparison Procedures with 
modeling techniques, MCP-Mod, will be used to analyze the dose-response data over the 
JNJ-64304500 doses. This approach consists of 2 major steps. The first step consists of 
testing the dose-response signal via multiple contrast tests while controlling the overall 
Type 1 error. If a dose-response signal is detected, the second step is to select a model that 
best describes the observed data and use it to estimate adequate doses with associated 
precision. The study will be considered positive if a dose-response signal for the primary 
endpoint is detected. In addition to the dose-response analysis, pairwise comparisons of the 
JNJ-64304500 treatment groups versus the placebo group will be performed for the change
from baseline in the CDAI score at Week 12; these comparisons will not be adjusted for 
multiplicity.
Section 2.1.2,
Endpoints; Section 
11.2.1.2, Other 
Efficacy Endpoint 
Analyses
Three efficacy endpoints were updated:

Clinical remission based on CDAI at Week 24 among subjects in clinical response at 
Week 12.

Clinical remission based on CDAI at Week 24 among subjects in clinical remission at 
Week 12.

Clinical remission based on CDAI at Week 12 by SNP status. Subjects who are 
positive in at least 1 of 2 SNPs (NKG2D or MICB) will be considered to be 
SNP-positive.
Section 3.1, Overview 
of Study Design
Figure 3 was updated to reflect that the primary endpoint analysis occurs at Week 12 
instead of Week 8. It was also updated with a note that the Final Safety and Efficacy Visit
will occur at Week 36 if the subject is not enrolling in the Part II LTE.


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Section 3.2.2, 
Efficacy Assessments
This section was revised to:
The efficacy evaluations selected for both parts of the study (eg, CDAI, CRP, fecal 
biomarkers; Section 9.2) are well-established measures that are accepted by regulatory 
agencies as primary or supportive of clinically relevant effect of disease activity in Crohn’s 
disease studies.
The primary endpoint for Part I is change from baseline in CDAI at Week 8. The primary 
endpoint for Part II is change from baseline in CDAI at Week 12.
Change in the CDAI is being used as the primary endpoint because this measure is more 
sensitive than remission (ie, the change in CDAI provides greater power than remission for 
the same sample size). Therefore, the study can be more efficient for Phase 2 using the 
change in CDAI.
To evaluate the level of efficacy after prolonged discontinuation of study drug, CDAI will 
be assessed at the final efficacy and safety visit in Part I and Part II for those subjects who 
do not enter the Part II LTE. The Crohn’s Disease Activity Index will be not assessed 
during the Part II LTE.
It is anticipated that endoscopic improvement will occur by Week 12. In order to have an 
appropriate comparison of JNJ-64304500 to placebo, the placebo-controlled period will 
continue to Week 12.
Efficacy evaluations will not be performed during the Part II LTE.
Section 9.1.3, 
Double-Blind 
Treatment Period
The first sentence in the first paragraph was revised to:
In Part I, the visit window should be ±4 days for each visit. In Part II, the visit window 
should be ±4 days, from the Week 0 visit up to and including the Week 12 visit, and 
±7 days from Week 16 until the end of the study.
Section 11.2.2.1, 
Primary Endpoint 
Analysis; Section 
11.2.2.2, Major 
Secondary Endpoint 
Analyses
All references to Week 8 were changed to Week 12.
Rationale: The Part II Week 24 optional endoscopy was removed. The optional Week 24 endoscopy in Part II was 
intended to obtain additional biomarker data. Similar to Part I, mandatory baseline and Week 12 endoscopies will be 
performed on all subjects in Part II, which will be used to assess efficacy in conjunction with the primary efficacy 
endpoint (change in CDAI from baseline at Week 12). Elimination of the optional Week 24 endoscopy in Part II
will therefore not impact the primary Part II endpoint and is expected to reduce the burden upon the patients, sites, 
and investigators at the Week 24 visit.
Table 2, Time and 
Events Schedule: Part 
II
Video ileocolonoscopy and ileocolonoscopy biopsy sample collection for RNA and 
histology were removed from the Week 24 visit.
Footnote t was removed; the Week 24 video ileocolonoscopy and related endoscopic 
assessments are optional.


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Section 9.2.11, 
Endoscopic Endpoints
The first paragraph was revised:
Endoscopic improvement will be assessed during endoscopy (ileocolonoscopy). A video 
ileocolonoscopic examination will be performed to determine the presence or absence of 
mucosal inflammation and ulceration at screening and Week 12, and Week 24 (optional in 
Part I), according to the Study Reference Manual provided to each site; if the video 
ileocolonoscopic examination is not performed on the day of the visit, it must be 
performed at least 8 days before the Week 0 visit and no more than 8 days before the Week 
12 visit. The Week 24 video ileocolonoscopy in Part I is suggested but not required; if 
performed, it should occur not more than 8 days before the Week 24 visit. The video 
ileocolonoscopy will not be performed at Week 24 in Part II. Video endoscopies will be 
assessed by a central facility that will be blinded to treatment group and study visit. A 
complete video endoscopic examination does not require assessment of the terminal ileum 
if it cannot be visualized. 
Rationale: Guidelines for administration of parenteral nutrition and enteral nutrition were updated. As a safety 
mitigation measure, exclusion of total parenteral nutrition has now been broadened to exclusion of both total and 
partial parenteral nutrition administered through any indwelling catheter. The exclusion of subjects recently 
initiating enteral therapy is added because initiation of enteral therapy may confound the efficacy endpoint 
evaluation in this study.
Section 4.2, 
Exclusion Criteria
Footnote 5i was added:
Initiation of total (complete) or partial (supplemental) parenteral nutrition administered 
through any indwelling catheter <3 weeks before baseline or anticipated to require 
parenteral nutrition administered through an indwelling catheter during enrollment in the 
study.
Footnote 5j was added:
Initiation of enteral therapy for Crohn’s disease (defined as liquid nutritional formula 
comprising ≥80% of total caloric intake administered through the gastrointestinal tract) <3 
weeks before baseline. Subjects who are on a stable regimen of enteral feeds ≥3 weeks 
before baseline may be considered for enrollment if they plan to continue enteral feeds as 
treatment for Crohn’s disease through the duration of the study (Week 24, Part I or Part II).
Section 8.1, 
Concomitant 
Medications
The first paragraph was revised to add enteral therapy:
Subjects who are receiving oral 5-ASA compounds, oral corticosteroids, conventional 
immunomodulators (ie, AZA, 6-MP, or MTX), enteral therapy, and/or antibiotics for the 
treatment of Crohn’s disease at baseline should maintain a stable dose for a specified 
period before baseline, as defined in the Inclusion Criteria (Section 4.1).
The 3rd paragraph, 5th bullet point was revised to:

Total (complete) or partial (supplemental) parenteral nutrition administered through 
an indwelling catheter as a treatment for Crohn’s disease.
A 6th bullet point was added to the 3rd paragraph:

Enteral therapy (liquid nutritional formula comprising ≥80% of total caloric intake) 
as treatment for Crohn’s disease.
Rationale: Discontinuation of study treatment guidelines were updated for clarification. 


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Section 10.2, 
Discontinuation of 
Study Treatment
The 5th bullet point was revised:
Adverse events of NCI-CTCAE grade ≥3 potentially related to worsening of Crohn’s disease
will be evaluated by the investigator and the study medical monitor to make a determination 
on discontinuation of study agent. Discontinuation of study agent should be considered in 
subjects with worsening Crohn’s disease where continuation of the study drug is not in the 
best interest of the subject.
The following was added as the 7th bullet point:
Total (complete) or partial (supplemental) parenteral nutrition is initiated through an 
indwelling catheter at any time during the study.
The 2nd paragraph was revised from:
Discontinuation of study agent administration must be considered for subjects who develop a 
severe injection-site or infusion reaction or who develop a serious infection.
To:
In the event of any serious infection, severe injection-site or infusion reaction, the study drug 
must be held and dosing may not be resumed until the investigator has discussed the case 
with the study medical monitor.
Rationale: Attachment 2: Definitions of Inadequate Response to or Intolerance of Corticosteroids or 
AZA/6-MP/MTX and Corticosteroid Dependence was updated to include Methotrexate (MTX). There is no change 
to the originally intended protocol criteria. The specified criteria for MTX were erroneously omitted in the original 
protocol.
Attachment 2:
Definitions of 
Inadequate 
Response to or 
Intolerance of 
Corticosteroids or 
AZA/6-MP/MTX 
and Corticosteroid 
Dependence
The content in this attachment was revised:
CORTICOSTEROIDS
Subjects have failed to respond to corticosteroids if they have had evidence of an initial 
inadequate response, recurrent disease, or a relapse despite receiving at least 0.75 mg/kg/day 
or >40 mg/day of prednisone (or corticosteroid equivalent, given orally or intravenously) for 
2 weeks; or ≥9 mg/day of budesonide or ≥5 mg/day of beclomethasone dipropionate given 
orally for at least 4 weeks.
Subjects are intolerant of corticosteroids if:

They have developed clinically significant adverse events (eg, osteonecrosis or 
osteoporosis, psychosis, uncontrolled diabetes) unresponsive to dose reduction that, in 
the judgment of the investigator, precluded the use of corticosteroids to treat Crohn’s 
disease.
OR

They have a medical condition that precludes the use of corticosteroids as a treatment 
for Crohn’s disease.
Subjects are corticosteroid dependent if they have failed to successfully taper their 
corticosteroid (ie, had a flare of disease) within 3 months of starting therapy, or if a relapse 
occurs within 3 months after stopping corticosteroids or if they are unable to discontinue 
these agents without flare within 3 months after starting them.
6-MERCAPTOPURINE (6-MP), AZATHIOPRINE (AZA), OR METHOTREXATE
(MTX):
Subjects have failed to respond to 6-MP, AZA, or MTX if they have had evidence of an 


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initial inadequate response, recurrent disease, or a relapse despite receiving:

At least 3 months of therapy with 1 mg/kg/day of 6-MP, 2 mg/kg/day of AZA, or 
25 mg/week (intramuscular or subcutaneous) of MTX.
OR

A lower dosage of 6-MP, AZA, or MTX when country or local guidelines specify a 
different treatment regimen. (In such an event, the country or local guidelines needs to 
be included in the source document).
OR

The dosage of 6-MP, AZA, or MTX confirmed to be therapeutic for the subject with 
whole blood thioguanine nucleotide levels >200 pmole/8x108 red blood cells.
OR

The highest tolerated dosage due to leukopenia, elevated liver enzymes, or nausea.
Subjects are intolerant of 6-MP, AZA, or MTX if:

They have developed clinically significant adverse events (eg, pancreatitis, arthritis 
accompanied by high fever and/or rash, leukopenia, or persistently elevated liver 
enzymes) unresponsive to dose reduction that, in the judgment of the investigator, 
precluded the use of 6-MP, AZA, or MTX to treat Crohn’s disease within the past 
5 years.
OR

They have a medical condition that precludes the use of 6-MP, AZA, or MTX.
Rationale: Attachment 3: QuantiFERON-TB Gold Testing was removed since most of this information is included 
in the Site Laboratory Manual and is not necessary to be included in the protocol. QuantiFERON-TB Gold test has 
been updated to QuantiFERON-TB test since there may be regional or country-specific variability in the type of 
QuantiFERON-TB test used based on changes in performance of the test by the central lab.
Table 1, Time and 
Events Schedule: Part 
I; Table 2, Time and 
Events Schedule: Part 
II; Section 4.1, 
Inclusion Criteria 
#11.d.1; Section 
9.1.2, Screening 
Period; Section 9.7, 
Safety Evaluations; 
Section 10.2, 
Discontinuation of 
Study Treatment
QuantiFERON-TB Gold test revised to QuantiFERON-TB test.
Attachment 3: 
QuantiFERON-TB 
Gold Testing
Removed from protocol.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 4 (24 April 2018)
The overall reason for the amendment: To revise the study drug concentrations in Section 6.2 for the JNJ-
64304500 low and middle doses in Part II of the study to correspond to the Investigational Product Preparation 
Instructions dilution regimen.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the study drug concentrations of JNJ-64304500 in Part II of the study.
6.2 Part II
The 3rd bullet is revised from:
JNJ-64304500 middle dose: 150 mg SC at Week 0 and 75 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20. (Study drug concentration=100 mg/mL and 50 mg/mL at Week 0, 75 mg/mL for 
subsequent doses)
To:
JNJ-64304500 middle dose: 150 mg SC at Week 0 and 75 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20 (study drug concentration=75 mg/mL).
The 4th bullet is revised from:
JNJ-64304500 low dose: 50 mg SC at Week 0 and 25 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20. (Study drug concentration=50 mg/mL at Week 0, 25 mg/mL for subsequent doses)
To:
JNJ-64304500 low dose: 50 mg SC at Week 0 and 25 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20 (study drug concentration=25 mg/mL).
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3 12 December 2017
This amendment is considered to be substantial based on the criteria set forth in the Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To change the timing and subject population for the Interim Analysis in 
Part I; change the overall sample size of Part I; and change the subject population and sample size in Part II.
Clarification of specific study procedures is also included in this amendment as described below.
Applicable Section(s)
Description of Change(s)
Rationale (To change the timing and subject population for the Interim Analysis in Part I): The original 
planned interim analysis was solely based on the Bio-IR population. It was projected that this study would enroll the 
Bio-IR population before the Bio-NF population. In actuality, both populations are enrolling at a similar rate. The 
change in the subject population reflects the current recruitment rate and will enable a decision based upon both 
populations. This is important considering the population in Part II will now also include Bio-NF subjects. In 
addition, a change from Week 8 to Week 12 for the interim analysis allows endoscopic data to be incorporated into 
the decision on whether to initiate Part II.
Applicable Section(s)
Description of Change(s)


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Synopsis
Under the Endpoints section, the following sentence was added:
The data from Study 1 and Study 2 in Part I will be pooled for analysis.
In the Overview of Study Design section, the fourth paragraph was revised to read:
An interim analysis is planned in Part I when 100 randomized Part I subjects (Study 1: Bio-
IR and Study 2: Bio-NF) have completed their Week 12 visit or have terminated their study 
participation before Week 12. If acceptable safety and efficacy are established in the 
combined Bio-IR and Bio-NF populations, Part II of the protocol, which consists of a dose-
ranging study in subjects who are Bio-IR or Bio-NF, will be initiated. The interim analysis 
will allow for timely evaluation of safety and efficacy in Part I and uninterrupted patient 
enrollment through a seamless transition from Part I to Part II of the trial. Enrollment for 
Part I will continue until the sponsor makes a decision on whether to start Part II based on 
the interim analysis or when a maximum of 170 subjects have been randomized, whichever 
occurs first. Part II will be initiated if results from Part I demonstrate acceptable safety and 
efficacy, either at the interim analysis or when all Part I subjects have completed their 
Week 12 visit (or 
have terminated study participation prior to Week 12). If Part II is not initiated based on the 
interim analysis results, then the results through Week 12 for all subjects in Part I (ie, when 
all randomized subjects in Part I have either completed the Week 12 visit or terminated 
study participation prior to Week 12) will be examined to determine whether to start Part II. 
Under this scenario, a pause in enrollment between Part I and Part II will occur.
In the Dosage and Administration Part I section, the first paragraph was revised to read:
In Part I, a minimum of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF) 
will be randomly assigned to receive placebo or the JNJ-64304500 high dose in a 1:1 ratio 
using permuted block randomization, stratified by baseline CDAI score (≤300 or >300) and 
SNP-positive status (yes or no). The Bio-IR and Bio-NF populations will be randomized 
separately.
2.1.2. Endpoints
The following sentence was added:
The data from Study 1 and Study 2 in Part I will be pooled for analysis.
3.1. Overview of 
Study Design
The fourth paragraph was revised to read:
The 2 studies in Part I serve to build on the original Phase 2a study findings by employing 
dedicated populations of both Bio-IR and Bio-NF subjects. If acceptable safety and 
efficacy are established in the combined Bio-IR and Bio-NF populations, Part II of the 
protocol, which consists of a dose-ranging study (Study 3) in subjects who are Bio-IR or 
Bio-NF, will be initiated.
The following sentence was removed from the tenth paragraph:
Each of the 3 studies will be analyzed separately.
3.1.1. Part I
This section was revised to read:
In Part I, a minimum of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF) 
will be randomly assigned to receive placebo or the JNJ-64304500 high dose in a 1:1 ratio 
using permuted block randomization, stratified by baseline CDAI score (≤300 or >300) and 
SNP-positive status (yes or no). Separate randomizations will be used for the Bio-IR and 
Bio-NF populations.
The treatment groups for each study in Part I will be as follows:

Placebo SC at Weeks 0, 2, 4, 6, 8, and 10; from Week 12, these subjects will receive 


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additional doses as follows:

Placebo-treated subjects who are in clinical response at Week 12 (≥100-point 
reduction from baseline in CDAI or CDAI <150) will continue to receive 
placebo SC injections q2w from Week 12 through Week 22.

Placebo-treated subjects who are not in clinical response at Week 12 will receive 
JNJ-64304500 400 mg SC at Week 12 and then 200 mg SC q2w from Week 14 
through Week 22. 

JNJ-64304500 400 mg SC at Week 0 then 200 mg SC q2w through Week 22.
An interim analysis is planned in Part I when 100 randomized subjects (Bio-IR and Bio-
NF) have completed their Week 12 visit or have terminated their study participation before 
Week 12. The interim analysis will allow for uninterrupted patient enrollment through a 
seamless transition from Part I to Part II of the trial.
To allow for uninterrupted patient enrollment through a seamless transition from Part I to 
Part II of the trial, enrollment for Part I will continue until the sponsor makes a decision on 
whether to start Part II based on the interim analysis or when a maximum of 170 subjects 
have been randomized, whichever occurs first. If Part II is not initiated based on the interim 
analysis results, then the results through Week 12 for all subjects in Part I (ie, when all 
randomized subjects in Part I have either completed the Week 12 visit or terminated study 
participation prior to Week 12) will be examined to determine whether to start Part II. 
Under this scenario, a pause in enrollment between Part I and Part II will occur.
3.1.3. Interim 
Analysis
The entire section was revised to read:
An interim analysis is planned in Part I when 100 randomized Part I subjects (Study 1: Bio-
IR and Study 2: Bio-NF) have completed their Week 12 visit or have terminated their study 
participation before Week 12.
This interim analysis will allow for uninterrupted patient enrollment through a seamless 
transition from Part I to Part II of the trial. As this interim analysis does not affect the 
conduct or completion of Part I it will be considered administrative and will not require 
multiplicity adjustment for the final Part I analysis.
A sponsor committee independent of the study team will be established to review the 
interim data and formulate recommended decisions/actions in accordance with predefined 
decision rules (to be defined in the Interim Analysis Plan).
An interim analysis is not planned for Part II.
Other planned DBLs are described in Section 5.2.
3.2. Study Design 
Rationale
The first paragraph was revised to read:
This protocol is comprised of 2 parts (Part I [Study 1: Bio-IR subjects and Study 2: Bio-NF 
subjects] and Part II [Bio-IR and Bio-NF subjects]) that are designed to evaluate the safety 
and efficacy of JNJ-64304500 in subjects with moderately to severely active Crohn’s 
disease. Study 1 and Study 2 constitute Part I of the protocol. In this part, the safety and 
efficacy of a single dosing regimen of JNJ-64304500 in Bio-IR and Bio-NF subjects with 
moderately to severely active Crohn’s disease is evaluated. If acceptable efficacy is 
established in Part I (for the combined Bio-IR and Bio-NF subjects), Part II (a dose-ranging 
study in Bio-IR and Bio-NF subjects) will be initiated.


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3.2.1. Study 
Population
The entire section was removed:
The target population for each of the 3 studies consists of men or women ≥18 years of age 
at the time of informed consent with moderately to severely active Crohn’s disease (of at 
least 3 months’ duration), defined as a CDAI score ≥220 and ≤450, with elevated CRP 
>0.3 mg/dL (>3.0 mg/L) and/or calprotectin >250 mg/kg.
Additionally, subjects in these studies must have previously failed or been intolerant to 1 or 
more approved biologic agents (ie, TNFα-antagonists or vedolizumab) or have 
demonstrated an inadequate response to or failed to tolerate corticosteroids or 
immunomodulators (ie, 6-mercaptopurine [6-MP], azathioprine [AZA], and MTX) but not 
a biologic agent.
The Bio-IR population, comprising subjects who have failed to respond, lost response, or 
have been intolerant to one or more biologic therapies, is the primary population of interest 
for this protocol because it has the highest unmet need with current therapies. Responses to 
therapies are generally lower in the Bio-IR population than in the Bio-NF population.
The cohort of Bio-NF subjects is included in Part I (Study 2) to obtain additional 
information about the effect of JNJ-64304500 in this population early in the development 
program.
3.2.3. Efficacy 
Assessments
The last sentence of the third paragraph was removed:
The clinical remission endpoint is being used for the interim analysis, however, as it is a 
more stringent endpoint and provides a more conservative decision rule to determine 
whether to start Part II early.
11.10 Interim 
Analysis
The entire section was revised to read:
An interim analysis is planned in Part I when 100 randomized subjects (Study 1: Bio-IR 
and Study 2: Bio-NF) have completed their Week 12 visit or have terminated their study 
participation before Week 12. This interim analysis will allow for uninterrupted patient 
enrollment through a seamless transition from Part I to Part II of the trial. As this interim 
analysis does not affect the conduct or completion of Part I, it will be considered 
administrative and will not require multiplicity adjustment for the final Part I analysis.
The primary efficacy evaluation is the comparison between JNJ-64304500 and placebo 
with respect to the change in CDAI from baseline (in the combined Bio-IR and Bio-NF 
subjects). Other selected efficacy analyses (eg, clinical remission, clinical response, and 
change in SES-CD) will also been performed; details will be provided in the Interim 
Analysis Plan.
A sponsor committee independent of the study team will be established to review the 
interim data and formulate recommended decisions/actions in accordance with predefined 
decision rules that will be defined in the Interim Analysis Plan.
Rationale (change the overall sample size of Part I): The Part I analysis is now focused on all subjects (Bio-IR vs. 
Bio-NF) due to the faster than anticipated enrollment of the Bio-NF population. This analysis may be more 
reflective of the patient population in need of therapy. The overall sample size of Part I was changed to a minimum 
of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF). 
Applicable Section(s)
Description of Change(s)


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Synopsis
The Overview of Study Design section was revised to read:
This protocol is comprised of 2 parts (Part I [Study 1: Bio-IR subjects and Study 2: Bio-NF 
subjects] and Part II [Bio-IR and Bio-NF subjects]). Each study is a randomized, double-
blind, placebo-controlled, parallel-group, multicenter study of JNJ-64304500 in subjects 
with moderately to severely active Crohn’s disease. A minimum of 120 subjects and a 
maximum of 170 subjects (Bio-IR and Bio-NF) will be randomized in Part I. An additional 
275 subjects will be randomized in Part II. Part I will study the safety and efficacy of a high 
dose regimen of JNJ-64304500 compared with placebo in subjects who have failed biologic 
or conventional therapy (Bio-IR or Bio-NF subjects, respectively). Part II will study the 
safety and efficacy of multiple-dose regimens of JNJ-64304500 compared with placebo, 
with ustekinumab (STELARA®) as a reference arm, in Bio-IR and Bio-NF subjects.
The duration of the study will be 38 weeks in Part I and 36 weeks in Part II for a subject 
who completes all scheduled visits, including study agent administration visits and a final 
efficacy and safety follow-up visit. Eligible subjects will only participate in Part I or Part II 
of the study.
The Time and Events Schedules summarize the frequency and timing of assessments for
efficacy, PK, biomarkers, immunogenicity, PD, and safety in Part I and Part II of the study.
An interim analysis is planned in Part I when 100 randomized Part I subjects (Study 1: Bio-
IR and Study 2: Bio-NF) have completed their Week 12 visit or have terminated their study 
participation before Week 12. If acceptable safety and efficacy are established in the 
combined Bio-IR and Bio-NF populations, Part II of the protocol, which consists of a dose-
ranging study in subjects who are Bio-IR or Bio-NF, will be initiated. The interim analysis 
will allow for timely evaluation of safety and efficacy in Part I and uninterrupted patient 
enrollment through a seamless transition from Part I to Part II of the trial. Enrollment for 
Part I will continue until the sponsor makes a decision on whether to start Part II based on 
the interim analysis or when a maximum of 170 subjects have been randomized, whichever 
occurs first. Part II will be initiated if results from Part I demonstrate acceptable safety and 
efficacy, either at the interim analysis or when all Part I subjects have completed their 
Week 12 visit (or have terminated study participation prior to Week 12). If Part II is not 
initiated based on the interim analysis results, then the results through Week 12 for all 
subjects in Part I (ie, when all randomized subjects in Part I have either completed the 
Week 12 visit or terminated study participation prior to Week 12) will be examined to 
determine whether to start Part II. Under this scenario, a pause in enrollment between Part I 
and Part II will occur.
An external Data Monitoring Committee (DMC) will review unblinded safety data from all 
subjects periodically to monitor subject safety.
The end of the 64304500CRD2001 study is defined as the date on which the last subject 
completes the last efficacy and safety follow-up visit.
In the Sample Size Determination section, the first and second paragraphs were revised to 
read:
Sample size calculations for Part I (Bio-IR subjects and Bio-NF subjects combined) were 
determined by the power to detect a significant difference in the change from baseline in 
the CDAI score at Week 8 between JNJ-64304500 and placebo using a 2-sample t-test. 
Sample size calculation for Part II (Bio-IR and Bio-NF subjects) was determined by the 
power to detect a dose-response signal in the change from baseline in the CDAI score at 
Week 8 (primary endpoint in Part II) using the Multiple Comparison Procedures with 
modeling techniques (MCP-Mod) method.
For Part I, assuming the mean CDAI change from baseline at Week 8 is -98 in the JNJ-
64304500 group and -46 in the placebo group with a common SD of 96, 60 subjects per 


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treatment group will provide 84% power to detect a treatment difference between JNJ-
64304500 and placebo at an overall Type 1 error of 0.05.
In the Efficacy Analyses section, the first 3 paragraphs were revised to read:
This protocol is comprised of 2 separate parts (Part I [Study 1: Bio-IR subjects and Study 2: 
Bio-NF subjects] and Part II [Bio-IR and Bio-NF subjects]). Part I and Part II will be 
analyzed separately with separate Type I error control for the primary endpoint (at the 0.05 
level of significance). The other endpoints within each part will not be controlled for 
multiplicity.
For each part, the analysis set is all randomized subjects who received study agent. Efficacy 
analyses will be based on a modified intent-to-treat principle. Therefore, the efficacy data 
for each subject who received study agent will be analyzed according to the assigned 
treatment regardless of the actual treatment received.
For Part I, the primary endpoint of change from baseline in the CDAI score at Week 8 will 
be compared between the JNJ-64304500 treatment group and the placebo treatment group 
by an analysis of covariance model on the van der Waerden normal scores with treatment 
as a fixed factor and baseline CDAI score, SNP-positive status (yes or no), and Bio-IR 
status (yes or no) as covariates. Part I will be considered to be positive if a significant 
improvement is detected in the change from baseline in the CDAI score at Week 8 in the 
JNJ-64304500 group compared with the placebo group at the 0.05 level of significance.
3.1. Overview of 
Study Design
The seventh paragraph was revised to read:
It is anticipated that approximately 395-445 subjects will be randomized overall across Part
I and Part II:

Part I will study the safety and efficacy of a high dose regimen of JNJ-64304500 
compared with placebo and will enroll a minimum of 120 subjects and a maximum of 
170 subjects (Bio-IR and Bio-NF).
3.1.1. Part I
The first paragraph was revised to read:
In Part I, a minimum of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF)
will be randomly assigned to receive placebo or the JNJ-64304500 high dose in a 1:1 ratio 
using permuted block randomization, stratified by baseline CDAI score (≤300 or >300) and 
SNP-positive status (yes or no). Separate randomizations will be used for the Bio-IR and 
Bio-NF populations. 
11.1. Sample Size 
Determination
The first paragraph was revised to read:
Sample size calculations for Part I and Part II were determined by the power to detect a 
significant difference in the change from baseline in the CDAI score at Week 8 (primary 
endpoint in each part) between JNJ-64304500 and placebo using a 2-sample t-test. 
11.1.1. Sample Size 
in Part I (Study 1 and 
Study 2)
The section header was updated to Sample Size in Part I.
Subheaders 11.1.1.1. Bio-IR Subjects (Study 1), 11.1.1.1.1. All Bio-IR Subjects, 11.1.1.1.2 
Bio-IR Subjects Who Are SNP-Positive (Bio-IR/SNP+), 11.1.1.1. Bio-NF Subjects 
(Study 2), 11.1.1.2.1. All Bio-NF Subjects, and 11.1.1.2.2. Bio-NF Subjects Who Are SNP-
Positive (Bio-NF/SNP+) were removed.
The entire section was revised to read:
Part I is powered based on the combined data from Study 1 and Study 2. Study 1 and Study 
2 were not individually powered to detect differences between JNJ-64304500 and placebo.


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The assumptions for the sample size calculations in Part I were based on data from 
CNTO1275CRD3001 (a study conducted by the sponsor in subjects with Crohn’s disease 
who had failed or were intolerant to TNF-antagonist therapy) and CNTO1275CRD3002 (a 
study conducted by the sponsor in subjects with Crohn’s disease who had failed or were 
intolerant to corticosteroids or immunomodulators but who had not failed TNF-antagonist 
therapy). In CNTO1275CRD3001, the mean CDAI change from baseline at Week 8 was -
25.1 (SD=91.41) and -78.7 (SD=91.79) for the placebo and ustekinumab 6 mg/kg groups, 
respectively. These assumptions incorporated the impact of 6% of subjects being 
noncompleters (in CNTO1275CRD3001). In CNTO1275CRD3002, the mean CDAI 
change from baseline at Week 8 was -66.3 (SD=97.81) and -116.3 (SD=102.88) for the 
placebo and ustekinumab 6 mg/kg groups, respectively. These assumptions incorporated 
the impact of 4% of subjects being noncompleters (in CNTO1275CRD3002).
For Part I, assuming the mean CDAI change from baseline at Week 8 is -98 in the JNJ-
64304500 group and -46 in the placebo group with a common SD of 96 (these values are 
derived assuming 1:1 ratio of Bio-IR and Bio-NF subjects) 60 subjects per treatment group 
(a total of 120 subjects) will provide 84% power to detect a treatment difference between 
JNJ-64304500 and placebo at an overall Type 1 error of 0.05 (2-sided).
Table 4 was updated.
Section 11.2. 
Efficacy Analyses
This section was revised to read:
This protocol is comprised of 2 separate parts (Part I [Study 1: Bio-IR subjects and Study 2: 
Bio-NF subjects] and Part II [Bio-IR and Bio-NF subjects]). Part I and Part II will be 
analyzed separately with separate Type I error control for the primary endpoint (at the 0.05 
level of significance). The other endpoints within each part will not be controlled for 
multiplicity.
For each part, the analysis set is all randomized subjects who received study agent. Efficacy 
analyses will be based on a modified intent-to-treat principle. Therefore, the efficacy data 
for each subject who received study agent will be analyzed according to the assigned 
treatment regardless of the actual treatment received.
11.2.1. Part I (Study 1 
and Study 2)
Subheader title updated to Part I
11.2.1.1 Primary 
Endpoint Analysis
Entire section revised to read:
The primary endpoint for Part I is the change from baseline in the CDAI score at Week 8.
The change from baseline in the CDAI score will be compared between the JNJ-64304500 
treatment group and the placebo treatment group for all subjects in Part I. For the 
comparison, an ANCOVA model on the van der Waerden normal scores will be used with 
treatment as a fixed factor and baseline CDAI score, SNP-positive status (yes or no), and 
Bio-IR status (yes or no) as covariates. For this analysis, treatment failure rules and missing 
data rules as specified in Section 11.2.2.1 will be applied.
Part I will be considered to be positive if a significant improvement is detected in the 
change from baseline in the CDAI score at Week 8 in the JNJ-64304500 group compared 
with the placebo group at the 0.05 level of significance.
11.2.1.2 Other 
Efficacy Endpoint 
Analyses
First sentence revised to read:
The following endpoints will be compared between the JNJ-64304500 treatment group and 


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the placebo treatment group for all subjects in Part I and by Bio-IR status (yes or no): 
11.2.2. Study 2 (Part I 
Bio-NF Subjects)
This section was removed.
Rationale (change the subject population in Part II): To evaluate the efficacy and safety of JNJ-64304500 in a 
broader population, the subject population in Part II was changed to include both Bio-IR and Bio-NF subjects.
Applicable Section(s)
Description of Change(s)
Synopsis
In the first section, the bullet regarding Part II, Study 3 was revised to read:
Study 3: A dose-ranging study in subjects who are Bio-IR or Bio-NF
In the Dosage and Administration Part II section, the first paragraph was revised to read:
In Part II of the study, subjects (Bio-IR and Bio-NF) will be randomly assigned in equal 
proportions to receive placebo, 1 of 3 dose regimens of JNJ-64304500, or ustekinumab, 
using permuted block randomization, stratified by baseline CDAI score (≤300 or >300), 
SNP-positive status (yes or no), and Bio-IR status (yes or no). The treatment groups are as 
follows:
In the Efficacy Analyses section, the fourth and fifth paragraphs were revised to read:
The primary endpoint for Part II is also the change from baseline in the CDAI score at 
Week 8. A unified strategy that combines Multiple Comparison Procedures with modeling 
techniques, MCP-Mod, will be used to analyze the dose-response data over the JNJ-
64304500 doses. This approach consists of 2 major steps. The first step consists of testing 
the dose-response signal via multiple contrast tests while controlling the overall Type 1 
error. If a dose-response signal is detected, the second step is to select a model that best 
describes the observed data and use it to estimate adequate doses with associated precision. 
The study will be considered positive if a dose-response signal for the primary endpoint is 
detected. In addition to the dose-response analysis, pairwise comparisons of the JNJ-
64304500 treatment groups versus the placebo group will be performed for the change from 
baseline in the CDAI score at Week 8; these comparisons will not be adjusted for 
multiplicity.
The major secondary endpoints are only specified in Part II. The major secondary endpoints 
that are dichotomous endpoints will be analyzed by the Cochran-Mantel-Haenszel chi-
square test (2-sided) stratified by baseline CDAI score (≤300 or >300), SNP-positive status 
(yes or no), and Bio-IR status (yes or no); the major secondary endpoints that are 
continuous endpoints will be analyzed by an analysis of covariance model on the van der 
Waerden normal scores with treatment as a fixed factor and appropriate baseline level of 
the variable, SNP-positive status (yes or no), and Bio-IR status (yes or no) as covariates. 
The major secondary endpoints will not be controlled for multiplicity.
1.2.2. Crohn’s 
Disease
The eighth paragraph was revised to read:
In Part II, the following study will be conducted:

Study 3: A dose-ranging study in subjects who are biologic intolerant or refractory 
(Bio-IR) or Biologic nonfailure (Bio-NF)
The following paragraph was removed from this section:
In order to provide an efficient means of rapidly moving to formal Phase 2 dose-ranging, 
this protocol is designed to be a comprehensive Phase 2 program in which the sponsor will 
evaluate safety and efficacy in subjects who are biologic intolerant or refractory (ie, Bio-IR 
population or Bio-NF). 


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The ninth paragraph was revised to read:
In Study 1, a higher dose regimen than was used in the Phase 2a study will be employed 
supported by the acceptable safety margins demonstrated in Phase 1 (the Novo Nordisk 
Phase 1 single ascending/multiple ascending dose study NN8555-3618), and the high 
exposure margins relative to NOAEL exposure in cynomolgus monkeys. This higher dose 
will be used to provide additional information on safety and efficacy for the Bio-IR 
population, as proof of concept was not established in this population in the Novo Nordisk 
Phase 2a study (NN8555-3797). In addition, this higher dose will also be evaluated in Bio-
NF subjects to determine if a more robust efficacy outcome than was shown in the Phase 2a 
study can be achieved while maintaining an acceptable safety profile. Combined with data 
from Phase 2a in Bio-NF subjects, Part I and Part II would provide valuable information for 
the assessment of dose/exposure-response and thus the selection of the optimal dose in Bio-
NF population for the Phase 3 program. Study 1 and Study 2 comprise Part I of the protocol 
and these 2 components will be initiated in parallel. The decision to initiate the dose-
ranging portion of the protocol (Part II, Bio-IR and Bio-NF) is dependent on demonstration 
of acceptable safety and efficacy in Part I (combined Bio-IR subjects and Bio-NF subjects). 
A ustekinumab reference arm will be included in Part II to provide context in the 
interpretation of results from the JNJ-64304500 and placebo groups and to assist in the 
overall selection of dose(s) to carry forward into the Phase 3 program. 
3.1. Overview of 
Study Design
The first bullet in the third paragraph was revised to read:

Study 3: A dose-ranging study in subjects who are Bio-IR or Bio-NF
Figure 1 was revised to include Bio-IR and Bio-NF subjects in Part II.
The 2nd bullet in the sixth paragraph was revised to read:

Biologic nonfailure (Bio-NF) subjects are defined as those who have demonstrated 
an inadequate response to or have failed to tolerate corticosteroids or the 
immunomodulators 6-MP, AZA, or MTX (Attachment 2). Subjects who have 
demonstrated corticosteroid dependence (ie, an inability to successfully taper 
corticosteroids without a return of the symptoms of Crohn’s disease) are also eligible. 
Bio-NF subjects may also have received biologic therapy but only if it was 
discontinued for reasons other than lack of efficacy or intolerance (eg, drug holiday).
The second bullet in the seventh paragraph was revised to read:

Part II will study the safety and efficacy of multiple-dose regimens of JNJ-64304500 
compared with placebo, with ustekinumab (STELARA®) as a reference arm. Part II 
will enroll approximately 275 subjects (Bio-NF subjects will be no more than 50% 
and Bio-IR subjects will be no more than 60%).
3.1.2. Part II
The first paragraph was revised to read:
In Part II, 275 additional Bio-IR or Bio-NF subjects will be randomly assigned to receive 
placebo or 1 of 3 dose levels of JNJ-64304500 or ustekinumab in a ratio of 1:1:1:1:1 using 
permuted block randomization, stratified by baseline CDAI score (≤300 or >300), SNP-
positive status (yes or no), and BIO-IR status (yes or no). Bio-NF subjects will be no more 
than 50% and Bio-IR subjects will be no more than 60%.
4.1. Inclusion Criteria
Inclusion Criterion 6 was revised to read:
6.
In Part II, meet the following requirement for prior or current medications for 
Crohn’s disease:
a.
Has previously demonstrated inadequate response, loss of response, or 
intolerance to 1 or more approved biologic therapies (eg, infliximab, 


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adalimumab, certolizumab pegol, or vedolizumab) as outlined in Attachment 1.
OR
b.
Has failed conventional therapy:
1)
Is currently receiving corticosteroids and/or immunomodulators (ie, AZA, 
6-MP, or MTX) at adequate therapeutic doses (Attachment 2).
OR
2)
Has a history of failure to respond to or tolerate an adequate course of 
corticosteroids and/or immunomodulators (ie, AZA, 6-MP, or MTX) 
(Attachment 2).
OR
3)
Is corticosteroid dependent or has had a history of corticosteroid 
dependency (Attachment 2).
5.1. Treatment 
Allocation
The first paragraph was revised to read:
Central randomization will be implemented in this study. Subjects will be randomly 
assigned to 1 of 2 treatment groups (1:1 ratio) in Part I and to 1 of 5 treatment groups 
(1:1:1:1:1 ratio) in Part II, based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. Each of the 3 studies will have 
separate randomizations. Each randomization will be balanced by using randomly permuted 
blocks and will be stratified by baseline CDAI score (≤300 or >300) and SNP-positive 
status (yes or no; Part II will also be stratified by Bio-IR status [yes or no]). 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.
11.2.2. Study 3 (Part 
II)
Subheader title revised to Part II.
Rationale (change the sample size in Part II): The sample size in Part II was increased to 275 subjects in order to 
have sufficient power based on the amended Part II population.
Applicable Section(s)
Description of Change(s)
Synopsis
In the Sample Size Determination section, the entire section was revised to read:
Sample size calculations for Part I (Bio-IR subjects and Bio-NF subjects combined) were 
determined by the power to detect a significant difference in the change from baseline in the 
CDAI score at Week 8 between JNJ-64304500 and placebo using a 2-sample t-test. Sample 
size calculation for Part II (Bio-IR and Bio-NF subjects) was determined by the power to 
detect a dose-response signal in the change from baseline in the CDAI score at Week 8 
(primary endpoint in Part II ) using the Multiple Comparison Procedures with modeling 
techniques (MCP-Mod) method.
For Part I, assuming the mean CDAI change from baseline at Week 8 is -98 in the JNJ-
64304500 group and -46 in the placebo group with a common SD of 96, 60 subjects per 
treatment group will provide 84% power to detect a treatment difference between JNJ-
64304500 and placebo at an overall Type 1 error of 0.05.
For Part II, assuming the mean CDAI change from baseline at Week 8 is -98 in the JNJ-
64304500 group and -46 in the placebo group with a common SD of 96, 55 subjects per 
treatment group will provide a mean power of 83% to detect a dose-response signal based on 


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7 candidate dose-response models at an overall Type 1 error of 0.05.
3.1.2. Part II
The first paragraph was revised to read:
In Part II, 275 additional Bio-IR or Bio-NF subjects will be randomly assigned to receive 
placebo or 1 of 3 dose levels of JNJ-64304500 or ustekinumab in a ratio of 1:1:1:1:1 using 
permuted block randomization, stratified by baseline CDAI score (≤300 or >300), SNP-
positive status (yes or no), and BIO-IR status (yes or no). Bio-NF subjects will be no more 
than 50% and Bio-IR subjects will be no more than 60%.
11.1.2. Sample Size 
in Part II (Study 3)
Subheader title changed to Sample Size in Part II
11.1.2.1 All Bio-IR 
Subjects
This subheader title was removed. The content for this section is now included in section 
11.1.2. Sample Size in Part II.
11.1.2.2. Bio-IR 
Subjects Who Are 
SNP-Positive(Bio-
IR/SNP+)
This section was removed.
Rationale: Contents for blinding and planned database locks were updated based on the changes to the study design.
Applicable Section(s)
Description of Change(s)
5.2. Blinding
The second and third paragraphs were revised to read:

Interim analysis lock for Part I: Occurs when 100 randomized subjects (Bio-IR and 
Bio-NF) in Part I have completed their Week 12 visit or have terminated their study 
participation before Week 12.

Week 12 DBL for Part I: Occurs when all subjects in Part I have completed their Week 
12 visit or have terminated their study participation before Week 12.

Week 12 DBL for Part II (final DBL for Part I occurs at the same time): Occurs 
when all Part II subjects have completed their Week 12 visit or have terminated their 
study participation before Week 12.

Week 24 DBL for Part II: Occurs when all Part II subjects have completed their 
Week 24 visit or have terminated their study participation before Week 24.

Final DBL for Part II: Occurs when all Part II subjects have completed their final 
efficacy and safety visit or have terminated their study participation before the final 
efficacy and safety visit.
At the time of the interim analysis lock for Part I, a limited number of sponsor personnel will 
become unblinded to treatment assignment. At the time of the Week 12 DBL for Part I and the 
Week 12 DBL for Part II, the sponsor, except for site monitors (who have interactions with 
the investigative sites), will become unblinded to treatment assignment. Identification of 
sponsor personnel who will have access to subject-level data for the interim analysis lock for 
Part I will be documented before the unblinding. The study blind will be maintained for 
investigators, site personnel, subjects, and sponsor site monitors until the final analyses have 
been completed for all subjects in Part I and Part II. This measure will mitigate the potential 
bias in the remaining investigator and subject assessments.
Rationale: Minor wording changes to the numerical rating scale (NRS) content based on feedback from a Health
Authority.
Applicable Section(s)
Description of Change(s)
9.2.3. Abdominal 
This section was updated to read:


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Pain Numerical 
Rating Scale
The NRS for pain is a unidimensional measure of pain intensity in adults.5 An 11-point (0-10) 
NRS will be used to evaluate abdominal pain. The score of 0 represents “no abdominal pain” 
and the score of 10 represents the “worst possible abdominal pain”, with greater scores 
indicating greater pain severity and intensity. Subjects will select only one number that best 
reflects their pain at its worst in the past 24 hours. The abdominal pain NRS will be assessed 
daily. Subjects will complete the NRS at approximately the same time each day before going 
to bed and bring the diary to each visit.
Rationale: Minor wording changes to Patient’s Global Impression of Severity (PGIS) content based on feedback 
from a Health Authority.
Applicable Section(s)
Description of Change(s)
9.2.4. Patient’s 
Global Impression of 
Severity of Crohn’s 
Disease
This section was updated to read:
The PGIS of Crohn’s disease is a 5-point scale (“None”, “Mild”, “Moderate”, “Severe” and 
“Very Severe”) to rate Crohn’s disease intensity. Subjects will rate their PGIS of Crohn’s 
disease at Weeks 0, 4, 8, 12, and 24.
Rationale: Minor edits were noted.
Applicable Section(s)
Description of Change(s)
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 2 (09 November 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: The overall reason for the amendment was to address health authority 
requests.
Clarification of specific study procedures is also included in this amendment, as described below. 
Applicable Sections
Description of Changes
Rationale: The 12-week follow-up period after the last administration of study agent was changed to a 16-week 
follow-up period in both Part I and Part II. Requirements for the duration of contraception use and the duration of 
avoidance of live vaccinations were also changed to 16 weeks after the last administration of study agent.
Due to the addition of 4 weeks to the follow-up period after the last study agent administration in both Part I and 
Part II of the study, the study duration was increased by 4 weeks in both Part I and Part II.
Synopsis 
In the Overview of Study Design section, the second paragraph was revised to read:
The duration of the study will be 38 weeks in Part I and 36 weeks in Part II for a subject 
who completes all scheduled visits, including study agent administration visits and a final 
efficacy and safety follow-up visit. Eligible subjects will only participate in Part I or Part II 
of the study.


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Time and Events 
Schedule: Part I
Footnote c was revised to read:
c. Subjects who terminate study participation should complete an early termination visit. If 
a subject completed assessments at Week 24 and terminated after Week 24, the only 
assessments that should be performed at the early termination visit are those planned for 
the final efficacy and safety follow-up. Subjects who discontinue study agent 
administration before Week 8 (but have not terminated study participation) should 
complete the Week 8 and Week 12 assessments and return for a final efficacy and safety 
follow-up visit approximately 16 weeks after their last study agent administration. Subjects 
who discontinue study agent administration after Week 8 (but have not terminated study 
participation) should complete the Week 12 and Week 24 assessments and return for a 
final efficacy and safety follow-up visit approximately 16 weeks after their last study agent 
administration. 
Footnote d was revised to read:
d. Subjects should complete a final efficacy and safety follow-up visit approximately 
16 weeks after their last study agent administration. For subjects who complete all visits, 
this will occur at Week 38.
Time and Events 
Schedule: Part II
Footnote d was revised to read:
d. Subjects should complete a final efficacy and safety follow-up visit approximately 
16 weeks after their last study agent administration. For subjects who complete all visits, 
this will occur at Week 36.
3.1 Overview of 
Study Design
Figure 2 was updated to indicate Week 38 as the final efficacy and safety visit in Part I, 
and Figure 3 was updated to indicate Week 36 as the final efficacy and safety visit in 
Part II. 
3.2.9.1. JNJ-
64304500
The following paragraph was added after the second paragraph:
A 16-week follow-up interval after the last administration of study agent has been 
employed based on the observed safety profile and PK profile of JNJ-64304500 in the 
completed clinical studies in RA and Crohn’s disease subjects. The average serum 
concentration of JNJ-64304500 at 16 weeks after the last administration of study agent is 
predicted to be approximately 0.01 μg/mL, which is considered unlikely to produce drug-
related effects or safety concerns.
4.1 Inclusion Criteria
Inclusion Criterion 13.b.2 was revised to read:
Agrees to remain on a highly effective method of contraception throughout the study and 
for at least 16 weeks after the last administration of study agent.
Inclusion Criterion 14 was revised to read:
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for a period of 16 weeks after the last administration of 
study agent.
The first part Inclusion Criterion 15 was revised to read:
During the study and for at least 16 weeks after the last administration of study agent, a 
man
4.2 Exclusion Criteria
Exclusion Criterion 28 was revised to read:
Is a woman who is pregnant, or breast-feeding, or planning to become pregnant or is a man 
who plans to father a child while enrolled in this study or within 16 weeks after the last 
administration of study agent.


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4.3.
Prohibitions 
and Restrictions
Restriction 3 was revised to read:
Subjects must agree not to receive a live virus or live bacterial vaccination, including a 
BCG vaccination, during the study and for 12 months after receiving the last dose of study 
agent for BCG vaccination or 16 weeks for other live vaccines.
9.1.2 Screening 
Period
The fourth paragraph was revised to read:
Women of childbearing potential must have a negative serum β-hCG pregnancy test result 
at screening. Subjects must be reminded that they are required to use a highly effective 
method of contraception during the study (as described in Inclusion Criterion 13) and must 
continue taking such precautions for 16 weeks after receiving the last administration of 
study agent. The method(s) of contraception used by each subject must be documented.
9.1.4. Final Efficacy 
and Safety Follow-up 
Visit
This section was revised to read:
Subjects in Part I and Part II should complete the final efficacy and safety follow-up visit 
approximately 16 weeks after the last study agent administration (Table 1, Table 2). 
10.1. Completion
The first paragraph was revised to read:
A subject will be considered to have completed the study if he or she has completed 
assessments through the final efficacy and safety visit (ie, Week 38 in Part I and Week 36 
in Part II), as specified in the Time and Events Schedules for Part I or Part II.
The third paragraph was revised to read:
The final efficacy and safety follow-up visit for subjects who discontinue study agent is 
approximately 16 weeks after the last administration of study agent in both Part I and 
Part II.
10.2. Discontinuation 
of Study Treatment
The second bullet of the second paragraph was revised to read:
The subject becomes pregnant or plans a pregnancy within the study period or within 
16 weeks after the last study agent administration.
12.3.1. All Adverse 
Events
The first paragraph was revised to read:
All AEs and special reporting situations, whether serious or nonserious, will be reported 
from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow-up of safety. Serious 
adverse events, including those spontaneously reported to the investigator within 16 weeks 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in this protocol.
Rationale: In response to a Health Authority request, the Patient’s Global Impression of Severity (PGIS) of Crohn’s 
disease and the Patient’s Global Impression of Change (PGIC) of severity of Crohn’s disease were added as efficacy 
assessments in Part II of the study.
Synopsis
In the Efficacy Evaluations section, the following were added:

Patient’s Global Impression of Severity (PGIS) of Crohn’s disease

Patient’s Global Impression of Change (PGIC) of severity of Crohn’s disease
Time and Events 
Schedule: Part II
The following efficacy assessments were added:
PGIS of Crohn’s disease assessment at Weeks 0, 4, 8, 12, 24, and Early termination.
PGIC of severity of Crohn’s disease assessment at Weeks 4, 8, 12, 24, and Early 
termination.


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2.1.2. Endpoints
The third paragraph was revised to read:
The following efficacy endpoints will be evaluated in each of the 3 studies (except for the 
Patient’s Global Impression of Severity [PGIS] of Crohn’s disease and the Patient’s Global 
Impression of Change [PGIC] of severity of Crohn’s disease, which will only be evaluated 
in Study 3):
The following were added to the list of efficacy endpoints:

Change in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12, and 24.

A ≥1-point improvement in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12,
and 24.

Improvement in PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.
9.2. Efficacy 
Evaluations
This section was revised to read:
The CDAI will be the primary tool for assessing disease activity response to JNJ-
64304500, along with PRO-2, PRO-3, Bristol stool form scale, abdominal pain based on 
NRS 0-10 scale, PGIS of Crohn’s disease, and PGIC of severity of Crohn’s disease. The 
degree of inflammation will be assessed by measuring serum CRP concentrations. Stool 
samples will be collected and analyzed to evaluate changes in markers that may reflect 
JNJ-64304500 or ustekinumab treatment. The well-being of subjects will be measured 
using the IBDQ and the SF-36. Mucosal healing will be assessed by ileocolonoscopy. For 
subjects with fistulizing disease, fistula closure will also be assessed.
9.2.4 Patient’s Global 
Impression of 
Severity of Crohn’s 
Disease
In Section 9.2 Efficacy Evaluations, a new section 9.2.4 Patient’s Global Impression of 
Severity of Crohn’s Disease was added:
The PGIS of Crohn’s disease is a 5-point scale (“Absent“, “Mild”, “Moderate”, “Severe” 
and “Very Severe”) to rate Crohn’s disease intensity. Subjects will rate their PGIS of 
Crohn’s disease at Weeks 0, 4, 8, 12, and 24.
9.2.5 Patient’s Global 
Impression of Change
of Severity of Crohn’s 
Disease
In Section 9.2 Efficacy Evaluations, a new section 9.2.5 Patient’s Global Impression of 
Change of Severity of Crohn’s Disease was added:
The PGIC of severity of Crohn’s disease is a 7-point scale ranging from “a lot better now” 
to “a lot worse now” with a neutral center point (“neither better nor worse”) to measure 
perceived change (improvement or deterioration) in severity of Crohn’s disease. Subjects 
will assess their PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.
11.2.3.3.
Other 
Efficacy Endpoint 
Analyses
This section was revised to read:
Comparisons between each of the JNJ-64304500 treatment groups and the placebo 
treatment group will also be made for each of the endpoints specified in Section 11.2.1.2 
and for the following endpoints.

Change in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12, and 24.

A ≥1-point improvement in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12, 
and 24.

Improvement in PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.
Pairwise comparisons of the ustekinumab treatment group with the JNJ-64304500 
treatment groups or with placebo are not planned for these endpoints, however summary 
statistics will be provided for the ustekinumab group.
15. Study-Specific 
Materials
The following was added to the list of supplies provided to the investigator:

Worksheets for data collection 
Rationale: In response to a Health Authority request, further clarification of the study design and protocol structure 


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was added. 
1.2.2. Crohn’s 
Disease
The second paragraph was revised to read:
Subjects were evaluated for the primary endpoint of change from baseline in the CDAI 
score at Week 4. Safety and efficacy evaluations were performed through Week 24. The 
observed 16-point greater reduction in CDAI in the JNJ-64304500 group at Week 4 
compared with the placebo group was not significant (p=0.403). Based on a predefined 
significance level of 0.10, however, the reduction in CDAI score was significantly higher 
in the JNJ-64304500 group compared with the placebo group at Week 12 (55-point greater 
reduction in CDAI was observed in JNJ-64304500 compared with placebo, p=0.056). 
Based on the same predefined significance level of 0.10, reductions in CDAI scores were 
significantly higher in the predefined subgroup of “no prior failure to biologics” (Bio-NF, 
71% of the study population) in the JNJ-64304500 group compared with placebo at all 
post baseline visits through Week 12 (Week 1, p=0.068; Week 2, p=0.048; Week 4, 
p=0.095; Week 8, p=0.015; and Week 12, p=0.025). The biologic intolerant or refractory 
population (Bio-IR) in the Novo Nordisk Phase 2a study constituted 29% of the study 
population (N=12 in the active treatment arm and N=11 in the placebo arm). In this 
subpopulation, a 45-point greater reduction in CDAI was observed at Week 12 in 
JNJ-64304500 compared with placebo.
The last paragraph was replaced with the following 3 paragraphs at the end of the section:
In order to provide an efficient means of rapidly moving to formal Phase 2 dose-ranging, 
this protocol is designed to be a comprehensive Phase 2 program in which the sponsor will 
evaluate safety and efficacy in subjects who are biologic intolerant or refractory (the Bio-
IR population, Study 1).
In Study 1, a higher dose regimen than was used in the Phase 2a study will be employed 
supported by the acceptable safety margins demonstrated in Phase 1 (the Novo Nordisk 
Phase 1 single ascending/multiple ascending dose study NN8555-3618), and the high 
exposure margins relative to NOAEL exposure in cynomolgus monkeys. This higher dose 
will be used to establish safety and efficacy (Proof of Concept) for the Bio-IR population, 
as this was not satisfactorily established in this population in the Novo Nordisk Phase 2a 
study (NN8555-3797). In addition, this higher dose will also be evaluated in subjects who 
have not previously failed a biologic therapy (Study 2, Bio-NF) to determine if a more 
robust efficacy outcome than was shown in the Phase 2a study can be achieved while 
maintaining an acceptable safety profile. Combined with data from Phase 2a in Bio-NF 
subjects, Study 2 would provide valuable information for the assessment of dose/exposure-
response and thus the selection of the optimal dose in Bio-NF population for the Phase 3 
program. Study 1 and Study 2 comprise Part I of the protocol and these 2 components will 
be initiated in parallel. It is anticipated that Bio-NF subjects will enroll slower than Bio-IR 
subjects. Therefore, initiation of Study 2 in parallel with Study 1 will facilitate the 
completion of Study 2 in a timely fashion to be able to inform Phase 3 study planning for 
the Bio-NF population. The decision to initiate the dose-ranging portion of the protocol 
(Study 3, Bio-IR) is dependent on demonstration of acceptable safety and efficacy in the 
Bio-IR subjects in Study 1. A ustekinumab reference arm will be included in Study 3 to 
provide context in the interpretation of results from the JNJ-64304500 and placebo groups 
and to assist in the overall selection of dose(s) to carry forward into the Phase 3 program.
The inclusion of the 3 component studies in a single protocol will facilitate both efficient 
trial conduct and program decision-making based on planned interim DBLs as described in 
Section 3.1.1, Section 3.1.3, and Section 5.2.
Rationale: Inclusion criteria related to prior or current medications for Crohn’s disease were updated to clarify the 
requirements for Part I (Study 1 and Study 2) and Part II (Study 3).
4.1. Inclusion Criteria
Inclusion Criterion 5 was revised to read:


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5. Criterion modified per Amendment 2:
5.1 In Study 1, meet the following requirements for prior or current medications for 
Crohn’s disease:
a. Has previously demonstrated inadequate response, loss of response, or intolerance 
to 1 or more approved biologic therapies (eg, infliximab, adalimumab, certolizumab 
pegol, or vedolizumab) as outlined in Attachment 1.
In Study 2, meet the following requirements for prior or current medications for 
Crohn’s disease:
b. Has failed conventional therapy as follows:
1)
Is currently receiving corticosteroids and/or immunomodulators (ie, AZA, 
6-MP, or MTX) at adequate therapeutic doses (Attachment 2).
OR
2)
Has a history of failure to respond to or tolerate an adequate course of 
corticosteroids and/or immunomodulators (ie, AZA, 6-MP, or MTX) 
(Attachment 2).
OR
3)
Is corticosteroid dependent or has had a history of corticosteroid dependency 
(Attachment 2).
Inclusion Criterion 6 was revised to read:
6. In Study 3, meet the following requirement for prior or current medications for 
Crohn’s disease: has previously demonstrated inadequate response, loss of response, or 
intolerance to 1 or more approved biologic therapies (eg, infliximab, adalimumab, 
certolizumab pegol, or vedolizumab) as outlined in Attachment 1.
Rationale: To accurately assess potential injection-site reactions, additional instructions regarding injection-site 
location were added.
Time and Events 
Schedule: Part I
Under Study Procedures, Administer study agent was revised to read:
Administer study agent e (SC study agent at a different location at each visit [Section 6])
Time and Events 
Schedule: Part II
Under Study Procedures, Administer study agent was revised to read:
Administer study agent e (SC study agent at a different location at each visit [Section 6])
6. Dosage and 
Administration
The following was added at the beginning of the section:
Subcutaneous injections of study agent should be administered at different locations at 
each visit at which study agent is administered to allow for assessment of potential 
injection-site reactions.
Rationale: The inclusion criterion related to contraception was revised to be consistent with the core safety 
information for JNJ-64304500. 
4.1. Inclusion Criteria
The following was added as the last sentence of Inclusion Criterion 13.b.1:
If using a hormone birth control method, a second method of birth control, such as a 
condom or diaphragm, must be used.
Rationale: The footnote for video ileocolonoscopy in the Time and Events Schedule Part II was updated to be 
consistent with the footnote for video ileocolonoscopy in the Time and Events Schedule Part I. 


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Time and Events 
Schedule Part II
Footnote r was revised to read:
r. Because these procedures must not interfere with the collection of CDAI data, if 
performed on the day of these visits, the 7 days before the initiation of the colonoscopy 
preparation should be used to calculate CDAI scores for these visits. If the video 
ileocolonoscopic examination is not performed on the day of the visit, it must be 
performed at least 8 days before the Week 0 visit and no more than 8 days before the 
Week 12 visit.
Rationale: The numbers of subjects exposed to JNJ-64304500 in clinical studies were updated to be consistent with 
the Investigator’s Brochure.
1.2. Clinical Studies
This section was revised to read:
As of 11 November 2015, a total of 128 subjects had been exposed to JNJ-64304500 in 
3 clinical studies: 88 subjects in 2 studies in rheumatoid arthritis (RA) and 40 subjects in a 
Phase 2a study in Crohn’s disease.
1.2.1. Rheumatoid 
Arthritis
This section was revised to read:
Two studies with JNJ-64304500 were conducted in subjects with active RA.
In NN8555-3618, a first-in-humans, Phase 1, single ascending dose/multiple ascending 
dose study that included single-dose (0.0002 to 7.5 mg/kg) and multiple-dose (0.02 to 4 
mg/kg every 2 weeks for 4 administrations) parts, 13 dose levels were evaluated in 24 
subjects exposed to JNJ-64304500 in the single ascending dose portion and 23 subjects 
exposed to JNJ-64304500 in the multiple ascending dose portion. Subcutaneous 
administration of JNJ-64304500 was well tolerated at the dose ranges investigated and no 
safety signals were associated with either the single- or multiple-dose regimens.
In NN8555-3796, a Phase 2a, randomized, single-dose, double-blind, placebo-controlled, 
parallel-group study, clinical efficacy was assessed in subjects with active RA 
concomitantly treated with methotrexate (MTX). In this study, a single SC injection of 
4 mg/kg JNJ-64304500 in 41 subjects exposed to JNJ-64304500 did not result in a 
statistically significant reduction in disease activity at Weeks 6, 12, or 24 after treatment 
compared with placebo. JNJ-64304500 was well tolerated and no safety concerns were 
raised during the study.
Additional details about these studies are provided in the latest version of the IB.
Rationale: The timing for the collection of the random population pharmacokinetic (PK) samples was clarified. 
Time and Events 
Schedule: Part I
Footnote x was revised to read:
x. Each random population PK sample should be collected at any time between Weeks 0 
and 2 (after the Week 0 study agent administration) and between Weeks 22 and 24 (after 
the Week 22 study agent administration). The date for the random population PK sample 
collection will be at the subject’s discretion. However, samples should not be drawn on or 
within 1 day of a scheduled visit (ie, the Week 0, 2, 22, or 24 visit) in this time period.
Time and Events 
Schedule: Part II
Footnote x was revised to read:
x. Each random population PK sample should be collected at any time between Weeks 0 
and 2 (after the Week 0 study agent administration) and between Weeks 20 and 24 (after 
the Week 20 study agent administration). The date for the random population PK sample 
collection will be at the subject’s discretion. However, samples should not be drawn on or 
within 1 day of a scheduled visit (ie, the Week 0, 2, 20, or 24 visit) in this time period.


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9.3.1. Evaluations
The first paragraph was revised to read:
Serum samples used to evaluate the PK and immunogenicity of JNJ-64304500 and 
ustekinumab (antibodies to JNJ-64304500 and antibodies to ustekinumab) will be 
collected according to the Time and Events Schedules. Samples collected for analyses of 
serum concentration of JNJ-64304500 and ustekinumab and antibodies to JNJ-64304500 
or ustekinumab may additionally be used to evaluate safety or efficacy aspects that address 
concerns arising during or after the study period, for further characterization of 
immunogenicity or for the evaluation of relevant biomarkers. Genetic analyses will not be 
performed on these serum samples. Subject confidentiality will be maintained. The exact 
dates and times of sample collection must be recorded on the laboratory requisition form.
Rationale: The instructions regarding the components of the CDAI were clarified. 
Time and Events 
Schedule: Part I
Footnote e was revised to read:
e. All assessments are to be completed before study agent administration, unless 
otherwise specified. It is recommended that PRO assessments be completed first, starting 
with the PRO components of the CDAI. 
Footnote n was revised to read:
n. The hematocrit value obtained during screening will be used to calculate CDAI at 
Week 0. For other visits, the most recent hematocrit value obtained before a visit will be 
used to calculate the CDAI for that visit. 
Time and Events 
Schedule: Part II
Footnote e was revised to read:
e. All assessments are to be completed before study agent administration, unless 
otherwise specified. It is recommended that PRO assessments be completed first, starting 
with the PRO components of the CDAI. 
Footnote n was revised to read:
n. The hematocrit value obtained during screening will be used to calculate CDAI at 
Week 0. For other visits, the most recent hematocrit value obtained before a visit will be 
used to calculate the CDAI for that visit. 
Rationale: The instructions regarding the procedures/assessments to be completed at early termination were 
clarified. 
Time and Events 
Schedule: Part I
Footnote c was revised to read:
c. Subjects who terminate study participation should complete an early termination visit. If 
a subject completed assessments at Week 24 and terminated after Week 24, the only 
assessments that should be performed at the early termination visit are those planned for 
the final efficacy and safety follow-up. Subjects who discontinue study agent 
administration before Week 8 (but have not terminated study participation) should 
complete the Week 8 and Week 12 assessments and return for a final efficacy and safety 
follow-up visit approximately 16 weeks after their last study agent administration. 
Subjects who discontinue study agent administration after Week 8 (but have not 
terminated study participation) should complete the Week 12 and Week 24 assessments 
and return for a final efficacy and safety follow-up visit approximately 16 weeks after 
their last study agent administration.


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Time and Events 
Schedule: Part II 
Footnote c was revised to read:
c. Subjects who terminate study participation should complete an early termination visit. 
If a subject completed assessments at Week 24 and terminated after Week 24, the only 
assessments that should be performed at the early termination visit are those planned for 
the final efficacy and safety follow-up. Subjects who discontinue study agent 
administration before Week 8 (but have not terminated study participation) should 
complete the Week 8 and Week 12 assessments and return for a final efficacy and safety 
follow-up visit approximately 16 weeks after their last study agent administration. Subjects 
who discontinue study agent administration after Week 8 (but have not terminated study 
participation) should complete the Week 12 and Week 24 assessments and return for a 
final efficacy and safety follow-up visit approximately 16 weeks after their last study agent 
administration.
Rationale: Exploratory histologic assessments were added.
Synopsis 
In the Efficacy Evaluations section, the following was added:

Histologic assessment
2.1.2 Endpoints
The following was added:

Endpoint(s) for histologic assessment based on the Global Histology Activity Score 
(GHAS; to be detailed in the Statistical Analysis Plan [SAP]). 
9.2.12 Histologic
Assessment 
In Section 9.2 Efficacy Evaluations, a new section 9.2.12 Histologic Assessment was 
added:
Histologic assessment will be performed using biopsy samples collected during 
endoscopy. Biopsy samples will be collected at screening, Week 12, and Week 24 from 
each of 3 predefined anatomic locations: the terminal ileum, splenic flexure, and rectum. 
The biopsy samples collected at Week 12 and Week 24 will be obtained near where the 
biopsy samples at screening were collected from each of the 3 predefined locations. 
Histologic assessment will be conducted by a central reader who is blinded to treatment 
groups. The GHAS will be used to evaluate histologic improvement. Additional details 
will be provided in the Study Reference Manual.
11.2.1.2
Other 
Efficacy Endpoint 
Analyses
The following was added:

Endpoint(s) for histologic assessment based on the GHAS (to be detailed in the 
SAP).
11.5.
Biomarker 
Analyses
The last sentence was revised to read:
Results of serum, whole blood analyses, stool, and mucosal biopsy analyses will be 
reported in separate technical reports.
Rationale: The requirement for an ileocolonoscopy biopsy sample collection at early termination was added as it 
was erroneously omitted from the protocol. 
Time and Events 
Schedule: Part II
In the Pharmacodynamics/Biomarkers Assessments section, an X was added in the Early 
Termination column of the Ileocolonoscopy biopsy sample collections for RNA and 
histology row.
Rationale: To clarify the efficacy assessment calculations for change in abdominal pain score and change in stool 
frequency score, mean daily average was revised to daily average. 


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2.1.2 Endpoints 
The following were revised to read:

Change in abdominal pain score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.

Change in stool frequency score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.
11.2.1.2.
Other 
Efficacy Endpoint 
Analyses
The following were revised to read:

Change in abdominal pain score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.

Change in stool frequency score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.
Rationale: The rationale for an interim analysis was clarified. 
Synopsis, Overview 
of Study Design
The fourth paragraph was revised to read:
An interim analysis is planned in Study 1 of Part I when the first 80% of the randomized 
Bio-IR subjects in Study 1 of Part I (at least 40 Bio-IR subjects and at least 30 Bio-
IR/SNP-positive subjects per treatment group) have completed their Week 8 visit or have 
terminated their study participation before Week 8. This interim analysis will allow for an 
earlier start of Part II (ie, Study 3, the dose-ranging part) if a sufficient effect is observed. 
Part II will be initiated if results from Study 1 of Part I demonstrates acceptable safety and 
efficacy, either at the interim analysis or when 100% of the Bio-IR subjects have 
completed their Week 12 visit (or have terminated study participation prior to this time).
3.1.3. Interim 
Analysis
The second paragraph was revised to read:
This interim analysis will allow for an earlier start of Part II (ie, Study 3, the dose-ranging 
part) if a sufficient effect is observed (see Section 11.10). As this interim analysis does not 
affect the conduct or completion of Study 1, it will be considered administrative and will 
not require multiplicity adjustment for the final Study 1 analysis.
11.10. Interim 
Analysis
The first paragraph was revised to read:
An interim analysis is planned in Study 1 when the first 80% of the randomized Part I Bio-
IR subjects (at least 40 Bio-IR subjects and at least 30 Bio-IR/SNP-positive subjects per 
treatment group) have completed their Week 8 visit or have terminated their study 
participation before Week 8. This interim analysis will allow for an earlier start of Part II 
(ie, Study 3, the dose-ranging part) if a sufficient effect is observed. As this interim 
analysis does not affect the conduct or completion of Study 1, it will be considered 
administrative and will not require multiplicity adjustment for the final Study 1 analysis.
Rationale: Safety data for dose selection were clarified. 
3.2.9.1. JNJ-
64304500
The first paragraph was revised to read:
The results of PK, PD and efficacy analyses and safety data from previous clinical studies 
of JNJ-64304500 in subjects with RA and Crohn’s disease were used to guide the dose 
selection for the 3 studies in this protocol. In study NN8555-3618, the highest single SC 
dose investigated was 7.5 mg/kg and the highest multiple SC dose regimen investigated 
was 4 mg/kg q2w for a total of 4 doses in RA subjects. JNJ-64304500 was well tolerated 
and no safety concerns were identified in subjects with RA or Crohn’s disease from the 
previous clinical studies. In addition, a 52-week repeat-dose toxicology study has 
demonstrated a no-observed-adverse-effect level (NOAEL) of 100 mg/kg SC once weekly 
in cynomolgus monkeys. The exposures achieved in the last dosage interval (100 mg/kg) 
of the 52-week study were 10,900 and 8,480 μg/mL for maximum concentration (Cmax),
and 1,520,000 and 1,250,000 hr·μg/mL for AUC0-168hr, for male and female monkeys, 
respectively. Based on these safety and toxicology findings, it is expected that the 


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proposed dose regimens of JNJ-64304500 would have acceptable safety profiles.
The last paragraph was revised to read:
The selection of the 4 different dosing regimens of JNJ-64304500 in Part I and Part II was 
based on all available PK, efficacy and safety data from the previous clinical studies and 
from a 52-week repeat-dose toxicology study. It should be noted that the current available 
information on JNJ-64304500 has not established the relationship between the NKG2D 
RO and clinical effects of the drug. In addition, the currently reported antibody distribution 
coefficients for intestinal tissues may have limitations and the JNJ-64304500 
concentrations in the intestine may not be accurately predicted. Nevertheless, the use of 4 
different dose regimens of JNJ-64304500 in Part I and Part II, which will provide a wide 
range of drug exposures while remaining within the acceptable safety margins, is 
anticipated to provide a robust characterization of the exposure-response relationship of 
JNJ-64304500 in the treatment of Crohn’s disease.
Rationale: The definitions of inadequate initial response, loss of response, or intolerance to TNF-antagonist 
therapies or vedolizumab were updated. 
Attachment 1
Attachment 1 was replaced with the updated definitions. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (14 June 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: The overall reason for the amendment was to address health authority 
requests.
Clarification of specific study procedures is also included in this amendment as described below. 
Applicable Sections
Description of Changes
Rationale: At the request of a health authority, collection of stool consistency data using the Bristol stool form 
scale and assessment of abdominal pain based on the Numerical Rating Scale (NRS) were added, as well as
exploratory analyses of these data.
Synopsis
In the Efficacy Evaluations section, the following bullets on Bristol stool form scale and 
assessment of abdominal pain were added:

Bristol stool form scale

Abdominal pain Numerical Rating Scale (NRS)
Time and Events
Schedule: Part I and 
Part II
In the Efficacy Assessments section, the Bristol stool form scale was added as an 
assessment with data collection at Weeks 0, 2, 4, 6, 8, 10, and 12. Also, a new footnote o 
was added and subsequent footnotes were renumbered:
o. Subject will complete the Bristol stool form scale as a daily diary entry and bring the 
diary to each visit. Daily diary information should be collected for every day prior to each 
visit.
In the Efficacy Assessments section, abdominal pain NRS was added as an assessment 
with diary data collection at all visits. Also, a new footnote p was added and subsequent 


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footnotes were renumbered:
p. Subject will complete the abdominal pain NRS assessment as a daily diary entry and 
bring the diary to each visit. For all visits up to Week 24, daily diary information should be 
collected for every day prior to the visits. For the final efficacy and safety visit, daily diary 
information should be collected for 14 days prior to the visit.
2.1.2 Endpoints
The following efficacy endpoints bullets were added to each of the 3 studies:

Change in abdominal pain score (mean daily average based on the CDAI assessment) 
from baseline at all postbaseline visits.

Change in stool frequency score (mean daily average based on the CDAI assessment) 
from baseline at all postbaseline visits.

Endpoint(s) based on Bristol stool form scale (to be detailed in the Statistical Analysis 
Plan).

Change in abdominal pain from baseline at all postbaseline visits based on a 0-10 
Numerical Rating Scale (NRS).
9.2 Efficacy 
Evaluations
The section was revised to read:
The CDAI will be the primary tool for assessing disease activity response to JNJ-
64304500, along with PRO-2, PRO-3, Bristol stool form scale, and abdominal pain based 
on NRS 0-10 scale. The degree of inflammation will be assessed by measuring serum CRP 
concentrations. Stool samples will be collected and analyzed to evaluate changes in 
markers that may reflect JNJ-64304500 or ustekinumab treatment. The well-being of 
subjects will be measured using the IBDQ and the SF-36. Mucosal healing will be assessed 
by ileocolonoscopy. For subjects with fistulizing disease, fistula closure will also be 
assessed.
9.2.2 Bristol Stool 
Form Scale
In Section 9.2 Efficacy Evaluations, a new Section 9.2.2 Bristol Stool Form Scale was 
added:
The Bristol stool form scale is a medical aid to classify the form (or consistency) of human 
feces into 7 categories.8 It has been used as a research tool to evaluate the effectiveness of 
treatments for various diseases of the bowel (eg, irritable bowel syndrome).4 Subjects will 
complete the Bristol stool form scale as a daily diary entry and bring the diary to each visit 
up to Week 12.
9.2.3 Abdominal Pain 
Numerical Rating 
Scale
In Section 9.2 Efficacy Evaluations, a new Section 9.2.3 Abdominal Pain Numerical
Rating Scale was added:
The NRS for pain is a unidimensional measure of pain intensity in adults.5 An 11-point (0-
10) NRS will be used to evaluate abdominal pain. The score of 0 represents “no pain” and 
the score of 10 represents the “pain as bad as you can imagine”, with greater scores 
indicating greater pain severity and intensity. Subjects will select only one number that 
best reflects their pain at its worst in the past 24 hours. The abdominal pain NRS will be 
assessed daily. Subjects are to complete a daily diary entry and bring the diary to each 
visit.


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11.2.1.2 Other 
Efficacy Endpoint 
Analyses
The following new bullets were added:

Change in abdominal pain score (mean daily average based on the CDAI assessment) 
from baseline at all postbaseline visits.

Change in stool frequency score (mean daily average based on the CDAI assessment) 
from baseline at all postbaseline visits.

Endpoint(s) based on Bristol stool form scale (to be detailed in the SAP).

Change in abdominal pain from baseline at all postbaseline visits based on a 0-10 NRS.
15 Study-Specific 
Materials
Study-specific materials pertaining to the Bristol stool form scale and assessment of 
abdominal pain were added:

Bristol stool form scale diary

Abdominal pain NRS diary
References
Two references for the Bristol stool form scale (Dove et al 2013 and Lewis/Heaton 1997) 
were added to the References and other references were renumbered accordingly.
One reference for the abdominal pain NRS assessment (Hawker et al 2011) was added to 
the References and other references were renumbered accordingly.
Rationale: Text was revised to clarify that the sample size for Study 3 was based on the power to detect a dose-
response signal and the sample size/power considerations for the pairwise comparisons of the JNJ-64304500 groups 
with placebo were based on the comparison of the high dose group with placebo.
Synopsis
In the Statistical Methods section, the text under Sample Size Determination was revised 
to read:
Sample size calculations for Study 1 (Part I Bio-IR subjects) and Study 2 (Part I Bio-NF 
subjects) were determined by the power to detect a significant difference in the change 
from baseline in the CDAI score at Week 8 (primary endpoint in each study) between 
JNJ-64304500 and placebo using a 2-sample t-test. Sample size calculation for Study 3 
(Bio-IR subjects) was determined by the power to detect a dose-response signal in the 
change from baseline in the CDAI score at Week 8 (primary endpoint in Study 3) using the 
Multiple Comparison Procedures with modeling techniques (MCP-Mod) method.
For Study 1, assuming the mean CDAI change from baseline at Week 8 is -79 in the 
JNJ-64304500 group and -25 in the placebo group with a common SD of 92, 50 subjects 
per treatment group will provide approximately 80% power to detect a treatment 
difference between JNJ-64304500 and placebo at an overall Type 1 error of 0.05.
For Study 2, assuming the mean CDAI change from baseline at Week 8 is -152 in the 
JNJ-64304500 group and -66 in the placebo group with a common SD of 100, 50 subjects 
per treatment group will provide approximately 99% power to detect a treatment 
difference between JNJ-64304500 and placebo at an overall Type 1 error of 0.05.
For Study 3, assuming the mean CDAI change from baseline at Week 8 is -79 in the 
JNJ-64304500 group and -25 in the placebo group with a common SD of 92, 50 subjects 
per treatment group will provide a mean power of 85% to detect a dose-response signal 
based on 7 candidate dose-response models at an overall Type 1 error of 0.05.


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11.1.2.1 All Bio-IR 
Subjects
The section was revised to read:
Using the same assumptions as were used for the Bio-IR population in Study 1, 50 subjects 
per treatment group will provide a mean power of 85% to detect a dose-response signal for 
change from baseline in CDAI at Week 8 based on 7 candidate dose-response models (to 
be detailed in the SAP) at an overall Type 1 error of 0.05 (2-sided). Fifty subjects per 
treatment group will also provide approximately 80% power to detect a treatment 
difference between the JNJ-64304500 treatment group with the highest dose and the 
placebo treatment group for change from baseline in CDAI at Week 8 at a Type I error of 
0.05 (2-sided; Table 4). This will result in a total sample size of 250 subjects in Part II 
(incorporating an additional 50 subjects for the ustekinumab treatment group).
Fifty Bio-IR subjects per treatment group in Part II will also provide 90% power to detect 
a difference between the JNJ-64304500 treatment group with the highest dose and the 
placebo treatment group in the proportion of subjects in clinical remission at Week 8 (the 
first major secondary endpoint) at a Type 1 error of 0.05 (2-sided; Table 4), assuming 
JNJ-64304500 has a remission rate of 31%, which is 10% greater than the ustekinumab 
remission rate in CNTO1275CRD3001.
11.1.2.2 Bio-IR 
Subjects Who Are 
SNP-Positive (Bio-
IR/SNP+)
The section was revised to read:
Based on the assumption that 75% of the Crohn’s disease population will be SNP-positive, 
50 Bio-IR subjects will provide approximately 38 Bio-IR/SNP+ subjects. Thirty-eight 
Bio-IR/SNP+ subjects per group will provide 80% power to detect a difference between 
the JNJ-64304500 treatment group with the highest dose and the placebo treatment group
in the proportion of subjects in clinical remission at Week 8 at a Type 1 error of 0.05 
(2-sided; Table 4), assuming JNJ-64304500 has a remission rate of 31%, which is 10% 
greater than the ustekinumab remission rate in CNTO1275CRD3001.
Rationale: In order to clarify the Efficacy Assessments (CDAI assessments, Fistula exam, and Collect and review 
diary cards) and the Clinical Laboratory Assessments (Hematology) in the Time and Events Schedules, the 
frequency of completing these events was increased to all visits of the Main Study phase (and to the Final efficacy 
and safety follow-up visit for the Fistula Exam).
Time and Events 
Schedule: Part I 
In the Efficacy Assessments section (CDAI assessments, Fistula exam, and Collect and 
review diary cards) and the Clinical Laboratory Assessments section (Hematology), an X 
was added at Weeks 14, 18, and 22 for completion of these events. An X was also added at 
the Final Efficacy and Safety Follow-Up Visit for completion of the Fistula Exam. A new 
footnote m was added for the collection and review of diary cards, and subsequent 
footnotes were renumbered:
m. For all visits up to Week 24, daily diary information should be collected for every day 
prior to each visit. For the final efficacy and safety visit, daily diary information should be 
collected for 14 days prior to the visit.
Time and Events 
Schedule: Part II
In the Efficacy Assessments section (CDAI assessments, Fistula exam, and Collect and 
review diary cards) and the Clinical Laboratory Assessments section (Hematology), an X 
was added at Week 14 for completion of these events. An X was also added at the Final 
Efficacy and Safety Follow-Up Visit for completion of the Fistula Exam. A new footnote 
m was added for the collection and review of diary cards, and subsequent footnotes were 
renumbered:
m. For all visits up to Week 24, daily diary information should be collected for every day 
prior to each visit. For the final efficacy and safety visit, daily diary information should be 
collected for 14 days prior to the visit.


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Rationale: At the request of a health authority to identify early immunogenic responses, an additional sample for 
anti-drug antibody analysis was added at Week 2 in Part I (Studies 1 and 2) and Part II (Study 3).
Time and Events
Schedule: Part I and 
Part II
Added an X for Week 2 collection of samples to measure antibodies to JNJ-64304500 in 
Part I, and Assessment for antibody to study agent in Part II.
Rationale: In order to clarify instructions on sample handling for site investigators, additional footnotes were added 
to the Time and Events Schedules, and new text was added to Section 9.3.1 Evaluations.
Time and Events
Schedule: Part I and 
Part II
To the events of ‘JNJ-64304500 serum concentration’, ‘JNJ-64304500 random population 
PK sample’ and ‘Antibodies to JNJ-64304500’ in Part I, and ‘Study agent serum 
concentration’, ‘JNJ-64304500 random population PK sample’ and ‘Assessment for 
antibody to study agent’ in Part II, a new footnote w was added:
w. At visits where only serum concentration of study agent will be evaluated (ie, no 
antibodies to study agent will be evaluated), 1 venous blood sample of sufficient volume 
should be collected, and each serum sample should be divided into 2 aliquots (1 for serum 
concentration of study agent, and a back-up). At visits where serum concentration of study 
agent and antibodies to study agent will be evaluated, 1 venous blood sample of sufficient 
volume should be collected. Each serum sample will be divided into 3 aliquots (1 each for
serum concentration of study agent, antibodies to study agent, and a back-up).
9.3.1 Evaluations
New text was added to the second paragraph in order to clarify instructions on sample 
handling for site investigators, as follows:
At visits where only serum concentration of study agent will be evaluated (ie, no 
antibodies to study agent will be evaluated), 1 venous blood sample of sufficient volume 
should be collected, and each serum sample should be divided into 2 aliquots (1 for serum 
concentration of study agent, and a back-up).
Rationale: The requirement for a video ileocolonoscopy at early termination was added as it was erroneously 
omitted from the protocol. 
Time and Events
Schedule: Part II
In the Efficacy Assessments section, an X was added in the Early Termination column of 
the Video ileocolonoscopy row. 
Rationale: In order to specify the type of procedures that will not be included in the category of Crohn’s disease-
related hospitalization and surgeries, a new footnote was added to the Time and Events Schedules.
Time and Events 
Schedule: Part I and 
Part II
To the event of ‘Crohn’s disease-related hospitalization and surgeries’, a new footnote aa 
was added:
aa. Hospitalization for ileocolonoscopy is not included in this category.
Rationale: In countries where tuberculin is not available for the skin test, this method of testing will not be
required. QuantiFERON-TB Gold and chest radiograph must still be done if tuberculosis (TB) is suspected, along 
with referral to a TB specialist if possible.
Time and Events
Schedule: Part I and 
Part II
Footnote g was revised to read:
g. All subjects will undergo QuantiFERON-TB Gold testing. In countries where the 
QuantiFERON-TB Gold test is not registered/approved, TB skin testing will also be 
required (recommended but not required for study centers in countries where tuberculin is 
not available). The QuantiFERON-TB Gold test is not required at screening for subjects 
with a history of latent TB and appropriate treatment (as described in Inclusion 
Criterion 11a).
Time and Events 
Schedule: Part I and 
Part II
Footnote l was revised to read:
l. If TB is suspected at any time during the study, a chest radiograph and QuantiFERON-


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TB Gold test should be performed. In countries where the QuantiFERON-TB Gold test is 
not registered/approved, TB skin testing should also be performed (recommended but not 
required for study centers in countries where tuberculin is not available). 
4.1 Inclusion Criteria
Inclusion Criterion 11d was revised to specify that a tuberculin skin test is recommended 
but not required for study centers in countries where tuberculin is not available, as follows:
Within 2 months before the first administration of study agent, either have negative 
QuantiFERON-TB Gold test (Attachment 3), or have a newly identified positive 
QuantiFERON-TB Gold test in which active TB has been ruled out, and for which 
appropriate treatment for latent TB has been initiated either before or simultaneously with 
the first administration of study agent (except in countries with high multidrug-resistant 
TB burden [eg, Brazil, China, India, the Russian Federation, and South Africa]), where 
subjects with a newly identified positive QuantiFERON-TB Gold test result are excluded). 
Indeterminate results should be handled as outlined in Section 9.1.2. A negative tuberculin 
skin test (Attachment 4) is additionally required if the QuantiFERON-TB gold test is not 
approved/registered in that country. A tuberculin skin test is recommended but not 
required for study centers in countries where tuberculin is not available. The 
QuantiFERON-TB Gold In-Tube test is not required at screening for subjects with a 
history of latent TB and appropriate treatment as described above in Inclusion 
Criterion 11a.
9.1.2 Screening 
Period
The sixth paragraph was revised as follows:
Subjects with a negative QuantiFERON-TB Gold test result (and a negative tuberculin 
skin test result in countries in which the QuantiFERON-TB Gold test is not 
approved/registered or the tuberculin skin is mandated by local health authorities) are 
eligible to continue with prerandomization procedures. A tuberculin skin test is 
recommended but not required for study centers in countries where tuberculin is not 
available. Subjects with a newly identified positive QuantiFERON-TB Gold (or tuberculin 
skin) test result must undergo an evaluation to rule out active TB and initiate appropriate 
treatment for latent TB. Appropriate treatment for latent TB is defined according to local 
country guidelines for immunocompromised patients. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed, or the subject will be 
excluded from the study. Note: Subjects in countries with high multidrug-resistant TB 
burden (eg, Brazil, China, India, the Russian Federation, and South Africa) identified with 
latent TB at screening will be excluded from participating in the study.
9.7 Safety 
Evaluations
Under the subheading Early Detection of Active Tuberculosis, the last paragraph was 
revised as follows:
Subjects who experience close contact with an individual with active TB during the 
conduct of the study must have a repeat chest radiograph, a repeat QuantiFERON®-TB 
Gold test, a repeat tuberculin skin test in countries in which the QuantiFERON-TB Gold 
test is not approved/registered and, if possible, referral to a physician specializing in TB to 
determine the subject’s risk of developing active TB and whether treatment for latent TB is 
warranted. A tuberculin skin test is recommended but not required for study centers in 
countries where tuberculin is not available. A positive QuantiFERON-TB Gold (or 
tuberculin skin) test result should be considered detection of latent TB. If the 
QuantiFERON-TB Gold test result is indeterminate, the test should be repeated as outlined 
in Section 9.1.2. If recommended, treatment for latent TB must be initiated before or 
simultaneously with the administration of further study agent. Subjects who discontinue 
treatment for latent TB prematurely or who are noncompliant with therapy must 
immediately discontinue further administration of study agent and be encouraged to return 
for all subsequent scheduled study visits.


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10.2 Discontinuation 
of Study Treatment
The following TB screening criterion for subject ineligibility was revised to read:

A subject undergoing continued evaluation has a chest radiograph with evidence 
of current active TB and/or a positive QuantiFERON-TB Gold test result and/or 
a positive tuberculin skin test result in countries in which the QuantiFERON-TB 
Gold is not approved/registered (recommended but not required for study 
centers in countries where tuberculin is not available) unless active TB can be 
ruled out and appropriate treatment for latent TB can be initiated either prior to 
or simultaneously with the next administration of study agent and continued to 
completion. (Note: Study agent must be discontinued for all subjects diagnosed 
with latent TB in countries with high multidrug-resistant TB burden [eg, Brazil, 
China, India, the Russian Federation, and South Africa]).
Attachment 3 
QuantiFERON-TB 
Gold Testing
Under the subheading Adherence to Local Guidelines, the following sentence was added to 
the second (and final) paragraph:
In countries where the QuantiFERON-TB Gold test is not approved/registered, the 
tuberculin skin test is recommended but not required if tuberculin is not available.
Attachment 4 
Tuberculin Skin 
Testing
The following sentence was added as the last sentence:
NOTE: The tuberculin skin test is recommended but not required in countries where 
tuberculin is not available.
Rationale: Language was added to clarify that an indeterminate result for SNP would not meet inclusion criteria for 
the study, and that the deoxyribonucleic acid (DNA) samples can be used for both the required and optional DNA 
research.
4.1 Inclusion Criteria
Inclusion Criterion 18 was revised to read:
DNA sample collection for SNP testing is required for all subjects in this study. Each 
subject must have a SNP status of either positive or negative. Each subject must sign a 
separate informed consent form (ICF) if he or she agrees to consent to additional optional 
DNA research where local regulations permit. Refusal to give consent for the optional 
DNA research does not exclude a subject from participation in the study.
Rationale: Additional details were added for maintaining the study blind during preparation of JNJ-64304500 and 
placebo.
5.2 Blinding
The first paragraph was updated to add the words ‘or syringe number’, and was revised to 
read:
To maintain the study blind, the study agent container will have a label containing the 
study name and medication number or syringe number. The label will not identify the 
study agent in the container. The medication number or syringe number will be entered in 
the case report form (CRF) when the drug is dispensed. The study agents will be identical 
in appearance and packaging.
Rationale: The text in the Prestudy and Concomitant Therapy section was updated for clarity.
8 Prestudy and 
Concomitant Therapy
The following (first) sentence was deleted for clarity:
Prestudy therapies administered up to 30 days before first dose of study drug must be 
recorded at screening.


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Rationale: The text pertaining to concomitant medications was updated to specify that medications are required to 
remain stable through the final study visit.
8.1 Concomitant 
Medications
The second paragraph was revised to specify that concomitant medications are required to 
remain stable through the final study visit as opposed to Week 24, as follows:
With the exception of oral corticosteroids, subjects who are receiving these medications for
Crohn’s disease at baseline should maintain a stable dose through the final efficacy and 
safety visit. Corticosteroids must be maintained at baseline doses through Week 12 (see 
Section 8.1.1).
Rationale: The third paragraph of Section 8.1.1 Corticosteroid Tapering was moved to Section 8.1 Concomitant 
Medications for alignment of flow of contents, and text was updated for clarity.
8.1 Concomitant 
Medications
The third paragraph of Section 8.1.1 Corticosteroid Tapering was moved to Section 8.1 
Concomitant Medications. In addition, the text was revised to indicate that subjects may 
transiently use increased doses of corticosteroids for reasons other than worsening of 
Crohn’s disease, but not for loss of response to treatment for Crohn’s disease, as follows:
After Week 12, subjects may transiently use (ie, for <4 weeks) increased doses of 
corticosteroids for reasons other than worsening of Crohn’s disease (eg, stress doses of 
corticosteroids for surgery, asthma, adrenocortical insufficiency).
Rationale: In Section 9.2.1 Crohn’s Disease Activity Index, the text was updated to clarify that subjects will 
complete CDAI as a daily diary entry and will bring the diary to each study visit.
9.2.1 Crohn’s Disease 
Activity Index
The section was revised to read:
The CDAI will be assessed by collecting information on 8 different Crohn’s disease-
related variables (Attachment 5):1 extra-intestinal manifestations, abdominal mass, weight, 
hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal 
drug(s) and/or opiates, and general well-being. The last 4 variables are scored over 7 days 
by the subject on a diary card. The PRO-2 score is based on the CDAI components of the 
total number of liquid stools and abdominal pain/cramping. The PRO-3 score, which is 
also based on the CDAI, comprises the PRO-2 components plus general well-being. 
Subjects are to complete a daily diary entry and bring the diary to each visit.
Rationale: At the request of a health authority, the National Cancer Institute Common Terminology Criteria for 
Adverse Events definitions of adverse events and hepatotoxicity guidelines were incorporated. 
9.7 Safety 
Evaluations
Under the subheading Clinical Laboratory Tests, the first paragraph was revised as 
follows:
Blood samples for serum chemistry and hematology will be collected. The investigator 
must review the laboratory results, document this review, and record any clinically 
relevant changes occurring during the study in the Adverse Event section of the CRF. 
Clinical hematology and chemistry laboratory test results will be graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
toxicity criteria. The laboratory reports must be filed with the source documents. 
10.2 Discontinuation 
of Study Treatment
The fourth bullet was revised as follows:

A serious adverse reaction occurs that is related to an injection or an infusion, 
including an injection-site or infusion reaction, resulting in bronchospasm with 
wheezing and/or dyspnea that requires ventilatory support OR that results in 
symptomatic hypotension with a decrease in systolic blood pressure >40 mm Hg or 
blood pressure <90/60 mm Hg. This may include events of NCI-CTCAE toxicity 
grade ≥3.
A new fifth bullet was added:


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
Adverse events of NCI-CTCAE grade ≥3 potentially related to worsening of Crohn’s 
disease will be evaluated by the investigator and the study medical monitor to make a 
determination on discontinuation of study agent. Discontinuation of study agent 
should be considered in subjects with worsening Crohn’s disease where continuation 
of the study drug is not in the best interest of the subject.
11.9 Safety Analyses
Under the subheading Clinical Laboratory Tests, the second bullet was revised to specify 
that the summary of maximum NCI-CTCAE toxicity grade for postbaseline hematology 
and chemistry laboratory values will be used to assess the safety of subjects, as follows:

Summary of maximum NCI-CTCAE toxicity grade for postbaseline laboratory 
values (hematology and chemistry).
12.1.3 Severity 
Criteria
The first sentence was revised as follows:
An assessment of severity grade will be made using the following general categorical 
descriptors as outlined in Section 12.1.3.1 and by NCI-CTCAE toxicity grade outlined in 
Section 12.1.3.2. 
12.1.3.1 Severity 
Criteria: General 
Categorical 
Descriptors
The following text was moved from Section 12.1.3 Severity Criteria to newly added 
Section 12.1.3.1 Severity Criteria: 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).
Note: Seriousness and severity should not be confused. A subject could experience a 
severe headache that would not qualify as a serious adverse event (SAE), while another 
might experience a mild stroke that, while not severe, would be considered serious.
12.1.3.2 Severity 
Criteria Based on 
National Cancer 
Institute Common 
Terminology Criteria 
for Adverse Events
Toxicity Grade
The following text was added to newly added Section 12.1.3.2 Severity Criteria Based on 
National Cancer Institute Common Terminology Criteria for Adverse Events Toxicity 
Grade:
An assessment of severity grade will also be made using the following NCI-CTCAE 
categorical descriptors. The NCI-CTCAE Grade refers to the severity of the AE. The NCI-
CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on this general guideline:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*.
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**.


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Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.
Rationale: At the request of a health authority, additional guidelines on the evaluation of abnormal liver function 
tests were added. 
9.7 Safety 
Evaluations
Under subheading Clinical Laboratory Tests, the following new bullet was added:

Abnormal liver function tests: If laboratory testing for a subject enrolled in the 
study and receiving study drug reveals an increase of serum aminotransferases (ALT 
or AST) to >3x the upper limit of normal (ULN) and an increase of bilirubin to >2x 
ULN, study agent should be suspended immediately. In addition, laboratory tests for 
ALT, AST, alkaline phosphatase, and total bilirubin should be confirmed by a retest 
within 24 hours if possible, but no later than 72 hours following notification of test 
results. See Attachment 6 (Liver Safety Monitoring and Assessment) for additional 
information on monitoring and assessment of abnormal liver function tests.
10.2 Discontinuation 
of Study Treatment
The following new bullet was added:

Severe hepatic function abnormalities as described in Section 9.7.
Rationale: An attachment was added to provide clarification regarding the definitions of inadequate response to or 
intolerance of corticosteroids or AZA/6-MP and corticosteroid dependence.
Attachment 2: 
Definitions of 
Inadequate Response 
to or Intolerance of 
Corticosteroids or 
AZA/6-MP and 
Corticosteroid 
Dependence 
The definitions of an inadequate response to or intolerance of corticosteroids or AZA/6-
MP and corticosteroid dependence were added to the protocol as Attachment 2.
Rationale: At the request of a health authority, additional guidance on the evaluation of subjects who have evidence 
of hepatotoxicity is provided. 
Attachment 6: Liver 
Safety Monitoring 
and Assessment
Liver Safety Monitoring and Assessment was added to the protocol as Attachment 6. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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SYNOPSIS
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Protocol to 
Evaluate the Safety and Efficacy of JNJ-64304500 in Subjects with Moderately to Severely Active 
Crohn’s Disease
Protocol Number:
64304500CRD2001
EudraCT Number:
2016-000634-21
JNJ-64304500 (formerly known as NNC0142-002) is a human immunoglobulin G4 isotype monoclonal 
antibody that binds specifically to the natural killer group 2 member D (NKG2D) receptor, and blocks 
NKG2D ligand binding, thereby preventing the downstream-signaling events that otherwise lead to cell 
proliferation and release of proinflammatory cytokines and cytotoxic mediators. Several lines of evidence 
from patients with Crohn’s disease support the hypothesis that NKG2D receptor activation plays a role in 
disease pathogenesis by mediating the production of local cytokines, activation of an immune response, 
and direct cytotoxicity of target intestinal cells. Collectively, preclinical and clinical data on the 
expression of NKG2D ligands or proinflammatory cytokines in the target tissue and abnormal expression 
and activation of the NKG2D receptor on CD8+ and CD4+ T cells provide a rationale for the clinical 
development of inhibitors of the NKG2D receptor.
Results from a Phase 2a study (conducted by Novo Nordisk) provided initial evidence for the efficacy of 
JNJ-64304500 in the treatment of Crohn’s disease, particularly in subjects who had not previously failed 
conventional therapy.
This Phase 2b protocol will further evaluate JNJ-64304500 in subjects with moderately to severely active
Crohn’s disease who have failed biologic or conventional therapy.
The protocol is divided into 2 parts.
In Part I, the following 2 studies will be conducted:

Study 1: A study in subjects who are biologic intolerant or refractory (Bio-IR);

Study 2: A study in subjects who have not previously failed a biologic therapy (Biologic 
nonfailure [Bio-NF]).
In Part II, the following study will be conducted:

Study 3: A dose-ranging study in subjects who are Bio-IR or Bio-NF
A long-term extension (LTE) for Part II of the study was added to the protocol as part of Protocol 
Amendment 5. After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments and who may benefit from continued treatment in the opinion of the investigator, are eligible 
to enter the Part II LTE to receive up to 52 weeks of additional treatment. Subjects who have completed 
Week 24 assessments prior to the implementation of Protocol Amendment 5 will not be eligible to enroll 
in the Part II LTE.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
The objectives are the same in each of the 2 parts.


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Primary Objectives

To evaluate the efficacy of JNJ-64304500 to reduce the Crohn’s Disease Activity Index (CDAI)
score from baseline.

To evaluate the safety of JNJ-64304500.
Secondary Objectives

To evaluate the efficacy of JNJ-64304500 to induce clinical remission, clinical response, and 
endoscopic healing of the mucosa, and to maintain remission.

To evaluate the relationship between efficacy and the presence of the NKG2D and/or MICB single 
nucleotide polymorphism (SNP) biomarkers.

To evaluate the efficacy of JNJ-64304500 to improve general and disease-specific health-related 
quality of life and to reduce Crohn’s disease-related hospitalizations and surgeries.

To evaluate the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and biomarkers 
(eg, reductions in C-reactive protein [CRP], fecal calprotectin, and fecal lactoferrin) of 
JNJ-64304500 therapy.
Endpoints
The data from Study 1 and Study 2 in Part I will be pooled for analysis.
Primary Endpoints
The primary endpoint for Part I is: Change from baseline in the CDAI score at Week 8.
The primary endpoint for Part II is: Change from baseline in the CDAI score at Week 12.
Major Secondary Endpoints
The following endpoints will be evaluated as major secondary endpoints only in Part II (the dose-ranging 
portion of the study); these endpoints will be evaluated in Part I but are not specified as major secondary 
endpoints.

Clinical remission at Week 12 as measured by CDAI (CDAI <150).

Clinical response at Week 12 as measured by CDAI (≥100-point reduction from baseline in CDAI or 
CDAI <150).

Change in PRO-2 (the sum of the abdominal pain and stool frequency subscores of the CDAI score) 
from baseline at Week 12.

Clinical remission at Week 12 as measured by PRO-2 (PRO-2 <75).

Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from baseline in PRO-2 or 
PRO-2 <75).

Change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline at Week 12.
Hypothesis
The hypothesis for Part I and Part II is that JNJ-64304500 is superior to placebo in inducing a reduction 
from baseline in CDAI in subjects with moderately to severely active Crohn’s disease.


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OVERVIEW OF STUDY DESIGN
This protocol is comprised of 2 parts (Part I [Study 1: Bio-IR subjects and Study 2: Bio-NF subjects] and 
Part II [Bio-IR and Bio-NF subjects]). Each study is a randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study of JNJ-64304500 in subjects with moderately to severely active Crohn’s 
disease. A minimum of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF) will be
randomized in Part I. An additional 250 subjects will be randomized in Part II. Part I will study the safety 
and efficacy of a high dose regimen of JNJ-64304500 compared with placebo in subjects who have failed 
biologic or conventional therapy (Bio-IR or Bio-NF subjects, respectively). Part II will study the safety 
and efficacy of multiple-dose regimens of JNJ-64304500 compared with placebo, with ustekinumab 
(STELARA®) as a reference arm, in Bio-IR and Bio-NF subjects.
The duration of the study will be 38 weeks in Part I and 36 weeks in Part II for subjects who do not enter 
the Part II LTE. The study duration includes study agent administration visits and a final efficacy and 
safety follow-up visit. Eligible subjects will only participate in Part I or Part II of the study.
After Protocol Amendment 5 is implemented, subjects who complete Part II of the study through 
Week 24 and who may benefit from continued treatment in the opinion of the investigator, will be eligible 
to enter the Part II LTE to receive up to 52 weeks of additional treatment.
The Time and Events Schedules summarize the frequency and timing of assessments for efficacy, PK, 
biomarkers, immunogenicity, PD, and safety in Part I and Part II of the study.
An interim analysis is planned in Part I when 100 randomized Part I subjects (Study 1: Bio-IR and 
Study 2: Bio-NF) have completed their Week 12 visit or have terminated their study participation before 
Week 12. If acceptable safety and efficacy are established in the combined Bio-IR and Bio-NF 
populations, Part II of the protocol, which consists of a dose-ranging study in subjects who are Bio-IR or 
Bio-NF, will be initiated. The interim analysis will allow for timely evaluation of safety and efficacy in 
Part I and uninterrupted patient enrollment through a seamless transition from Part I to Part II of the trial. 
Enrollment for Part I will continue until the sponsor makes a decision on whether to start Part II based on 
the interim analysis or when a maximum of 170 subjects have been randomized, whichever occurs first. 
Part II will be initiated if results from Part I demonstrate acceptable safety and efficacy, either at the 
interim analysis or when all Part I subjects have completed their Week 12 visit (or have terminated study 
participation prior to Week 12). If Part II is not initiated based on the interim analysis results, then the 
results through Week 12 for all subjects in Part I (ie, when all randomized subjects in Part I have either 
completed the Week 12 visit or terminated study participation prior to Week 12) will be examined to 
determine whether to start Part II. Under this scenario, a pause in enrollment between Part I and Part II 
will occur.
An external Data Monitoring Committee (DMC) will review unblinded safety data from all subjects
periodically to monitor subject safety.
The end of the 64304500CRD2001 study is defined as the date on which the last subject completes the 
last efficacy and safety follow-up visit.
SUBJECT POPULATION
The subject population consists of men or women ≥18 years of age with moderately to severely active 
Crohn’s disease (of at least 3 months’ duration), defined as a CDAI score ≥220 and ≤450, with elevated 
CRP >0.3 mg/dL (>3.0 mg/L) and/or calprotectin >250 mg/kg. Subjects must have colitis, ileitis, or 
ileocolitis previously confirmed at any time in the past by radiography, histology, and/or endoscopy. 
Subjects also must have previously failed or been intolerant to 1 or more approved biologic agents (ie, 
tumor necrosis factor alpha antagonists or vedolizumab; Bio-IR subjects) or have demonstrated an 
inadequate response to or failed to tolerate corticosteroids or immunomodulators (ie, 6-mercaptopurine, 
azathioprine, and methotrexate) but not a biologic (Bio-NF subjects).


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DOSAGE AND ADMINISTRATION
Part I
In Part I, a minimum of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF) will be 
randomly assigned to receive placebo or the JNJ-64304500 high dose in a 1:1 ratio using permuted block 
randomization, stratified by baseline CDAI score (≤300 or >300) and SNP-positive status (yes or no). The 
Bio-IR and Bio-NF populations will be randomized separately.
The treatment groups in Part I will be as follows:

Placebo subcutaneously (SC) at Weeks 0, 2, 4, 6, 8, and 10; from Week 12, these subjects will 
receive additional doses as follows:

Placebo-treated subjects who are in clinical response at Week 12 (≥100-point reduction from 
baseline in CDAI or CDAI <150) will continue to receive placebo SC injections every 2 weeks 
(q2w) from Week 12 through Week 22.

Placebo-treated subjects who are not in clinical response at Week 12 will receive JNJ-64304500 
400 mg SC at Week 12, and then JNJ-64304500 200 mg SC from Week 14 through Week 22.

JNJ-64304500 400 mg SC at Week 0 then 200 mg SC q2w through Week 22.
Part II
In Part II of the study, subjects (Bio-IR and Bio-NF) will be randomly assigned in equal proportions to 
receive placebo, 1 of 3 dose regimens of JNJ-64304500, or ustekinumab, using permuted block 
randomization, stratified by baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), and 
Bio-IR status (yes or no). The treatment groups are as follows:

Placebo SC at Weeks 0, 2, 4, 8; from Week 12, these subjects will receive additional doses as 
follows:
o
Placebo-treated subjects who are in clinical response at Week 12 (≥100-point reduction 
from baseline in CDAI or CDAI <150) will continue to receive placebo SC injections at 
Weeks 12, 14, 16 and 20.
o
Placebo-treated subjects who are not in clinical response at Week 12 will receive 
JNJ-64304500 150 mg SC at Week 12 and JNJ-64304500 75 mg SC at Weeks 14, 16, 
and 20.

JNJ-64304500 high dose: 400 mg SC at Week 0 and 200 mg SC at Week 2 and Week 4, then 200 mg 
every 4 weeks (q4w) through Week 20.

JNJ-64304500 middle dose: 150 mg SC at Week 0 and 75 mg SC at Week 2 and Week 4, then 75 mg 
q4w through Week 20.

JNJ-64304500 low dose: 50 mg SC at Week 0 and 25 mg SC at Week 2 and Week 4, then 25 mg 
q4w through Week 20.

Ustekinumab: tiered doses approximating 6 mg/kg intravenously (IV) at Week 0 and 90 mg SC at 
Weeks 8 and 16.
Long-term Extension
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 assessments, and
who may benefit from continued treatment in the opinion of the investigator, are eligible to enter the Part 
II LTE. In the Part II LTE, each subject will be eligible to receive up to 52 weeks of additional study drug 
(for a total of up to 72 weeks of study drug in Part II). The first dose of study drug within the Part II LTE 


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will be administered after the Week 24 assessments have been completed. The dose may be administered 
on the same day as the Week 24 assessments, or may be administered on a later date, as long as the dose 
is administered within the Week 24 visit window.
Subjects will continue to receive the same treatment regimen during the Part II LTE that they were 
receiving between Week 12 and Week 20 in the main study phase of Part II (placebo, high, middle, low 
dose JNJ-64304500 or ustekinumab). To maintain the study blind, all patients, investigators, and sites will 
remain blinded to treatment allocation during the Part II LTE until the last subject in the Part II main 
study phase has completed the Week 24 assessments and the Sponsor unblinds the study.
The timing of the Week 24 data analysis is dependent upon the timing and completion of Part II 
enrollment. An individual subject’s unblinding during the Part II LTE will depend upon his/her Part II 
enrollment date. Therefore, a portion of subjects will complete the entire Part II LTE in a blinded fashion 
before study unblinding, while other subjects could be unblinded to treatment allocation during their 
participation in the Part II LTE.
On 15 March 2021, sites were informed that due to lack of sufficient efficacy of JNJ-64304500, subjects 
who were receiving JNJ-64304500 or placebo in the LTE were discontinued, subjects receiving 
ustekinumab in countries where ustekinumab is not commercially available were continued in the LTE. 
Any subject who withdraws from the Part II LTE prior to study unblinding will return for a final safety 
follow-up visit 16 weeks after the last dose of study drug. For subjects that remain in the Part II LTE at 
the time of study unblinding, continuation of study drug during the Part II LTE will be dependent upon 
treatment allocation as follows:

JNJ-64304500: Subjects receiving JNJ-64304500 during the LTE will stop receiving study drug and 
will have a final safety follow-up visit 16 weeks after the last dose of study drug.

Placebo: Subjects receiving placebo who remain in the Part II LTE at the time of study unblinding 
will have their final safety follow-up visit subsequent to unblinding and will be discontinued from the 
study. No further follow-up visits will be performed.

Ustekinumab: Subjects receiving ustekinumab will continue to receive it during the Part II LTE until 
unblinding occurs. After unblinding, based on the treating physician’s clinical judgment, subjects may 
receive ustekinumab in a manner dependent on the country in which they are located:
o
If a subject is not continuing on ustekinumab after unblinding, the subject will need to return 
for a final safety follow-up visit that will be performed 16 weeks after the final dose of study 
ustekinumab.
o
If a subject continues on ustekinumab in a country where commercial ustekinumab is 
available and approved for the treatment of adult Crohn’s disease, the treating physician is 
responsible for providing the subject with commercial ustekinumab, which should be 
administered according to the approved dosing regimen in each country. The final safety 
follow-up visit should be performed after unblinding but before receiving the first dose of 
commercial ustekinumab.


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o
If a subject continues on ustekinumab in countries where commercial ustekinumab is not 
available or approved for adult Crohn’s disease, ustekinumab will continue to be provided to 
subjects through Week 72.
For eligible Part II subjects, participation in the Part II LTE is entirely voluntary. Eligible subjects who do 
not wish to enter the Part II LTE will complete the Part II Week 24 safety and efficacy assessments, 
followed by the final efficacy and safety assessments at Week 36.
During the Part II LTE, all concomitant medications, including Crohn’s disease-specific medications 
(except for the prohibited medications listed in Section 8.2) may be administered at the discretion of the 
investigator.
All subjects in the Part II LTE (before unblinding for JNJ-64304500, ustekinumab, and placebo and after 
unblinding for JNJ 64304500) will be assessed according to the Time & Events Schedule (Table 3), 
which includes assessments, adverse events (AEs), laboratory analyses, and PK and immunogenicity 
samples. Ustekinumab subjects in the Part II LTE (after unblinding for ustekinumab subjects in countries 
where ustekinumab is not commercially available) will be assessed according to the Time & Events 
Schedule (Table 4), which includes assessments and adverse events (AEs).
EFFICACY EVALUATIONS
The following efficacy evaluations will be performed in Part I and Part II of the main study phase.

Crohn’s Disease Activity Index (CDAI)

C-reactive protein (CRP)

Fecal lactoferrin and fecal calprotectin

Inflammatory Bowel Disease Questionnaire (IBDQ)

36-Item Short Form Health Survey (SF-36)

Fistula assessment

Bristol stool form scale

Abdominal pain Numerical Rating Scale (NRS)

Patient’s Global Impression of Severity (PGIS) of Crohn’s disease

Patient’s Global Impression of Change (PGIC) of severity of Crohn’s disease

Ileocolonoscopy

Histologic assessment
Efficacy evaluations will not be performed during the Part II LTE.
PHARMACOKINETIC, PHARMACODYNAMIC, AND IMMUNOGENICITY EVALUATIONS
Serum samples will be used to evaluate the PK, PD, and immunogenicity of JNJ-64304500 (and 
ustekinumab in Part II) and will be collected from each subject at the timepoints indicated in the Time and 
Events Schedules.


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DNA AND BIOMARKER EVALUATIONS
Biomarker assessments will be made to examine the biologic response to treatment and to identify 
biomarkers that are relevant to JNJ-64304500 treatment and/or Crohn’s disease. Blood samples for 
serum-based biomarker analyses will be collected from all subjects to assess proteins related to the 
NKG2D pathway or the pathogenesis of Crohn’s disease. Whole blood samples will be collected from all 
subjects for the analysis of RNA expression and T-cell receptor repertoire. Mucosal biopsy samples will 
be collected during ileocolonoscopy for the analysis of gene and/or protein expression and the histologic 
assessment of disease and/or healing. Receptor occupancy assessments for NKG2D and
immunophenotyping assessments (including natural killer [NK] cells and CD8+ T cells) will also be 
performed.
Whole blood will be collected from all subjects for SNP analysis (the NKG2D SNP rs2255336 and the 
MICB [NKG2D ligand]); subjects who have signed an optional pharmacogenomics consent form will 
undergo complete genomic testing.
SAFETY EVALUATIONS
Safety evaluations will include AEs; clinical laboratory tests (chemistry and hematology); vital signs and 
physical examinations; a screening electrocardiogram; allergic reactions, infusion reactions and 
injection-site reactions; infections; and early detection of active tuberculosis.
STATISTICAL METHODS
Sample Size Determination
Sample size calculations for Part I (Bio-IR subjects and Bio-NF subjects combined) were determined by 
the power to detect a significant difference in the change from baseline in the CDAI score at Week 8
between JNJ-64304500 and placebo using a 2-sample t-test. Sample size calculations for Part II (Bio-IR
and Bio-NF subjects) were determined by the power to detect a dose-response signal for the change from 
baseline in the CDAI score at Week 12 (primary endpoint in Part II) using the Multiple Comparison 
Procedures with modeling techniques (MCP-Mod) method.
For Part I, assuming the mean CDAI change from baseline at Week 8 is -98 in the JNJ-64304500 group 
and -46 in the placebo group with a common standard deviation (SD) of 96, 60 subjects per treatment 
group will provide 84% power to detect a treatment difference between JNJ-64304500 and placebo at an 
overall Type 1 error rate of 0.05.
For Part II, assuming the mean CDAI change from baseline at Week 12 is -111 in the JNJ-64304500 
group and -51 in the placebo group with a common SD of 102, 50 subjects per treatment group will 
provide a mean power of 85% to detect a dose-response signal based on 7 candidate dose-response 
models at an overall Type 1 error rate of 0.05.
Efficacy Analyses
This protocol is comprised of 2 separate parts (Part I [Study 1: Bio-IR subjects and Study 2: Bio-NF 
subjects] and Part II [Bio-IR and Bio-NF subjects]). Part I and Part II will be analyzed separately with 
separate Type I error control for the primary endpoint (at the 0.05 level of significance). The other 
endpoints within each part will not be controlled for multiplicity.


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For each part, the analysis set is all randomized subjects who received study agent. Efficacy analyses will 
be based on a modified intent-to-treat principle. Therefore, the efficacy data for each subject who 
received study agent will be analyzed according to the assigned treatment regardless of the actual 
treatment received.
For Part I, the primary endpoint of change from baseline in the CDAI score at Week 8 will be compared 
between the JNJ-64304500 treatment group and the placebo treatment group by an analysis of covariance 
model on the van der Waerden normal scores with treatment as a fixed factor and baseline CDAI score, 
SNP-positive status (yes or no), and Bio-IR status (yes or no) as covariates. Part I will be considered to be 
positive if a significant improvement is detected in the change from baseline in the CDAI score at Week 8 
in the JNJ-64304500 group compared with the placebo group at the 0.05 level of significance.
The primary endpoint for Part II is the change from baseline in the CDAI score at Week 12. A unified 
strategy that combines Multiple Comparison Procedures with modeling techniques, MCP-Mod, will be 
used to analyze the dose-response data over the JNJ-64304500 doses. This approach consists of 2 major 
steps. The first step consists of testing the dose-response signal via multiple contrast tests while 
controlling the overall Type 1 error rate. If a dose-response signal is detected, the second step is to select 
a model that best describes the observed data and use it to estimate adequate doses with associated 
precision. The study will be considered positive if a dose-response signal for the primary endpoint is 
detected. In addition to the dose-response analysis, pairwise comparisons of the JNJ-64304500 treatment 
groups versus the placebo group will be performed for the change from baseline in the CDAI score at 
Week 12; these comparisons will not be adjusted for multiplicity.
The major secondary endpoints are only specified in Part II. The major secondary endpoints that are 
dichotomous endpoints will be analyzed by the Cochran-Mantel-Haenszel chi-square test (2-sided) 
stratified by baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), and Bio-IR status (yes 
or no); the major secondary endpoints that are continuous endpoints will be analyzed by an analysis of 
covariance model on the van der Waerden normal scores with treatment as a fixed factor and appropriate 
baseline level of the variable, SNP-positive status (yes or no), and Bio-IR status (yes or no) as covariates. 
The major secondary endpoints will not be controlled for multiplicity.
Safety Analyses
Safety will be assessed by analyses of the incidence and type of AEs, serious AEs, AEs considered by the 
investigator to be reasonably related to study drug, AEs leading to discontinuation of study agent, 
infections, infusion reactions, and injection-site reactions. Safety assessments will also include analyses 
of change from baseline in laboratory parameters (hematology and chemistry) and summary of maximum 
National Cancer Institute Common Terminology Criteria for Adverse Events toxicity grade for 
postbaseline laboratory values.


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TIME AND EVENTS SCHEDULE: PART I
Table 1:
Time and Events Schedule, Part I
Period
Screeningw
Main Study phase x
Early 
termination c 
Final 
efficacy 
& safety 
follow-
up d
Week
-5 weeks
0
2
4
6
8
10
12
14
16
18
20
22
24
Study Proceduresaa
Screening/Administrative
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Chest radiographbb
X
QuantiFERON-TB Test cc
X
Stool studies to evaluate for enteric 
pathogens dd
X
Training on diary card completion
X
Study Agent Administration
Randomization
X
Administer study agent aa (SC study 
agent at a different location at each 
visit [Section 6])
X
X
X
X
Xe
e
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Vital signs ff
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Baseline 12-lead ECG
X
Serum pregnancy test
X
Urine pregnancy test gg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB evaluation hh/other infection 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection-site evaluation 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Collect and review diary cards ii
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDAI assessments jj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1:
Time and Events Schedule, Part I
Period
Screeningw
Main Study phase x
Early 
termination c 
Final 
efficacy 
& safety 
follow-
up d
Week
-5 weeks
0
2
4
6
8
10
12
14
16
18
20
22
24
Study Proceduresaa
Fistula exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bristol stool form scale kk
X
X
X
X
X
X
X
Abdominal pain NRS assessment ll
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample (fecal lactoferrin and 
calprotectin) and microbiome
X mm
X
X
X
mm
X
mm
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
Video ileocolonoscopy nn
X
X
Xoo
X
IBDQ pp
X
X
X
X
X
SF-36 pp
X
X
X
X
X
Clinical Laboratory Assessments
Hematology
X
GQ
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
,q
X
X
X
X
X
X
X
HBV and HCV testing
X
HIV test
X
Pharmacokinetics/ Immunogenicity
JNJ-64304500 serum concentration rr, 
ss
X
X
X
X
X
X
X
X
X
X
X
X
JNJ-64304500 random population PK 
sample tt, ss
----X----
----X----
Antibodies to JNJ-64304500 rr, ss
X
X
X
X
X
X
X
X
Receptor occupancy
X
X
X
X
X
X
X
X
Immunophenotyping (NK cells and 
CD8+ T cells) 
X
X
X
X
X
X
X
X
Pharmacodynamics/Biomarkers
Blood sample collection (T-cell 
receptor repertoire)
X
X
X
X
X
X
Whole blood sample collection for 
RNA analysis uu
X
X
X
X
X
X
Serum proteins
X
X
X
X
X
X
Ileocolonoscopy biopsy sample 
X
X
Xoo
X


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Table 1:
Time and Events Schedule, Part I
Period
Screeningw
Main Study phase x
Early 
termination c 
Final 
efficacy 
& safety 
follow-
up d
Week
-5 weeks
0
2
4
6
8
10
12
14
16
18
20
22
24
Study Proceduresaa
collections for RNA and histology
Pharmacogenomics (DNA)
Whole blood sample collection for 
SNPs and DNA analysis vv
X
Ongoing Subject Review
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Crohn’s disease-related 
hospitalizations and surgeries ww
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: CDAI=Crohn’s Disease Activity Index; CRP=C-reactive protein; ECG=electrocardiogram; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; IBDQ=Inflammatory Bowel Disease Questionnaire; NK=natural killer; NKG2D=natural killer group 2 member D; PK=pharmacokinetics; 
PRO=patient-reported outcome; SF-36=36-Item Short Form Health Survey; SNP=single nucleotide polymorphism; TB=tuberculosis.
w.
Screening period should be a minimum of 7 days to allow for collection of CDAI data. Subjects who are rescreened do not need to have a minimum of 7 days, 
provided that they have enough data to support CDAI calculation.
x.
Visit windows should be ± 4 days for each visit.
y.
Subjects who terminate study participation should complete an early termination visit. If a subject completed assessments at Week 24 and terminated after 
Week 24, the only assessments that should be performed at the early termination visit are those planned for the final efficacy and safety follow-up. Subjects 
who discontinue study agent administration before Week 8 (but have not terminated study participation) should complete the Week 8 and Week 12 
assessments and return for a final efficacy and safety follow-up visit approximately 16 weeks after their last study agent administration. Subjects who 
discontinue study agent administration after Week 8 (but have not terminated study participation) should complete the Week 12 and Week 24 assessments and 
return for a final efficacy and safety follow-up visit approximately 16 weeks after their last study agent administration.
z.
Subjects should complete a final efficacy and safety follow-up visit approximately 16 weeks after their last study agent administration. For subjects who 
complete all visits, this will occur at Week 38.
aa.
All assessments are to be completed before study agent administration, unless otherwise specified. It is recommended that PRO assessments be completed 
first, starting with the PRO components of the CDAI.
bb.
Chest radiograph (posterior-anterior and lateral views) may be obtained within 3 months before the Week 0 visit.
cc.
All subjects will undergo QuantiFERON-TB testing. In countries where the QuantiFERON-TB test is not registered/approved, TB skin testing will also be 
required (recommended but not required for study centers in countries where tuberculin is not available). The QuantiFERON-TB test is not required at 
screening for subjects with a history of latent TB and appropriate treatment (as described in Inclusion Criterion 11a).


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dd.
Stool studies for enteric pathogens may be performed at either the central or a local laboratory and must include a stool culture and Clostridium difficile toxin 
assay. These must have been performed within 4 months before Week 0. Additional testing, such as ova and parasites or Escherichia coli O157:H7 
assessment, may be performed at the investigator’s clinical discretion.
ee.
Administration of study agent at the Week 8 visit must occur after all other procedures and assessments specified for the Week 8 visit have been completed.
ff.
Temperature, pulse/heart rate, respiratory rate, and blood pressure.
gg.
Must be performed before every study agent administration in female subjects of childbearing potential.
hh.
If TB is suspected at any time during the study, a chest radiograph and QuantiFERON-TB test should be performed. In countries where the QuantiFERON-TB 
test is not registered/approved, TB skin testing should also be performed (recommended but not required for study centers in countries where tuberculin is not 
available).
ii.
For all visits up to Week 24, daily diary information should be collected for every day prior to each visit. For the final efficacy and safety visit, daily diary 
information should be collected for 14 days prior to the visit.
jj.
The hematocrit value obtained during screening will be used to calculate CDAI at Week 0. For other visits, the most recent hematocrit value obtained before a 
visit will be used to calculate the CDAI for that visit.
kk.
Subject will complete the Bristol stool form scale as a daily diary entry and bring the diary to each visit. Daily diary information should be collected for every 
day prior to each visit.
ll.
Subject will complete the abdominal pain NRS assessment as a daily diary entry and bring the diary to each visit. For all visits up to Week 24, daily diary 
information should be collected for every day prior to the visits. For the final efficacy and safety visit, daily diary information should be collected for 14 days 
prior to the visit.
mm. Stool samples required for this visit should be obtained before the start of the bowel preparation for the video ileocolonoscopy that is also scheduled for the 
visit.
nn.
Because these procedures must not interfere with the collection of CDAI data, if performed on the day of these visits, the 7 days before the initiation of the 
colonoscopy preparation should be used to calculate CDAI scores for these visits. If the video ileocolonoscopic examination is not performed on the day of the 
visit, it must be performed at least 8 days before the Week 0 visit and no more than 8 days before the Week 12 visit and Week 24 visit.
oo.
The Week 24 video ileocolonoscopy and related endoscopic assessments are optional.
pp.
The IBDQ and SF-36 survey should be administered before any clinical procedures or tests are performed.
qq.
Laboratory tests at Week 0 are not required if screening laboratory tests were performed within 2 weeks before the Week 0 visit.
rr.
Blood samples should be collected before SC injection of study agent. All reasonable attempts should be made to collect samples at the scheduled timepoints 
and record the actual times of PK sample collections.
ss.
At visits where only serum concentration of study agent will be evaluated (ie, no antibodies to study agent will be evaluated), 1 venous blood sample of 
sufficient volume should be collected, and each serum sample should be divided into 2 aliquots (1 for serum concentration of study agent, and a back-up). At 
visits where serum concentration of study agent and antibodies to study agent will be evaluated, 1 venous blood sample of sufficient volume should be 
collected. Each serum sample will be divided into 3 aliquots (1 each for serum concentration of study agent, antibodies to study agent, and a back-up).
tt.
Each random population PK sample should be collected at any time between Weeks 0 and 2 (after the Week 0 study agent administration) and between 
Weeks 22 and 24 (after the Week 22 study agent administration). The date for the random population PK sample collection will be at the subject’s discretion. 
However, samples should not be drawn on or within 1 day of a scheduled visit (ie, the Week 0, 2, 22, or 24 visit) in this time period.
uu.
Whole blood for RNA analysis will be collected from all subjects in the study.
vv.
Whole blood for SNP analysis will be collected from all subjects. All subjects will be tested for the NKG2D SNP rs2255336 and the MICB (NKG2D ligand) 
SNP rs2239705 at screening. For subjects who have signed a separate informed consent form, DNA testing will be done to search for links of specific genes to 
disease or response.
ww. Hospitalization for ileocolonoscopy is not included in this category. 


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TIME AND EVENTS SCHEDULE: PART II MAIN STUDY PHASE
Table 2:
Time and Events Schedule, Part II
Period
Screeninga
Main study phaseb
Early 
termination c
Final 
efficacy & 
safety 
follow-up d,f
Week
-5 weeks
0
2
4
6
8
10
12
14
16
20
24
Study Procedurese
Screening/Administrative
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Chest radiograph g
X
QuantiFERON-TB Test h
X
Stool studies to evaluate for enteric 
pathogen i
X
Training on diary card completion
X
Study Drug Administration
Randomization
X
Administer study agent e (SC study agent 
at a different location at each visit 
[Section 6])
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Vital signs j
X
X k
X
X
X
X
X
X
X
X
X
X
Baseline 12-lead ECG
X
Serum pregnancy test
X
Urine pregnancy test l
X
X
X
X
X
X
X
X
X
X
TB evaluation m/other infection 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection-site evaluation 
X
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Collect and review diary cards n
X
X
X
X
X
X
X
X
X
X
X
X
X
CDAI assessments o
X
X
X
X
X
X
X
X
X
X
X
X
X
Fistula exam
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 2:
Time and Events Schedule, Part II
Period
Screeninga
Main study phaseb
Early 
termination c
Final 
efficacy & 
safety 
follow-up d,f
Week
-5 weeks
0
2
4
6
8
10
12
14
16
20
24
Study Procedurese
Bristol stool form scale p
X
X
X
X
X
X
X
Abdominal pain NRS assessment q
X
X
X
X
X
X
X
X
X
X
X
X
X
PGIS of Crohn’s disease assessment
X
X
X
X
X
X
PGIC of severity of Crohn’s disease 
assessment
X
X
X
X
X
Stool sample (fecal lactoferrin and 
calprotectin) and microbiome
X r
X
X
X r
X r
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
Video ileocolonoscopy s
X
X
X
IBDQ t
X
X
X
X
X
SF-36 t
X
X
X
X
X
Clinical Laboratory Assessments
Hematology 
X
Xu
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
Xu
X
X
X
X
X
X
X
HBV and HCV testing
X
HIV test
X
Pharmacokinetics/ Immunogenicity
Study agent serum concentrationv, w
X
X
X
X
X
X
X
X
X
X
X
X
JNJ-64304500 random population PK 
samplex, w
----X----
----X----
Assessment for antibody to study agent v, 
w
X
X
X
X
X
X
X
X
Receptor occupancy
X
X
X
X
X
X
X
X
Immunophenotyping (NK cells and 
CD8+ T cells)
X
X
X
X
X
X
X
X


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Table 2:
Time and Events Schedule, Part II
Period
Screeninga
Main study phaseb
Early 
termination c
Final 
efficacy & 
safety 
follow-up d,f
Week
-5 weeks
0
2
4
6
8
10
12
14
16
20
24
Study Procedurese
Pharmacodynamics/Biomarkers
Blood sample collection (T-cell receptor 
repertoire)
X
X
X
X
X
X
Whole blood sample collection for RNA 
analysis y
X
X
X
X
X
X
Serum proteins
X
X
X
X
X
X
Ileocolonoscopy biopsy sample 
collections for RNA and histology
X
X
X
Pharmacogenomics (DNA)
Whole blood sample collection for SNPs 
and DNA analysis z
X
Ongoing Subject Review
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Crohn’s disease-related hospitalizations 
and surgeries aa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: CDAI=Crohn’s Disease Activity Index; CRP=C-reactive protein; ECG=electrocardiogram; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; IBDQ=Inflammatory Bowel Disease Questionnaire; NK=natural killer; NKG2D=natural killer group 2 member D; PGIC=Patient’s Global 
Impression of Change; PGIS=Patient’s Global Impression of Severity; PK=pharmacokinetics; PRO=patient-reported outcome; SF-36=36-Item Short Form Health 
Survey; SNP=single nucleotide polymorphism; TB=tuberculosis.
a.
Screening period should be a minimum of 7 days to allow for collection of CDAI data. Subjects who are rescreened do not need to have a minimum of 7 days, 
provided that they have enough data to support CDAI calculation.
b.
Visit windows should be ±4 days for each visit up to and including Week 12; from Week 16 to end of study, visit window should be ± 7 days.
c.
Subjects who terminate study participation should complete an early termination visit. If a subject completed assessments at Week 24 and terminated after 
Week 24, the only assessments that should be performed at the early termination visit are those planned for the final efficacy and safety follow-up visit. 
Subjects who discontinue study agent administration before Week 12 (but have not terminated study participation) should complete the Week 12 assessments 
and return for a final efficacy and safety follow-up visit approximately 16 weeks after their last study agent administration. Subjects who discontinue study 
agent administration after Week 12 (but have not terminated study participation) should complete the Week 24 assessments and return for a final efficacy and 
safety follow-up visit approximately 16 weeks after their last study agent administration.
d.
Subjects should complete a final efficacy and safety follow-up visit approximately 16 weeks after their last study agent administration. For subjects who 
complete all visits and are not enrolling in the Part II LTE, this will occur at Week 36.


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e.
All assessments are to be completed before study agent administration, unless otherwise specified. It is recommended that PRO assessments be completed 
first, starting with the PRO components of the CDAI.
f.
The final efficacy and safety follow-up visit in Part II will only occur for those subjects not enrolling into the Part II LTE.
g.
Chest radiograph (posterior-anterior and lateral views) may be obtained within 3 months before the Week 0 visit.
h.
All subjects will undergo QuantiFERON-TB testing. In countries where the QuantiFERON-TB test is not registered/approved, TB skin testing will also be 
required (recommended but not required for study centers in countries where tuberculin is not available). The QuantiFERON-TB test is not required at 
screening for subjects with a history of latent TB and appropriate treatment (as described in Inclusion Criterion 11a).
i.
Stool studies for enteric pathogens may be performed at either the central or a local laboratory and must include a stool culture and Clostridium difficile toxin 
assay. These must have been performed within 4 months before Week 0. Additional testing, such as ova and parasites or Escherichia coli O157:H7 
assessment, may be performed at the investigator’s clinical discretion.
j.
Temperature, pulse/heart rate, respiratory rate, and blood pressure.
k.
At Week 0, vital signs must be obtained before the IV infusion, approximately every 30 minutes during the infusion, and twice (at approximately 30-minute 
intervals) after completion of the infusion.
l.
Must be performed before every study agent administration in female subjects of childbearing potential.
m.
If TB is suspected at any time during the study, a chest radiograph and QuantiFERON-TB test should be performed. In countries where the QuantiFERON-TB 
test is not registered/approved, TB skin testing should also be performed (recommended but not required for study centers in countries where tuberculin is not 
available).
n.
For all visits up to Week 24, daily diary information should be collected for every day prior to each visit. For the final efficacy and safety visit, daily diary 
information should be collected for 14 days prior to the visit.
o.
The hematocrit value obtained during screening will be used to calculate CDAI at Week 0. For other visits, the most recent hematocrit value obtained before a 
visit will be used to calculate the CDAI for that visit.
p.
Subject will complete the Bristol stool form scale as a daily diary entry and bring the diary to each visit. Daily diary information should be collected for every 
day prior to each visit.
q.
Subject will complete the abdominal pain NRS assessment as a daily diary entry and bring the diary to each visit. For all visits up to Week 24, daily diary 
information should be collected for every day prior to the visits. For the final efficacy and safety visit, daily diary information should be collected for 14 days 
prior to the visit.
r.
Stool samples required for this visit should be obtained before the start of the bowel preparation for the video ileocolonoscopy that is also scheduled for the 
visit.
s.
Because these procedures must not interfere with the collection of CDAI data, if performed on the day of these visits, the 7 days before the initiation of the 
colonoscopy preparation should be used to calculate CDAI scores for these visits. If the video ileocolonoscopic examination is not performed on the day of the 
visit, it must be performed at least 8 days before the Week 0 visit and no more than 8 days before the Week 12 visit and Week 24 visit.
t.
The IBDQ and SF-36 survey should be administered before any clinical procedures or tests are performed.
u.
Laboratory tests at Week 0 are not required if screening laboratory tests were performed within 2 weeks before the Week 0 visit.
v.
At all visits when study intervention will be administered, 1 blood sample should be collected prior to study intervention administration for evaluation of 
serum concentrations and/or antibodies to the study interventions. For the IV infusion related visit (Week 0), the SC study intervention should be administered 
first, followed by IV infusion; another blood draw should be taken approximately 60 minutes after completion of the infusion for serum concentration 
measurement.
w.
At visits where only serum concentration of study agent will be evaluated (ie, no antibodies to study agent will be evaluated), 1 venous blood sample of 
sufficient volume should be collected, and each serum sample should be divided into 2 aliquots (1 for serum concentration of study agent, and a back-up). At 


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visits where serum concentration of study agent and antibodies to study agent will be evaluated, 1 venous blood sample of sufficient volume should be 
collected. Each serum sample will be divided into 3 aliquots (1 each for serum concentration of study agent, antibodies to study agent, and a back-up).
x.
Each random population PK sample should be collected at any time between Weeks 0 and 2 (after the Week 0 study agent administration) and between 
Weeks 20 and 24 (after the Week 20 study agent administration). The date for the random population PK sample collection will be at the subject’s discretion. 
However, samples should not be drawn on or within 1 day of a scheduled visit (ie, the Week 0, 2, 20, or 24 visit) in this time period.
y.
Whole blood for RNA analysis will be collected from all subjects in the study.
z.
Whole blood for SNP analysis will be collected from all subjects. All subjects will be tested for the NKG2D SNP rs2255336 and the MICB (NKG2D ligand) 
SNP rs2239705 at screening. For subjects who have signed a separate informed consent form, DNA testing will be done to search for links of specific genes to 
disease or response.
aa.
Hospitalization for ileocolonoscopy is not included in this category.


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TIME AND EVENTS SCHEDULE: PART II LONG-TERM EXTENSION
Table 3:
Time and Events Schedule, Long-term Extension Before Unblinding for JNJ-64304500, Ustekinumab, and Placebo and After Unblinding for 
JNJ-64304500j
Period
Long-term Extension
Week 24a,o
Every 4 
weeksa,l
Every 3 
monthsa,m
Every 6 
monthsa,n
Week 72a
Final safety 
follow-upa,d
Early 
terminationa
Study Procedures
Study Drug Administration
Administer study agent (SC study agent at a 
different location at each visit [Section 6])b,c
X
Xi
Safety Assessments
Symptom-driven physical examination
X
X
X
X
X
Vital signse
X
X
X
X
X
Urine pregnancy testf
X
X
X
X
X
TB evaluation /other infection assessmentg
X
X
X
X
Injection-site evaluation 
X
X
X
X
X
Clinical Laboratory Assessments
Hematology 
X
X
X
X
Chemistry
X
X
X
X
Pharmacokinetics/ Immunogenicityk
Study agent serum concentrationh
X
X
X
Assessment for antibody to study agent 
X
X
X
Ongoing Subject Review
Concomitant therapy
X
X
X
X
Adverse events
X
X
X
X
X
Crohn’s disease-related hospitalizations and 
surgeries 
X
X
X
X
a.
Visit window is ±7days for each visit.
b.
All assessments are to be completed before study agent administration unless otherwise specified. 
c.
The first study agent administration in the Part II LTE will occur at Week 24. After the main study is unblinded to the investigative sites, subjects in the Part II LTE receiving placebo 
will be terminated from study participation, and subjects receiving ustekinumab will receive ustekinumab until commercial ustekinumab becomes available to them. Subjects 
receiving JNJ-64304500 will continue to receive JNJ-64304500 every 4 weeks. Those subjects still receiving ustekinumab will return to the clinic every 8 weeks to receive drug for
SC ustekinumab injections.
d.
Final safety visit at Week 88 or approximately 16 weeks after a subject’s last administration of study agent (for subjects who have not terminated study participation). If a subject’s 
treatment allocation is unblinded while the LTE is ongoing and the subject was receiving placebo, the site may schedule the final safety visit to occur earlier than 16 weeks after the 
subject’s last administration of study drug.
e.
Temperature, pulse/heart rate, respiratory rate, and blood pressure. At a study agent administration visit, vital signs should be obtained before and approximately 30 minutes after SC 
injection.


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f.
Urine pregnancy test must be performed before each study agent administration in female subjects of childbearing potential.
g.
If TB is suspected at any time, a chest radiograph and QuantiFERON-TB test should be performed. In countries where the QuantiFERON is not registered/approved, TB skin testing 
should also be performed (recommended but not required for study centers in Ukraine if tuberculin is not available).
h.
Serum concentration of study agent and antibodies to study agent will be evaluated. One venous blood sample of sufficient volume should be collected (at visits where study 
intervention will be administered, blood samples should be collected prior to study intervention administration). Each serum sample will be divided into 3 aliquots (1 each for serum 
concentration of study agent, antibodies to study agent and a back-up).
i.
JNJ-64304500 dosing only after unblinding.
j.
This Time & Events Schedule outlines the tasks that need to be completed during the Part II LTE prior to unblinding for all study subjects and after unblinding for study subjects 
receiving JNJ-64304500. Table 4 outlines the tasks that need to be completed during the Part II LTE after study unblinding for study subjects receiving ustekinumab in countries 
where it is not commercially available.
k.
Pharmacokinetic and immunogenicity samples will be obtained only at the specified timepoints and when SAEs are reported by study subjects.
l.
Visits every 4 weeks include scheduled visits at Weeks 28, 32, 36, 40, 44, 48, 52 56, 60, 64, 68, and 72.
m.
Visits every 3 months include scheduled visits at Weeks 36, 48, 60, and 72.
n.
Visits every 6 months include scheduled visits at Weeks 48 and 72.
o.
Subjects may receive the first LTE dose of study drug at the Week 24 visit after the Week 24 assessments are completed or the subject may return to the study site for the first LTE 
does of study drug within the 7-day visit window.


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TIME AND EVENTS SCHEDULE: PART II LONG-TERM EXTENSION
Table 4: 
Time and Events Schedule, Long-term Extension Phase After Unblinding for Ustekinumab Subjects in Countries Where Ustekinumab Is Not 
Commercially Available
Period
Long-term Extension
Every 8 Weeksa,h
Early terminationa
Study Procedures
Study Drug Administration
Administer study agentb,c 
X
Safety Assessments
Symptom-driven physical examination
X
X
Vital signse
X
X
Urine pregnancy testf
X
X
TB evaluation /other infection 
assessmentg
X
X
Injection-site evaluation 
X
X
Ongoing Subject Review
Concomitant therapy
X
X
Adverse events
X
X
Crohn’s disease-related hospitalizations 
and surgeries 
X
X
a.
Visit window is ±7 days for each visit.
b.
All assessments are to be completed before study agent administration unless otherwise specified.
c.
The first study agent administration in the Part II LTE will occur at Week 24. After the main study is unblinded to the investigative sites, subjects in the Part II LTE receiving placebo 
will be terminated from study participation, and subjects receiving ustekinumab will return to the clinic every 8 weeks for SC ustekinumab injections.
d.
The final safety follow-up visit should occur after unblinding but before receiving the first dose of commercial ustekinumab.
e.
Temperature, pulse/heart rate, respiratory rate, and blood pressure. At a study agent administration visit, vital signs should be obtained before and approximately 30 minutes after SC 
injection.
f.
Urine pregnancy test must be performed before each study agent administration in female subjects of childbearing potential.
g.
If TB is suspected at any time, a chest radiograph and QuantiFERON-TB test should be performed. In countries where the QuantiFERON is not registered/approved, TB skin testing 
should also be performed (recommended but not required for study centers in Ukraine if tuberculin is not available).
h.
Visits every 8 weeks may include scheduled visits at Weeks 32, 40, 48, 56, 64, and 72. The final safety assessment should be performed at the final dosing visit.


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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
6-TG
6-thioguanine
ADL
Activities of Daily Living
AE
adverse event
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance 
anti-HBc
HBV core antibody
anti-HBs
HBV surface antibody 
AST
aspartate aminotransferase
AUC
area under the serum concentration–time curve
AZA
azathioprine
BCG
Bacille Calmette-Guérin
-hCG
-human chorionic gonadotropin
Bio-IR
biologic intolerant or refractory 
Bio-NF
biologic nonfailure, ie, inadequate response to or failed to tolerate corticosteroids or 
immunomodulators, but not a biologic
CDAI
Crohn’s Disease Activity Index
Cmax
maximum concentration
CRF
case report form (paper or electronic, as appropriate for this study)
CRP
C-reactive protein
DBL
database lock
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eDC
electronic data capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GHAS
Global Histology Activity Score
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus 
HCV
hepatitis C virus 
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL
interleukin
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWRS
interactive web response system
JAK
Janus kinase
LTE
long-term extension
MCP-Mod
Multiple Comparison Procedures with modeling
MCS
Mental Component Summary
MICA
major histocompatibility class I chain-related protein A
MICB
major histocompatibility class I chain-related protein B
MTX
methotrexate
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NKG2D
natural killer group 2D 


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NRS
numerical rating scale
PCS
Physical Component Summary
PD
pharmacodynamic
PFS
prefilled syringe
PGIC
Patient’s Global Impression of Change 
PGIS
Patient’s Global Impression of Severity 
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
patient-reported outcome(s)
q2w
every 2 weeks
q4w
every 4 weeks
RA
rheumatoid arthritis 
RNA
ribonucleic acid
RO
receptor occupancy
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation
SES-CD
Simple Endoscopic Score for Crohn's Disease
SF-36
36-item Short Form Health Survey
SNP
single nucleotide polymorphism
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TNF
tumor necrosis factor 
TNFα
tumor necrosis factor alpha 
ULN
upper limit of normal


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1.
INTRODUCTION
The natural killer group 2 member D (NKG2D) is an activating receptor expressed on the surface 
of natural killer (NK) cells, CD8+ T cells, and subsets of CD4+ T cells, invariant NK T cells, 
and gamma/delta (γδ) T cells. It signals via the noncovalently associated DNAX-activating 
protein of 10 kDa and a phosphoinositide 3-kinase. The receptor recognizes an extensive 
repertoire of self-ligands (ie, ligands encoded by the host's own genome as opposed to foreign 
antigens), encoded by at least 8 genes including the major histocompatibility class I chain-related 
proteins A and B (MICA and MICB), and proteins from the ULPB/RAET1 family (ULBP1-6), 
some of which have extensive allelic polymorphisms. Expression of NKG2D ligands is tightly 
regulated. All NKG2D ligands are expressed at very low levels in healthy adult tissues; however,
cellular stress, cancer, or virus infection can upregulate the expression of these self-encoded 
NKG2D ligands. Recognition of these self-encoded NKG2D ligands on unhealthy cells by the 
NKG2D receptor (“induced self-recognition”) results in the proliferation and the subsequent 
release of proinflammatory cytokines and cytotoxic mediators such as interferon gamma, Vav1 
guanine nucleotide exchange factor, interleukin (IL)-9, IL-10, vascular endothelial growth 
factor-A, IL-13, and tumor necrosis factor alpha (TNFα) by these NKG2D receptor-bearing NK 
and T cells leading to a deoxyribonucleic acid (DNA) damage response and inflammation.
Several lines of evidence from patients with Crohn’s disease support the hypothesis that NKG2D 
receptor activation plays a role in disease pathogenesis by mediating the production of local 
cytokines, activation of an immune response, and direct cytotoxicity of target intestinal cells. In 
Crohn’s disease, CD4+ and CD8+ T cells expressing the NKG2D receptor accumulate at sites of 
intestinal inflammation. The level of circulating NKG2D+CD4+ T cells rapidly declines 
following surgical removal of inflamed intestinal tissue, and their concentration increases at the 
relapse of disease. Approximately 40% of patients with Crohn’s disease have circulating 
NKG2D+CD4+ T cells, and these cells were found in virtually all samples of inflamed intestine. 
Expression of NKG2D ligands has been demonstrated to be upregulated in intestinal biopsies in 
patients with Crohn’s disease compared with healthy subjects, further supporting a role for the 
involvement of the NKG2D receptor in inflammation. In addition, blockade of the NKG2D 
receptor is effective in preventing disease progression in preclinical animal models of human 
inflammatory diseases. Collectively, preclinical and clinical data on the expression of 
NKG2D-ligands or proinflammatory cytokines in the target tissue and abnormal expression and 
activation of the NKG2D receptor on CD8+ and CD4+ T cells provide a rationale for the clinical 
development of inhibitors of the NKG2D receptor.
JNJ-64304500 (formerly known as NNC0142-002) is a human immunoglobulin G4 isotype 
monoclonal antibody that binds specifically to the NKG2D receptor, and blocks NKG2D ligand 
binding, thereby preventing the downstream-signaling events that otherwise lead to cell 
proliferation and release of proinflammatory cytokines and cytotoxic mediators. Results from a 
Phase 2a study in subjects with moderately to severely active Crohn’s disease who had failed or 
were intolerant to conventional therapy or TNFα antagonists for Crohn’s disease (conducted by 
Novo Nordisk) provided evidence for the efficacy of JNJ-64304500 in the treatment of Crohn’s 
disease.


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For the most comprehensive nonclinical and clinical information regarding JNJ-64304500, refer 
to the latest version of the Investigator's Brochure (IB) for JNJ-64304500. 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.
Nonclinical Studies
For the most comprehensive nonclinical information regarding JNJ-64304500, refer to the latest 
version of the IB for JNJ-64304500.
1.2.
Clinical Studies
As of 11 November 2015, a total of 128 subjects had been exposed to JNJ-64304500 in 3 clinical 
studies: 88 subjects in 2 studies in rheumatoid arthritis (RA) and 40 subjects in a Phase 2a study 
in Crohn’s disease.
1.2.1.
Rheumatoid Arthritis
Two studies with JNJ-64304500 were conducted in subjects with active RA.
In NN8555-3618, a first-in-humans, Phase 1, single ascending dose/multiple ascending dose
study that included single-dose (0.0002 to 7.5 mg/kg) and multiple-dose (0.02 to 4 mg/kg every 2 
weeks [q2w] for 4 administrations) parts, 13 dose levels were evaluated in 24 subjects exposed to 
JNJ-64304500 in the single ascending dose portion and 23 subjects exposed to JNJ-64304500 in 
the multiple ascending dose portion. Subcutaneous (SC) administration of JNJ-64304500 was 
well tolerated at the dose ranges investigated and no safety signals were associated with either 
the single- or multiple-dose regimens.
In NN8555-3796, a Phase 2a, randomized, single-dose, double-blind, placebo-controlled, 
parallel-group study, clinical efficacy was assessed in subjects with active RA concomitantly 
treated with methotrexate (MTX). In this study, a single SC injection of 4 mg/kg JNJ-64304500 
in 41 subjects exposed to JNJ-64304500 did not result in a statistically significant reduction in 
disease activity at Weeks 6, 12, or 24 after treatment compared with placebo. JNJ-64304500 was 
well tolerated and no safety concerns were raised during the study.
Additional details about these studies are provided in the latest version of the IB.
1.2.2.
Crohn’s Disease
NN8555-3797 was a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, single-dose study in subjects with moderately to severely active Crohn’s disease 
who had failed or were intolerant to conventional therapy (corticosteroids or immunomodulators) 
or were intolerant or refractory to 1 TNFα antagonist therapy. Only subjects who had a Crohn’s 
Disease Activity Index (CDAI) score ≥220 but ≤450 and inflammation confirmed by CRP 
≥10 mg/dL or by endoscopy (endoscopic verification of active ulceration performed during 
screening and read by a blinded central imaging reader) were included in the study. The study 
enrolled and randomized 78 subjects at 32 investigational sites in North America, Europe, and 
Israel. All subjects were randomly assigned in a 1:1 ratio at Week 0 to receive placebo SC 


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(n=38) or 2 mg/kg JNJ-64304500 SC (n=40). Among the 78 randomized subjects, the mean 
baseline CDAI score was 330.5, and 29.5% were intolerant or refractory to a maximum of 1 
TNFα antagonist therapy.
Subjects were evaluated for the primary endpoint of change from baseline in the CDAI score at 
Week 4. Safety and efficacy evaluations were performed through Week 24. The observed 
16-point greater reduction in CDAI in the JNJ-64304500 group at Week 4 compared with the 
placebo group was not significant (p=0.403). Based on a predefined significance level of 0.10, 
however, the reduction in CDAI score was significantly higher in the JNJ-64304500 group 
compared with the placebo group at Week 12 (55-point greater reduction in CDAI was observed 
in JNJ-64304500 compared with placebo, p=0.056). Based on the same predefined significance 
level of 0.10, reductions in CDAI scores were significantly higher in the predefined subgroup of 
“no prior failure to biologics” (Bio-NF, 71% of the study population) in the JNJ-64304500 group 
compared with placebo at all post baseline visits through Week 12 (Week 1, p=0.068; Week 2, 
p=0.048; Week 4, p=0.095; Week 8, p=0.015; and Week 12, p=0.025). The biologic intolerant or 
refractory (Bio-IR) population in the Novo Nordisk Phase 2a study constituted 29% of the study 
population (N=12 in the active treatment arm and N=11 in the placebo arm). In this 
subpopulation, a 45-point greater reduction in CDAI was observed at Week 12 in JNJ-64304500 
compared with placebo.
As a part of this study, genetic polymorphisms in the genes for the NKG2D receptor and 
NKG2D ligands of subjects were evaluated. A post hoc analysis of efficacy data demonstrated 
greater efficacy in a subgroup of subjects with a specific single nucleotide polymorphism (SNP) 
in the NKG2D receptor and/or MICB ligand (SNP-positive cohort). The association between 
SNP-positive status and higher clinical efficacy will be tested prospectively in this Phase 2b 
study.
The mean duration of study participation was equivalent between the 2 treatment groups. No 
deaths or medical events of special interest were reported. Through Week 24, the proportions of 
subjects with 1 or more adverse events (AEs) were similar in the JNJ-64304500 and placebo 
groups. Gastrointestinal events were the most commonly reported AEs in both groups (17 and 
14 subjects in the JNJ-64304500 and placebo groups, respectively). Serious AEs (SAEs) were 
uncommon and reported in 7 of 78 (9%) randomized subjects with 1 SAE each: 2 in the placebo 
group (1 Crohn's disease, 1 nephrolithiasis) compared with 5 in the JNJ-64304500 group 
(4 Crohn's disease, 1 Clostridium difficile infection). All SAEs were evaluated as unlikely related 
to treatment with study agent.
Collectively, these data support the further development of JNJ-64304500 in subjects with 
moderately to severely active Crohn’s disease.
This 
protocol 
(64304500CRD2001) 
is 
comprised 
of 
2 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter parts designed to evaluate the safety and efficacy 
of JNJ-64304500 in subjects with moderately to severely active Crohn’s disease who have 
previously failed or who were intolerant to 1 or more approved biologic agents (Bio-IR) or those 


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who have demonstrated an inadequate response to or have failed to tolerate corticosteroids or 
immunomodulators (Bio-NF).
In Part I, the following 2 studies will be conducted:

Study 1: A study in subjects who are biologic intolerant or refractory (Bio-IR);

Study 2: A study in subjects who have not previously failed a biologic therapy (Biologic 
nonfailure [Bio-NF]).
In Part II, the following study will be conducted:

Study 3: A dose-ranging study in subjects who are biologic intolerant or refractory (Bio-IR) 
or Biologic nonfailure (Bio-NF)
In Study 1, a higher dose regimen than was used in the Phase 2a study will be employed 
supported by the acceptable safety margins demonstrated in Phase 1 (the Novo Nordisk Phase 1 
single ascending/multiple ascending dose study NN8555-3618), and the high exposure margins 
relative to no-observed-adverse-effect level (NOAEL) exposure in cynomolgus monkeys. This 
higher dose will be used to provide additional information on safety and efficacy for the Bio-IR 
population, as proof of concept was not established in this population in the Novo Nordisk 
Phase 2a study (NN8555-3797). In addition, this higher dose will also be evaluated in Bio-NF 
subjects to determine if a more robust efficacy outcome than was shown in the Phase 2a study 
can be achieved while maintaining an acceptable safety profile. Combined with data from 
Phase 2a in Bio-NF subjects, Part I and Part II would provide valuable information for the 
assessment of dose/exposure-response and thus the selection of the optimal dose in Bio-NF 
population for the Phase 3 program. Study 1 and Study 2 comprise Part I of the protocol and 
these 2 components will be initiated in parallel. The decision to initiate the dose-ranging portion 
of the protocol (Part II, Bio-IR and Bio-NF) is dependent on demonstration of acceptable safety 
and efficacy in Part I (combined Bio-IR subjects and Bio-NF subjects). A ustekinumab reference 
arm will be included in Part II to provide context in the interpretation of results from the 
JNJ-64304500 and placebo groups and to assist in the overall selection of dose(s) to carry 
forward into the Phase 3 program.
A long-term extension (LTE) for Part II of the study was added to the protocol as part of 
Protocol Amendment 5. After Protocol Amendment 5 is implemented, subjects who complete 
Part II Week 24 assessments and who may benefit from continued treatment, in the opinion of 
the investigator, are eligible to enter the Part II LTE to receive up to 52 weeks of additional 
treatment. Subjects who have completed Week 24 assessments prior to the implementation of 
Protocol Amendment 5 will not be eligible to enroll in the Part II LTE.
The inclusion of the 3 component studies in a single protocol is intended to facilitate both 
efficient trial conduct and program decision-making based on planned interim database locks 
(DBLs) as described in Section 3.1.1, Section 3.1.2, and Section 5.2.


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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
The objectives are the same in each of the 2 parts.
Primary Objectives

To evaluate the efficacy of JNJ-64304500 to reduce the CDAI score from baseline.

To evaluate the safety of JNJ-64304500.
Secondary Objectives

To evaluate the efficacy of JNJ-64304500 to induce clinical remission, clinical response, 
and endoscopic healing of the mucosa, and to maintain remission.

To evaluate the relationship between efficacy and the presence of the NKG2D and/or MICB 
SNP biomarkers.

To evaluate the efficacy of JNJ-64304500 to improve general and disease-specific 
health-related quality of life and to reduce Crohn’s disease-related hospitalizations and 
surgeries.

To evaluate the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and 
biomarkers (eg, reductions in CRP, fecal calprotectin, and fecal lactoferrin) of 
JNJ-64304500 therapy.
2.1.2.
Endpoints
The data from Study 1 and Study 2 in Part I will be pooled for analysis.
The primary endpoint for Part I is: Change from baseline in the CDAI score at Week 8.
The primary endpoint for Part II is: Change from baseline in the CDAI score at Week 12.
The following endpoints will be evaluated as major secondary endpoints only in Part II (the 
dose-ranging portion of the study); these endpoints will be evaluated in Part I but are not 
specified as major secondary endpoints.

Clinical remission at Week 12 as measured by CDAI (CDAI <150).

Clinical response at Week 12 as measured by CDAI (≥100-point reduction from baseline in 
CDAI or CDAI <150).

Change in PRO-2 (the sum of the abdominal pain and stool frequency subscores of the 
CDAI score) from baseline at Week 12.

Clinical remission at Week 12 as measured by PRO-2 (PRO-2 <75).

Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from baseline in 
PRO-2 or PRO-2 <75).


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
Change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline at 
Week 12.
The following efficacy endpoints will be evaluated in Part I and Part II (except for the Patient’s 
Global Impression of Severity [PGIS] of Crohn’s disease and the Patient’s Global Impression of 
Change [PGIC] of severity of Crohn’s disease, which will only be evaluated in Part II):

Change in CDAI from baseline at all postbaseline visits.

Clinical remission based on CDAI at all postbaseline visits.

Clinical response based on CDAI at all postbaseline visits.

Change in PRO-2 from baseline at all postbaseline visits.

Change in abdominal pain score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.

Change in stool frequency score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.

Clinical remission based on PRO-2 at all postbaseline visits.

Clinical response based on PRO-2 at all postbaseline visits.

Change in PRO-3 (the sum of abdominal pain, stool frequency, and general well-being 
subscores of the CDAI score) from baseline at all postbaseline visits.

Clinical remission based on CDAI at Week 24 among subjects in clinical response at 
Week 12.

Clinical remission based on CDAI at Week 24 among subjects in clinical remission at 
Week 12.

Change in SES-CD score from baseline at Weeks 12 and 24.

Endoscopic improvement at Weeks 12 and 24 based on a reduction from baseline in 
SES-CD score ≥3. Endoscopy will only be performed during Part I.

At least 50% improvement from baseline in SES-CD at Weeks 12 and 24.

Endoscopic healing (defined as the absence of mucosal ulcerations) at Weeks 12 and 24.

Endpoint(s) for histologic assessment based on the Global Histology Activity Score (GHAS; 
to be detailed in the Statistical Analysis Plan [SAP]).

Fistula response at all postbaseline visits, defined as a ≥50% reduction from baseline in the 
number of draining fistulas.

Endpoint(s) based on Bristol stool form scale (to be detailed in the SAP).

Change in abdominal pain from baseline at all postbaseline visits based on a 0-10 Numerical 
Rating Scale (NRS).

Change in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12, and 24.

A ≥1-point improvement in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12, and 
24.


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
Improvement in PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.

Change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline at 
Weeks 8, 12, and 24.

Clinical remission based on IBDQ (≥170) at Weeks 8, 12, and 24.

A ≥16-point improvement in IBDQ from baseline at Weeks 8, 12, and 24.

Change from baseline in the Physical Component Summary (PCS) and Mental Component 
Summary (MCS) scores of the 36-item Short Form Health Survey (SF-36) at Weeks 8, 12, 
and 24.

A ≥5-point improvement in PCS or MCS scores of the SF-36 at Weeks 8, 12, and 24.

Change in biomarkers (CRP, fecal calprotectin, fecal lactoferrin) from baseline at Weeks 8, 
12, and 24.

Clinical remission based on CDAI at Week 12 by SNP status. Subjects who are positive in at 
least 1 of 2 SNPs (NKG2D or MICB) will be considered to be SNP-positive.
Other efficacy endpoints may be examined by SNP status (to be detailed in the SAP).
Refer to Section 9, Study Evaluations, for evaluations related to endpoints.
2.2.
Hypothesis
The hypothesis for Part I and Part II is that JNJ-64304500 is superior to placebo in inducing a 
reduction from baseline in CDAI in subjects with moderately to severely active Crohn’s disease.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This protocol is comprised of 2 parts (Part I [Bio-IR subjects and Bio-NF subjects] and Part II 
[Bio-IR and Bio-NF subjects]) (Figure 1) that are designed to evaluate the safety and efficacy of 
JNJ-64304500 in subjects with moderately to severely active Crohn’s disease.
In Part I, the following 2 studies will be conducted:

Study 1: A study in subjects who are biologic intolerant or refractory (Bio-IR);

Study 2: A study in subjects who have not previously failed a biologic therapy (Biologic 
nonfailure [Bio-NF]).
In Part II, the following study will be conducted:

Study 3: A dose-ranging study in subjects who are Bio-IR or Bio-NF
The 2 studies in Part I serve to build on the original Phase 2a study findings by employing 
dedicated populations of both Bio-IR and Bio-NF subjects. If acceptable safety and efficacy are
established in the combined Bio-IR and Bio-NF populations, Part II of the protocol, which 
consists of a dose-ranging study (Study 3) in subjects who are Bio-IR or Bio-NF, will be 
initiated.


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After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments and who may benefit from continued treatment, in the opinion of the investigator, 
are eligible to enter the Part II LTE to receive up to 52 weeks of additional treatment. Subjects 
who have completed Week 24 prior to the implementation of Protocol Amendment 5 will not be 
eligible to enroll in the Part II LTE.
Figure 1:
Schematic representation of 64304500CRD2001
The target population for each of the studies consists of men or women ≥18 years of age with
moderately to severely active Crohn’s disease (of at least 3 months’ duration), defined as a CDAI 
score ≥220 but ≤450 at Week 0, with elevated CRP >0.3 mg/dL (>3.0 mg/L) and/or calprotectin 
>250 mg/kg at screening. Subjects must have colitis, ileitis, or ileocolitis previously confirmed at 
any time in the past by radiography, histology, and/or endoscopy.
Additionally, subjects must have previously failed or been intolerant to 1 or more approved 
biologic agents (ie, TNFα-antagonists or vedolizumab, hereafter referred to as Bio-IR subjects) 
or have demonstrated an inadequate response to or failed to tolerate corticosteroids or 
immunomodulators (ie, 6-mercaptopurine [6-MP], azathioprine [AZA], and MTX) but not a 
biologic agent (hereafter referred to as biologic nonfailure subjects). These 2 populations are 
described below:

Biologic intolerant or refractory (Bio-IR) subjects are defined as those who have received 
infliximab (or a biosimilar for infliximab), adalimumab (or a biosimilar for adalimumab), 
certolizumab pegol, or vedolizumab at a dose approved for the treatment of Crohn’s disease, 
and either did not respond initially, responded initially but then lost response, or were 
intolerant to the medication (Attachment 1). Bio-IR subjects must allow a ≥8-week washout 
for prior TNFα antagonist use and a 16-week washout period for prior vedolizumab use.


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
Biologic nonfailure (Bio-NF) subjects are defined as those who have demonstrated an 
inadequate response to or have failed to tolerate corticosteroids or the immunomodulators 
6-MP, AZA, or MTX (Attachment 2). Subjects who have demonstrated corticosteroid 
dependence (ie, an inability to successfully taper corticosteroids without a return of the 
symptoms of Crohn’s disease) are also eligible. Bio-NF subjects may also have received 
biologic therapy but only if it was discontinued for reasons other than lack of efficacy or 
intolerance (eg, drug holiday).
It is anticipated that approximately 370 to 420 subjects will be randomized overall across Part I 
and Part II:

Part I will study the safety and efficacy of a high dose regimen of JNJ-64304500 compared 
with placebo and will enroll a minimum of 120 subjects and a maximum of 170 subjects
(Bio-IR and Bio-NF).

Part II will study the safety and efficacy of multiple-dose regimens of JNJ-64304500 
compared with placebo, with ustekinumab (STELARA®) as a reference arm. Part II will 
enroll approximately 250 subjects (the maximum proportion of either Bio-NF or Bio-IR 
subjects will be 60%).
Schematic representations of Part I and Part II are shown in Figure 2 and Figure 3, respectively.


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Figure 2:
Schematic Overview of Part I of Study 64304500CRD2001
Throughout Part I and the main study phase of Part II efficacy, PK, PD, immunogenicity, 
biomarkers, and safety will be assessed at timepoints indicated in the appropriate Time and 
Events Schedules (Table 1 and Table 2). Efficacy evaluations will not be assessed in the Part II 
LTE.
Blood samples for pharmacogenomic analyses will be collected from subjects who consent 
separately to this component of the protocol (where local regulations permit). Subject 
participation in pharmacogenomic research is optional.
The primary endpoint for Part I is the change from baseline in the CDAI score at Week 8. The 
primary endpoint for Part II is the change from baseline in the CDAI score at Week 12.
After Protocol Amendment 5 is implemented, all subjects who complete Part II of the study 
through Week 24, and who may benefit from continued treatment in the opinion of the 
investigator, are eligible to enter the Part II LTE and continue to receive treatment for up to 


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52 weeks (Week 24 to Week 72), as described in Section 3.1.4. A schematic representation of the 
Part II LTE is shown in Figure 3.
Figure 3:
Schematic Overview of the 64304500CRD2001 Part II (Including the Long-term Extension)
An external Data Monitoring Committee (DMC) will review unblinded safety data from all 
subjects periodically to monitor subject safety. The DMC will consist of at least one medical 
expert in the relevant therapeutic area and at least one statistician. The DMC responsibilities, 
authorities, and procedures will be documented in its charter. Refer to Section 11.11, Data 
Monitoring Committee, for details.


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3.1.1.
Part I
In Part I, a minimum of 120 subjects and a maximum of 170 subjects (Bio-IR and Bio-NF) will 
be randomly assigned to receive placebo or the JNJ-64304500 high dose in a 1:1 ratio using 
permuted block randomization, stratified by baseline CDAI score (≤300 or >300) and 
SNP-positive status (yes or no). Separate randomizations will be used for the Bio-IR and Bio-NF 
populations.
The treatment groups for each study in Part I will be as follows:

Placebo SC at Weeks 0, 2, 4, 6, 8, and 10; from Week 12, these subjects will receive 
additional doses as follows:

Placebo-treated subjects who are in clinical response at Week 12 (≥100-point reduction 
from baseline in CDAI or CDAI <150) will continue to receive placebo SC injections
q2w from Week 12 through Week 22.

Placebo-treated subjects who are not in clinical response at Week 12 will receive 
JNJ-64304500 400 mg SC at Week 12 and then 200 mg SC q2w from Week 14 through 
Week 22.

JNJ-64304500 400 mg SC at Week 0 then 200 mg SC q2w through Week 22.
An interim analysis is planned in Part I when 100 randomized subjects (Bio-IR and Bio-NF)
have completed their Week 12 visit or have terminated their study participation before Week 12. 
The interim analysis will allow for uninterrupted patient enrollment through a seamless transition 
from Part I to Part II of the trial.
To allow for uninterrupted patient enrollment through a seamless transition from Part I to Part II 
of the trial, enrollment for Part I will continue until the sponsor makes a decision on whether to 
start Part II based on the interim analysis or when a maximum of 170 subjects have been 
randomized, whichever occurs first. If Part II is not initiated based on the interim analysis results, 
then the results through Week 12 for all subjects in Part I (ie, when all randomized subjects in 
Part I have either completed the Week 12 visit or terminated study participation prior to 
Week 12) will be examined to determine whether to start Part II. Under this scenario, a pause in 
enrollment between Part I and Part II will occur.
3.1.2.
Part II
In Part II, 250 additional Bio-IR or Bio-NF subjects will be randomly assigned to receive 
placebo or 1 of 3 dose levels of JNJ-64304500 or ustekinumab in a ratio of 1:1:1:1:1 using 
permuted block randomization, stratified by baseline CDAI score (≤300 or >300), SNP-positive 
status (yes or no), and Bio-IR status (yes or no). The maximum proportion of either Bio-NF or 
Bio-IR subjects will be 60%.
The treatment groups in Part II will be as follows:

Placebo SC at Weeks 0, 2, 4, and 8; from Week 12, these subjects will receive additional 
doses as follows:


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
Placebo-treated subjects who are in clinical response at Week 12 (≥100-point reduction 
from baseline in CDAI or CDAI <150) will continue to receive placebo at Weeks 12, 
14, 16, and 20.

Placebo-treated subjects who are not in clinical response at Week 12 will receive 
JNJ-64304500 150 mg SC at Week 12 and then JNJ-64304500 75 mg SC at Weeks 14, 
16, and 20.

High dose: JNJ-64304500 400 mg SC at Week 0 and 200 mg SC at Weeks 2 and 4, then 
200 mg SC every 4 weeks (q4w) through Week 20.

Middle dose: JNJ-64304500 150 mg SC at Week 0 and 75 mg SC at Weeks 2 and 4, then 
75 mg SC q4w through Week 20.

Low dose: JNJ-64304500 50 mg SC at Week 0 and 25 mg SC at Weeks 2 and 4, then 25 mg 
SC q4w through Week 20.

Ustekinumab (tiered doses approximating 6 mg/kg intravenously [IV]) at Week 0 (as 
indicated in the bullets below), followed by 90 mg SC at Weeks 8 and 16.

Ustekinumab 260 mg (weight ≤55 kg).

Ustekinumab 390 mg (weight >55 kg and ≤85 kg).

Ustekinumab 520 mg (weight >85 kg);
As indicated in Figure 2, subjects will also receive placebo administrations, as necessary, to 
maintain the blind of Part II; see Section 6.2 for details.
3.1.3.
Interim Analysis
An interim analysis is planned in Part I when 100 randomized subjects (Bio-IR and Bio-NF)
have completed their Week 12 visit or have terminated their study participation before Week 12.
This interim analysis will allow for uninterrupted patient enrollment through a seamless 
transition from Part I to Part II of the trial. As this interim analysis does not affect the conduct or 
completion of Part I, it will be considered administrative and will not require multiplicity 
adjustment for the final Part I analysis.
A sponsor committee independent of the study team will be established to review the interim 
data and formulate recommended decisions/actions in accordance with predefined decision rules
(to be defined in the Interim Analysis Plan).
An interim analysis is not planned for Part II.
Other planned DBLs are described in Section 5.2.
3.1.4.
Part II Long-Term Extension
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments, and who may benefit from continued treatment in the opinion of the investigator, 
are eligible to enter the Part II LTE. In the Part II LTE, each subject will be eligible to receive up 
to 52 weeks of additional study drug (for a total of up to 72 weeks of study drug in Part II). The 


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first dose of study drug within the Part II LTE will be administered after the Week 24 
assessments have been completed. The dose may be administered on the same day as the Week 
24 assessments, or may be administered on a later date, as long as the dose is administered 
within the Week 24 visit window.
Subjects will continue to receive the same treatment regimen during the Part II LTE that they 
were receiving between Week 12 and Week 20 in the main study phase of Part II (placebo, high, 
middle, low dose JNJ-64304500 or ustekinumab). To maintain the study blind, all patients, 
investigators, and sites will remain blinded to treatment allocation during the Part II LTE until 
the last subject in the Part II main study phase has completed the Week 24 assessments and the 
Sponsor unblinds the study.
The timing of the Week 24 data analysis is dependent upon the timing and completion of Part II 
enrollment. Whether an individual subject will receive his/her treatment allocation during the
Part II LTE will depend upon his/her Part II enrollment date. Therefore, a portion of subjects will 
complete the entire Part II LTE in a blinded fashion before study unblinding, while other subjects
could be unblinded to treatment allocation during their participation in the Part II LTE.
On 15 March 2021, sites were informed that due to lack of sufficient efficacy of JNJ-64304500, 
subjects who were receiving JNJ-64304500 or placebo in the LTE were discontinued, subjects 
receiving ustekinumab in countries where ustekinumab is not commercially available were 
continued in the LTE.
Any subject who withdraws from the Part II LTE prior to study unblinding will return for a final 
safety follow-up visit 16 weeks after the last dose of study drug. For subjects who remain in the 
Part II LTE at the time of study unblinding, continuation of study drug during the Part II LTE 
will be dependent upon treatment allocation, as follows:

JNJ-64304500: Subjects receiving JNJ-64304500 during the LTE will stop receiving study 
drug and will have a final safety follow-up visit 16 weeks after the last dose of study drug.

Placebo: Subjects receiving placebo who remain in the Part II LTE at the time of study 
unblinding will have their final safety follow-up visit subsequent to unblinding and will be 
discontinued from the study. No further follow-up visits will be performed.

Ustekinumab: Subjects receiving ustekinumab will continue to receive it during the Part II 
LTE until unblinding occurs. After unblinding, based on the treating physician’s clinical 
judgment, subjects may receive ustekinumab in a manner dependent on the country in which 
they are located:
o
If a subject is not continuing on ustekinumab after unblinding, the subject will need to 
return for a final safety follow-up visit that will be performed 16 weeks after the final 
dose of study ustekinumab.


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o
If a subject continues on ustekinumab in a country where commercial ustekinumab is 
available and approved for adult Crohn’s disease, the treating physician is responsible 
for providing the subject with commercial ustekinumab, which should be 
administered according to the approved dosing regimen in each country. The final 
safety follow-up visit should be performed after unblinding but before receiving the 
first dose of commercial ustekinumab.
o
If a subject continues on ustekinumab in countries where commercial ustekinumab is 
not available or approved for adult Crohn’s disease, ustekinumab will continue to be 
provided to subjects through Week 72.
For eligible Part II subjects, participation in the Part II LTE is entirely voluntary. Eligible 
subjects who do not wish to enter the Part II LTE will complete the Part II Week 24 safety and 
efficacy assessments, followed by the final efficacy and safety assessments at Week 36.
During the Part II LTE, all concomitant medications, including Crohn’s disease-specific 
medications (except for the prohibited medications listed in Section 8.2) may be administered at 
the discretion of the investigator.
All subjects in the Part II LTE (before unblinding for JNJ-64304500, ustekinumab, and placebo 
and after unblinding for JNJ 64304500) will be assessed according to the Time & Events 
Schedule (Table 3), which includes assessments, AEs, laboratory analyses, and PK and 
immunogenicity samples. Ustekinumab subjects in the Part II LTE (after unblinding for 
ustekinumab subjects in countries where ustekinumab is not commercially available) will be 
assessed according to the Time & Events Schedule (Table 4), which includes assessments and 
AEs.
3.2.
Study Design Rationale
This protocol is comprised of 2 parts (Part I [Study 1: Bio-IR subjects and Study 2: Bio-NF 
subjects] and Part II [Bio-IR and Bio-NF subjects]) that are designed to evaluate the safety and 
efficacy of JNJ-64304500 in subjects with moderately to severely active Crohn’s disease. 
Study 1 and Study 2 constitute Part I of the protocol. In this part, the safety and efficacy of a 
single dosing regimen of JNJ-64304500 in Bio-IR and Bio-NF subjects with moderately to 
severely active Crohn’s disease is evaluated. If acceptable efficacy is established in Part I (for the 
combined Bio-IR and Bio-NF subjects), Part II (a dose-ranging study in Bio-IR and Bio-NF
subjects) will be initiated. After Protocol Amendment 5 is implemented, subjects who complete 
Part II Week 24 assessments and who may benefit from continued treatment in the opinion of the 
investigator, are eligible to enter the Part II LTE to receive up to 52 weeks of additional 
treatment. Subjects who have completed Week 24 prior to the implementation of Protocol 
Amendment 5 will not be eligible to enroll in the Part II LTE.
3.2.1.
Choice of JNJ-64304500 Dose for Placebo Nonresponders
In Part I, the high dose of JNJ-64304500 (400 mg/200 mg) was chosen for placebo 
nonresponders because it is the only dose regimen studied in this part.


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In Part II, the middle dose was chosen for placebo nonresponders as it is believed that this dose 
will be effective since it is higher than the dose studied in the prior Phase 2a study (where 
efficacy was shown). The middle dose also requires fewer injections compared with the high 
dose.
3.2.2.
Efficacy Assessments
The efficacy evaluations selected for both parts of the study (eg, CDAI, CRP, fecal biomarkers; 
Section 9.2) are well-established measures that are accepted by regulatory agencies as primary or 
supportive of clinically relevant effect of disease activity in Crohn’s disease studies.
The primary endpoint for Part I is change from baseline in CDAI at Week 8. The primary 
endpoint for Part II is change from baseline in CDAI at Week 12.
Change in the CDAI is being used as the primary endpoint because this measure is more 
sensitive than remission (ie, the change in CDAI provides greater power than remission for the 
same sample size). Therefore, the study can be more efficient for Phase 2 using the change in 
CDAI.
To evaluate the level of efficacy after prolonged discontinuation of study drug, CDAI will be 
assessed at the final efficacy and safety visit in Part I and in Part II for those subjects who do not 
enter the Part II LTE. The CDAI will be not assessed during the Part II LTE.
It is anticipated that endoscopic improvement will occur by Week 12. In order to have an 
appropriate comparison of JNJ-64304500 to placebo, the placebo-controlled period will continue 
to Week 12.
Efficacy evaluations will not be performed during the Part II LTE.
3.2.3.
Pharmacokinetic Assessments
Pharmacokinetic assessments will be used to further understand the disposition of JNJ-64304500 
in subjects with Crohn’s disease.
3.2.4.
Immunogenicity Assessments
Serum samples for the detection of antibodies to JNJ-64304500 will be collected to further 
evaluate the immunogenicity of JNJ-64304500 in subjects with Crohn’s disease.
3.2.5.
Pharmacodynamic Assessments
Serum samples for the analysis of PD will be collected to further understand the response of 
subjects with Crohn’s disease to treatment with JNJ-64304500.


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3.2.6.
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug.
Whole blood will be collected from all subjects for SNP analysis (the NKG2D SNP rs2255336 
and the MICB [NKG2D ligand] SNP rs2239705) to understand the association of these SNPs 
with response to JNJ-64304500 (refer to the latest version of the IB for more information). In
addition, subjects who sign an optional pharmacogenomics consent form will undergo complete 
genomic testing.
The goal of this pharmacogenomic component is to collect DNA to allow the identification of 
genetic factors that may influence the PK, PD, efficacy, safety, or tolerability of JNJ-64304500
and to identify genetic factors associated with Crohn’s disease.
Biomarker assessments will be made to examine the biologic response to treatment and to 
identify biomarkers that are relevant to JNJ-64304500 treatment and/or Crohn’s disease. Blood 
samples for serum-based biomarker analyses will be collected from all subjects to assess proteins 
related to the NKG2D pathway or the pathogenesis of Crohn’s disease. Whole blood samples 
will be collected from all subjects for the analysis of ribonucleic acid (RNA) expression and 
T-cell receptor repertoire. Mucosal biopsy samples will be collected during ileocolonoscopy for 
the analysis of gene and/or protein expression and the histologic assessment of disease and/or 
healing.
Receptor occupancy (RO) assessments for NKG2D and immunophenotyping assessments 
(including NK cells and CD8+ T cells) will also be performed. Immunophenotyping will be 
conducted using flow cytometry to assess the number of CD4, CD8, and NK cells before versus 
after dose administration.
3.2.7.
Control, Randomization, and Blinding
In both parts of the study, 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. In 
addition to placebo control, a ustekinumab reference arm will be used in Part II to determine the 
sensitivity of the clinical endpoints in this study.
Ustekinumab was chosen for use as a reference arm because the efficacy and safety profile of 
ustekinumab are well described. It is also recognized that use of other therapeutics (eg, TNFα 
antagonists) could potentially confound the population of Bio-IR subjects and introduce 
substantial patient burden to maintain blinding.


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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. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints.
3.2.8.
Dose Selection
3.2.8.1.
JNJ-64304500
The results of PK, PD and efficacy analyses and safety data from previous clinical studies of 
JNJ-64304500 in subjects with RA and Crohn’s disease were used to guide the dose selection for 
the 3 studies in this protocol. In study NN8555-3618, the highest single SC dose investigated 
was 7.5 mg/kg and the highest multiple SC dose regimen investigated was 4 mg/kg q2w for a 
total of 4 doses in RA subjects. JNJ-64304500 was well tolerated and no safety concerns were 
identified in subjects with RA or Crohn’s disease from the previous clinical studies. In addition, 
a 52-week repeat-dose toxicology study has demonstrated a NOAEL of 100 mg/kg SC once 
weekly in cynomolgus monkeys. The exposures achieved in the last dosage interval (100 mg/kg) 
of the 52-week study were 10,900 and 8,480 μg/mL for maximum concentration (Cmax), and 
1,520,000 and 1,250,000 hr·μg/mL for AUC0-168hr, for male and female monkeys, respectively. 
Based on these safety and toxicology findings, it is expected that the proposed dose regimens of 
JNJ-64304500 would have acceptable safety profiles.
Population PK/PD modeling and simulation was performed using JNJ-64304500 PK and 
NKG2D RO data from the previous clinical studies. The model-predicted JNJ-64304500 
concentrations and NKG2D RO in the intestines were used to help guide the selection of the dose 
regimens for the present study. NKG2D RO in the intestines is predicted by assuming that the 
concentration of JNJ-64304500 in the intestines is approximately 10% of the concentration in the 
peripheral circulation because a 5%-15% antibody distribution coefficient between the general 
circulation and the intestines has been reported.9
A 16-week follow-up interval after the last administration of study agent has been employed 
based on the observed safety profile and PK profile of JNJ-64304500 in the completed clinical 
studies in RA and Crohn’s disease subjects. The average serum concentration of JNJ-64304500 
at 16 weeks after the last administration of study agent is predicted to be approximately
0.01 μg/mL, which is considered unlikely to produce drug-related effects or safety concerns.
PART I
The selected JNJ-64304500 dose regimen for Part I includes a loading dose of 400 mg SC at 
Week 0, followed by 200 mg SC q2 weeks through Week 22. The loading dose of 400 mg at 
Week 0 is intended to produce rapid onset of clinical response. The Part I dose regimen is 
predicted to achieve systemic exposures similar to the maximum systemic exposure that has been 
well tolerated in previous clinical studies. In the first-in-human study (NN8555-3618), the
highest multiple-dose regimen of 4 mg/kg SC q2w (4 doses) provided a median (range) Cmax in 
serum of 79.3 (52.8 to 91.2) µg/mL. The predicted median JNJ-64304500 Cmax in serum 


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is 64.64 μg/mL, median JNJ-64304500 concentration in serum at Week 8 is 38.94 μg/mL and 
median steady state trough JNJ-64304500 serum concentration is 38.31 μg/mL in subjects with 
Crohn’s disease (Table 5).
Assuming the concentration of JNJ-64304500 in the intestines is approximately 10% of 
concentration of JNJ-64304500 in serum, the predicted median peak and trough concentrations 
of JNJ-64304500 in the intestines are 6.46 μg/mL and 3.83 μg/mL, respectively. Analysis of the 
ex vivo relationship between the NKG2D RO and the JNJ-64304500 serum concentration 
suggests that 90% RO is achieved when the JNJ-64304500 serum concentration is 3 μg/mL. 
As a result, the Part I dose regimen is expected to result in approximately 99% NKG2D RO in 
the intestine (Table 5). Thus, the Part I dose regimen is expected to increase the probability to 
achieve maximum clinical response while remaining within the acceptable safety margins in 
subjects with Crohn’s disease.
Table 5:
Predicted median serum JNJ-64304500 concentrations and NKG2D receptor occupancy 
after administration of the selected dose regimens of JNJ-64304500
Dosing
Regimen 
(SC)
JNJ-64304500 Serum Concentration 
(μg/mL)
NKG2D Receptor Occupancy (%RO)
Parameter
Value
Week
%RO in blood
%RO in intestine
400 mg at 
Week 0 
then 200 
mg q2w
Cmax
64.64
-
-
-
Cmin (Week 8)
38.94
8
100
99
Ctrough
(steady state)
38.31
24
100
99
400 mg 
(Wk0), 
200 mg 
(Wks 2 &4) 
then 200 
mg q4w
Cmax
53.99
-
-
-
Cmin (Week 8)
18.95
8
100
97
Ctrough
(steady state)
12.00
24
100
96
150 mg 
(Wk0), 
75 mg 
(Wks 2 &4) 
then 75 mg 
q4w
Cmax
19.53
-
-
-
Cmin (Week 8)
6.34
8
100
91
Ctrough
(steady state)
4.24
24
99
87
50 mg 
(Wk0),
25 mg 
(Wks 2 &4) 
then 25 mg 
q4w
Cmax
6.46
-
-
-
Cmin (Week 8)
1.77
8
97
76
Ctrough
(steady state)
0.74
24
94
64
Cmax=maximum concentration; Cmin (Week 8)=concentration at Week 8; Ctrough (steady state)=steady state trough 
concentration; NKG2D=natural killer group 2D; q2w=every 2 weeks; q4w=every 4 weeks; %RO=percent 
receptor occupancy; SC=subcutaneous; Wk=Week


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PART II
Three dose regimens of JNJ-64304500 (high, middle and low) have been selected for Part II 
which are expected to provide a wide range of systemic drug exposures in order to assess 
exposure-response relationship in subjects with Crohn’s disease. The loading doses at Week 0, 2,
and 4 are intended to produce rapid onset of clinical response. Since the apparent terminal half-
life of JNJ-64304500 at the proposed dose regimens is about 2 to 3 weeks, SC administration of 
JNJ-64304500 at 4-week intervals from Week 4 through Week 20 is expected to produce median 
steady state trough serum JNJ-64304500 concentrations that are likely to maintain clinical 
response in Crohn’s disease subjects. In addition, the PK/PD modeling results described below 
support the use of a 4-week dosing interval in Part II.
The high dose regimen for Part II is 400 mg at Week 0, 200 mg at Weeks 2 and 4, followed by 
200 mg q4 weeks through Week 20. This dose regimen is predicted to result in a median 
JNJ-64304500 Cmax in serum of 53.99 µg/mL, a median JNJ-64304500 serum concentration at 
Week 8 of 18.95 µg/mL, and a median trough serum JNJ-64304500 concentration at steady state 
of 12.00 µg/mL in subjects with Crohn’s disease. Simulations results suggest that 89% of 
subjects on this high dose regimen are expected to maintain trough serum JNJ-64304500
concentrations >3 µg/mL at steady state, and the predicted median intestinal NKG2D RO is 
>96% (Table 5).
The middle dose regimen for Part II is 150 mg SC at Week 0, 75 mg at Weeks 2 and 4, followed 
by 75 mg q4w through Week 20. This middle dose regimen is predicted to result in 
approximately 38% of the systemic exposure achieved with the high dose regimen. The predicted 
median intestinal NKG2D RO at steady state is 87%.
The low dose regimen for Part II is 50 mg SC at Week 0, 25 mg at Weeks 2 and 4, followed by 
25 mg q4 weeks through Week 20. The low dose regimen is selected to explore the minimum 
effective dose of JNJ-64304500 in subjects with Crohn’s disease. The predicted median serum 
trough concentration of JNJ-64304500 at steady state is 0.74 μg/mL which is predicted to result 
in a median NKG2D RO of 64% in the intestine. Furthermore, in the first-in-humans study in RA 
subjects, a decrease in NKG2D expression on NK cells was not observed until the dose of 
JNJ-64304500 was 0.3 mg/kg q2w, and decreases in NKG2D expression on both CD8+ T cells 
and NK cells were not observed until the dose was 1 mg/kg q2w. These observations suggest 
that a dose regimen of at least 0.3 mg/kg q2w may be required to produce pharmacological 
effects, and the selected low maintenance dose regimen of 25 mg q4w would likely produce 
treatment effect at the lower part of the exposure-response curve.


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Part I and Part II
The selection of the 4 different dosing regimens of JNJ-64304500 in Part I and Part II was based 
on all available PK, efficacy and safety data from the previous clinical studies and from a 
52-week repeat-dose toxicology study. It should be noted that the current available information 
on JNJ-64304500 has not established the relationship between the NKG2D RO and clinical 
effects of the drug. In addition, the currently reported antibody distribution coefficients for 
intestinal tissues may have limitations and the JNJ-64304500 concentrations in the intestine may 
not be accurately predicted. Nevertheless, the use of 4 different dose regimens of JNJ-64304500 
in Part I and Part II, which will provide a wide range of drug exposures while remaining within
the acceptable safety margins, is anticipated to provide a robust characterization of 
the exposure-response relationship of JNJ-64304500 in the treatment of Crohn’s disease.
3.2.8.2.
Ustekinumab
Results from the 2 Phase 3 induction studies of IV ustekinumab (Study CNTO1275CRD3001 in 
subjects with Crohn’s disease who failed 1 or more TNFα antagonists, and Study 
CNTO1275CRD3002 in subjects who failed conventional therapy with immunomodulators 
and/or corticosteroids) and 1 Phase 3 maintenance study with SC ustekinumab 
(Study CNTO1275CRD3003, which enrolled clinical responders from the 2 IV induction 
studies) were used to determine the appropriate dose regimen of ustekinumab for the treatment of 
Crohn’s disease. As a result, a single IV induction dose of 6 mg/kg ustekinumab (administered as 
body weight-based tiered fixed doses, see Section 3.1.2 for details) at Week 0, followed by SC 
maintenance therapy of 90 mg every 8 weeks has been demonstrated to provide robust efficacy 
across a range of endpoints including patient-reported outcomes, objective measures of 
inflammation, and health-related quality of life measures, as well as a favorable safety profile.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 5 weeks before administration of the 
study drug.
The inclusion and exclusion criteria for enrolling subjects in the 2 studies are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.1, 
Sample Size Determination.
The following inclusion and exclusion criteria apply to Part I and Part II within this protocol.


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4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be randomized in the study:
1.
Be a man or woman 18 years of age.
2.
Have Crohn’s disease or fistulizing Crohn’s disease of at least 3 months’ duration, with 
colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, 
and/or endoscopy.
3.
Have active Crohn’s disease, defined as a baseline CDAI score of 220 but 450.
4.
Have at least one of the following at screening:
a.
An abnormal CRP (>0.3 mg/dL [>3.0 mg/L])
OR
b.
Calprotectin >250 mg/kg.
5.
Criterion modified per Amendment 2:
In Study 1 of Part I, meet the following requirements for prior or current medications for 
Crohn’s disease:
a.
Has previously demonstrated inadequate response, loss of response, or intolerance to 1 
or more approved biologic therapies (eg, infliximab, adalimumab, certolizumab pegol,
or vedolizumab) as outlined in Attachment 1.
In Study 2 of Part I, meet the following requirements for prior or current medications for 
Crohn’s disease:
b.
Has failed conventional therapy:
1)
Is currently receiving corticosteroids and/or immunomodulators (ie, AZA, 6-MP, or 
MTX) at adequate therapeutic doses (Attachment 2).
OR
2)
Has a history of failure to respond to or tolerate an adequate course of 
corticosteroids 
and/or 
immunomodulators 
(ie, 
AZA, 
6-MP, 
or 
MTX)
(Attachment 2).
OR
3)
Is corticosteroid dependent or has had a history of corticosteroid dependency
(Attachment 2).
6.
In Part II, meet the following requirement for prior or current medications for Crohn’s 
disease:
a.
Has previously demonstrated inadequate response, loss of response, or intolerance to 1 
or more approved biologic therapies (eg, infliximab, adalimumab, certolizumab pegol, 
or vedolizumab) as outlined in Attachment 1.
OR
b.
Has failed conventional therapy:


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1)
Is currently receiving corticosteroids and/or immunomodulators (ie, AZA, 6-MP, or 
MTX) at adequate therapeutic doses (Attachment 2).
OR
2)
Has a history of failure to respond to or tolerate an adequate course of 
corticosteroids 
and/or 
immunomodulators 
(ie, 
AZA, 
6-MP, 
or 
MTX) 
(Attachment 2).
OR
3)
Is corticosteroid dependent or has had a history of corticosteroid dependency 
(Attachment 2).
7.
Adhere to the following requirements for concomitant medication for the treatment of 
Crohn's disease, which are permitted provided that doses meeting these requirements are 
stable, or have been discontinued, for at least 3 weeks before baseline (Week 0), unless 
otherwise specified:
a.
Oral 5-aminosalicylic acid (5-ASA) compounds.
b.
Oral corticosteroids at a prednisone-equivalent dose at or below 40 mg/day, or 9 mg/day 
of budesonide, or 5 mg/day beclomethasone dipropionate.
c.
Antibiotics being used as a primary treatment of Crohn's disease.
d.
Conventional immunomodulators (ie, AZA, 6-MP, or MTX): subjects must have been 
taking them for at least 12 weeks and at a stable dose for at least 4 weeks before
baseline.
8.
A subject with a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factor must be up-to-date on colorectal 
cancer surveillance (may be performed during screening). Adenomatous polyps must be 
removed before the first administration of study agent.
9.
A subject who has had extensive colitis for ≥8 years, or disease limited to the left side of the 
colon for ≥12 years, must either have had a colonoscopy to assess for the presence of 
dysplasia within 1 year before the first administration of study agent or a colonoscopy to 
assess for the presence of malignancy at the screening visit, with no evidence of malignancy.
10. Have screening laboratory test results within the following parameters:
a.
Hemoglobin ≥8.0 g/dL.
b.
White blood cell count ≥3.0×103/µL.
c.
Neutrophils ≥1.5×103/µL.
d.
Platelets ≥100×103/µL.
e.
Serum creatinine <1.7 mg/dL.
f.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations 
must be within 2 times the upper limit of the normal (ULN) range for the laboratory 
conducting the test.
g.
Direct (conjugated) bilirubin <1.0 mg/dL.


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11. Are considered eligible according to the following tuberculosis (TB) screening criteria:
a.
Have no history of latent or active TB before screening. Exceptions are made for 
subjects currently receiving treatment for latent TB, if there is no evidence of active TB, 
or who have a history of latent TB and documentation of having completed adequate 
treatment for latent TB within 3 years before the first administration of study agent. It is 
the responsibility of the investigator to verify the adequacy of previous TB treatment 
and provide appropriate documentation.
Note: The exceptions outlined above exclude subjects in countries with high 
multidrug-resistant TB burden (eg, Brazil, China, India, the Russian Federation, and 
South Africa), due to potential concerns for multi-drug-resistant TB.
b.
Have no signs or symptoms suggestive of active TB upon medical history and/or 
physical examination.
c.
Have had no recent close contact with a person with active TB or, if there has been such 
contact, will be referred to a physician specializing in TB to undergo additional 
evaluation and, if warranted, receive appropriate treatment for latent TB before or 
simultaneously with the first administration of study agent.
d.
Criterion modified per Amendment 1.
d.1
Within 2 months before the first administration of study agent, either have 
negative QuantiFERON-TB test, or have a newly identified positive 
QuantiFERON-TB test in which active TB has been ruled out, and for which 
appropriate treatment for latent TB has been initiated either before or 
simultaneously with the first administration of study agent (except in countries 
with high multidrug-resistant TB burden [eg, Brazil, China, India, the Russian 
Federation, and South Africa]), where subjects with a newly identified positive 
QuantiFERON-TB test result are excluded). Indeterminate results should be 
handled as outlined in Section 9.1.2. A negative tuberculin skin test 
(Attachment 3) is additionally required if the QuantiFERON-TB test is not 
approved/registered in that country. A tuberculin skin test is recommended but not 
required for study centers in countries where tuberculin is not available. The 
QuantiFERON-TB test is not required at screening for subjects with a history of 
latent TB and appropriate treatment as described above in Inclusion Criterion 11a.
e.
Have a chest radiograph (posterior-anterior and lateral views), taken within 3 months 
before the first administration of study agent and read by a qualified radiologist, with no 
evidence of current active TB or old inactive TB.
12. A woman of childbearing potential must have a negative highly sensitive serum (β-human 
chorionic gonadotropin [β-hCG]) pregnancy test result at screening and a negative urine 
pregnancy test result at Week 0.
13. Before randomization, a female subject must be either:
a.
Not of childbearing potential, defined as:
1)
Premenarchal: A premenarchal state is one in which menarche has not yet occurred.


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2)
Postmenopausal: A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle-stimulating hormone level 
(>40 IU/L or mIU/mL) in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy; however, in the absence of 12 months of amenorrhea, a single 
follicle-stimulating hormone measurement is insufficient.
3)
Permanently sterile: Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy.
OR
b.
Of childbearing potential and:
1)
Practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly), consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical studies.
Examples of highly effective contraceptives include user-independent methods
such as implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS); vasectomized partner; or sexual abstinence (considered a highly 
effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study drug, and if in line with the 
preferred and usual lifestyle of the subject); or user-dependent methods such as 
combined (estrogen-
and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal); or 
progestogen-only hormone contraception associated with inhibition of ovulation 
(oral, injectable). If using a hormone birth control method, a second method of 
birth control, such as a condom or diaphragm, must be used.
2)
Agrees to remain on a highly effective method of contraception throughout the 
study and for at least 16 weeks after the last administration of study agent.
Note: If a subject’s 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.
14. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for a period of 16 weeks after the last administration of 
study agent.
15. During the study and for at least 16 weeks after the last administration of study agent, a man
a.
who is sexually active with a woman of childbearing potential must agree to use a 
barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository).
b.
who is sexually active with a pregnant woman must use a condom.
c.
must agree not to donate sperm.
16. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.


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17. Must sign an informed consent form (ICF) indicating that he or she understands the purpose 
of and procedures required for the study and is willing to participate in the study.
18. Criterion modified per Amendment 1.
18.1
DNA sample collection for SNP testing is required for all subjects in this study. Each 
subject must have a SNP status of either positive or negative. Each subject must sign 
a separate ICF if he or she agrees to consent to additional optional DNA research 
where local regulations permit. Refusal to give consent for the optional DNA research 
does not exclude a subject from participation in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Has complications of Crohn’s disease such as symptomatic strictures or stenoses, short gut 
syndrome, or any other manifestation that might be anticipated to require surgery, could 
preclude the use of the CDAI to assess response to therapy, or would possibly confound the 
ability to assess the effect of treatment with JNJ-64304500 or ustekinumab.
2.
Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses 
are not exclusionary if drained and adequately treated at least 3 weeks before baseline, or 
8 weeks before baseline for intra-abdominal abscesses, provided that there is no anticipated 
need for any further surgery. Subjects with active fistulas may be included if there is no 
anticipation of a need for surgery and there are currently no abscesses identified.
3.
Has had any kind of bowel resection within 6 months or any other intra-abdominal surgery 
within 3 months before baseline.
4.
Has a draining (ie, functioning) stoma or ostomy.
5.
Has received any of the following prescribed medications or therapies within the specified 
period:
a.
IV corticosteroids <3 weeks before baseline.
b.
Other oral immunomodulatory agents (eg, 6-thioguanine [6-TG], cyclosporine, 
tacrolimus, sirolimus, or mycophenolate mofetil, tofacitinib and other Janus kinase 
[JAK] inhibitors) <6 weeks or within 5 half-lives of agent before baseline, whichever is 
longer.
c.
Nonbiologic experimental or investigational agents <4 weeks or within 5 half-lives of 
agent before baseline, whichever is longer.
d.
Nonautologous stem cell therapy (eg, Prochymal), natalizumab, efalizumab, or biologic 
agents that deplete B or T cells (eg, rituximab, alemtuzumab, or visilizumab) 
<12 months before baseline.
e.
TNFα-antagonist biologic agents (eg, monoclonal antibody therapies) or other agents 
intended to suppress or eliminate TNFα <8 weeks before baseline.
f.
Vedolizumab <16 weeks before baseline.
g.
Other immunomodulatory biologic agents <12 weeks or within 5 half-lives of agent 
before baseline, whichever is longer.


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h.
Treatment with apheresis (eg, Adacolumn apheresis) <3 weeks before baseline.
i.
Initiation of total (complete) or partial (supplemental) parenteral nutrition administered 
through any indwelling catheter <3 weeks before baseline or anticipated to require 
parenteral nutrition administered through an indwelling catheter during enrollment in 
the study.
j.
Initiation of enteral therapy for Crohn’s disease (liquid nutritional formula comprising 
≥80% of total caloric intake administered through the gastrointestinal tract) <3 weeks 
before baseline. Subjects who are on a stable regimen of enteral feeds ≥3 weeks before 
baseline may be considered for enrollment if they plan to continue enteral feeds as 
treatment for Crohn’s disease through the duration of the study (Week 24, Part I or 
Part II).
6.
Has a stool culture or other examination positive for an enteric pathogen, including 
Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative and 
there are no signs of ongoing infection with that pathogen.
7.
Has previously received a biologic agent targeting IL-12 or IL-23, including but not limited 
to ustekinumab or briakinumab (ABT-874).
8.
Has previously received JNJ-64304500 or NNC0142-002.
9.
Has received a Bacille Calmette-Guérin (BCG) vaccination within 12 months or any other 
live bacterial or live viral vaccination within 12 weeks before baseline.
10. Has a history of, or ongoing, chronic or recurrent infectious disease, including but not 
limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection 
(eg, recurrent pyelonephritis or chronic nonremitting cystitis), or open, draining, or infected 
skin wounds or ulcers.
11. Has current signs or symptoms of infection. Established nonserious infections (eg, acute 
upper respiratory tract infection, simple urinary tract infection) need not be considered 
exclusionary at the discretion of the investigator.
12. Has a history of serious infection (eg, sepsis, pneumonia, or pyelonephritis), including any 
infection requiring hospitalization or IV antibiotics, for 8 weeks before baseline.
13. Has evidence of a Herpes zoster infection 8 weeks before baseline.
14. Has a history of latent or active granulomatous infection, including histoplasmosis or 
coccidioidomycosis, before screening. Refer to Inclusion Criteria 11 a for information 
regarding eligibility with a history of latent TB.
15. Has evidence of current active infection, including TB, or a nodule suspicious for lung 
malignancy on screening or any other available chest radiograph, unless definitively 
resolved surgically or by additional imaging and with source document confirmation.
16. Has or ever has had a nontuberculous mycobacterial infection or serious opportunistic 
infection (eg, cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
17. Has a history of human immunodeficiency virus (HIV) antibody positivity, or tests positive 
for HIV at screening.


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18. Are seropositive for antibodies to hepatitis C virus (HCV) without a history of successful 
treatment, defined as being negative for HCV RNA at least 24 weeks after completing 
antiviral treatment.
19. Subjects must undergo screening for hepatitis B virus (HBV). At a minimum, this includes 
testing for HBV surface antigen (HBsAg), HBV surface antibody (anti-HBs), and HBV core 
antibody (anti-HBc) total:
a.
Subjects who test negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs-) are eligible for this study.
b.
Subjects who test positive for surface antigen (HBsAg+) are not eligible for this study, 
regardless of the results of other hepatitis B tests.
c.
Subjects who test negative for surface antigen (HBsAg-) and test positive for core 
antibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study.
d.
Subjects who test positive only for surface antibody (anti-HBs+) are eligible for this 
study.
e.
Subjects who test positive only for core antibody (anti-HBc+) must undergo further 
testing for hepatitis B DNA acid (HBV DNA test). If the HBV DNA test is positive, the 
subject is not eligible for this study. If the HBV DNA test is negative, the subject is 
eligible for this study. In the event the HBV DNA test cannot be performed, the subject 
is not eligible for this study.
Note: For subjects who are not eligible for this study due to HIV, HCV, and HBV test 
results, consultation with a physician with expertise in the treatment of those infections is 
recommended.
20. Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms 
thereof.
21. Has a transplanted organ (with exception of a corneal transplant >12 weeks before
screening).
22. Has a known history of lymphoproliferative disease, including monoclonal gammopathy of 
unknown significance (MGUS), lymphoma, or signs and symptoms suggestive of possible 
lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
23. Has any known malignancy or has a history of malignancy (with the exception of basal cell 
carcinoma; squamous cell carcinoma in situ of the skin; or cervical carcinoma in situ that 
has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin that 
has been treated with no evidence of recurrence within 5 years before screening).
24. Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack 
of easy access to veins.
25. Is known to have had a substance abuse (drug or alcohol) problem within the previous 
12 months before baseline.
26. Has known allergies, hypersensitivity, or intolerance to JNJ-64304500 or ustekinumab or 
any of their excipients (refer to IBs).


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27. Are currently or intending to participate in any other study using an investigational agent or 
procedure during participation in this study.
28. Is a woman who is pregnant, or breast-feeding, or planning to become pregnant or is a man 
who plans to father a child while randomized in this study or within 16 weeks after the last 
administration of study agent.
29. Has any condition that, in the opinion of the investigator, would make participation not be in 
the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, 
or confound the protocol-specified assessments.
30. Is an employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as family 
members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given, such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 9.1.2 describes options for retesting. Section 17.4 describes the 
required documentation to support meeting the enrollment criteria.
Long-term Extension Phase
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments and who may benefit from continued treatment in the opinion of the investigator, are 
eligible to enter the Part II LTE to receive up to 52 weeks of additional treatment. Subjects must 
be excluded from LTE if they have developed Crohn’s disease complications which may be 
anticipated to require surgery in the next 12 months, if they have clinical evidence of a serious 
infection at Week 24, or if they intend to participate in any other study using an investigational 
agent or procedure during participation in the LTE. Investigators who have questions regarding 
subject eligibility for the LTE should contact the sponsor.
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.
Subjects must agree to follow the contraceptive requirements noted in the Inclusion Criteria.
2.
Subjects must not receive ustekinumab outside of this protocol or participate in any other 
clinical study with an investigational agent while in this study, and must terminate study 
participation if they do. A subject who intends to participate in any other clinical study with 
an investigational agent should undergo an early termination visit before he or she 
withdraws from study participation.
3.
Subjects must agree not to receive a live virus or live bacterial vaccination, including a BCG 
vaccination, during the study and for 12 months after receiving the last dose of study agent 
for BCG vaccination or 16 weeks for other live vaccines.
A complete list of prohibited therapies is provided in Section 8.2.


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5.
TREATMENT ALLOCATION AND BLINDING
5.1.
Treatment Allocation
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups (1:1 ratio) in Part I and to 1 of 5 treatment groups (1:1:1:1:1 ratio) in 
Part II, based on a computer-generated randomization schedule prepared before the study by or 
under the supervision of the sponsor. Each of the 2 studies will have separate randomizations. 
Each randomization will be balanced by using randomly permuted blocks and will be stratified 
by baseline CDAI score (≤300 or >300) and SNP-positive status (yes or no) (Part II will also be 
stratified by Bio-IR status [yes or no]). 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.
5.2.
Blinding
To maintain the study blind, the study agent container will have a label containing the study 
name and medication number or syringe number. The label will not identify the study agent in 
the container. The medication number or syringe number will be entered in the case report form 
(CRF) when the drug is dispensed. The study agents will be identical in appearance and 
packaging.
Planned efficacy and safety evaluations will be performed after the following planned DBLs
(additional DBLs may occur and would be described in the SAP):

Interim analysis lock for Part I: Occurs when 100 randomized subjects (Bio-IR and Bio-
NF) in Part I have completed their Week 12 visit or have terminated their study participation 
before Week 12.

Week 12 DBL for Part I: Occurs when all subjects in Part I have completed their Week 12 
visit or have terminated their study participation before Week 12.

Final DBL for Part I: Occurs when all Part I subjects have completed their final efficacy 
and safety visit or have terminated their study participation before the final efficacy and 
safety visit.

Week 12 DBL for Part II: Occurs when all Part II subjects have completed their Week 12 
visit or have terminated their study participation before Week 12.

Week 24 DBL for Part II: Occurs when all Part II subjects have completed their Week 24 
visit or have terminated their study participation before Week 24.

Final DBL for Part II: Occurs when all Part II subjects who entered the Part II LTE have 
completed their final safety visit in the Part II LTE or have terminated their study 
participation before the final safety visit in the Part II LTE.
At the time of the interim analysis lock for Part I, a limited number of sponsor personnel will 
become unblinded to treatment assignment. At the time of the Week 12 DBL for Part I and the 
Week 12 DBL for Part II, the sponsor, except for site monitors, who have interactions with the 


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investigative sites, will become unblinded to treatment assignment. Identification of sponsor 
personnel who will have access to subject-level data for the interim analysis lock for Part I will 
be documented before the unblinding. The study blind will be maintained for investigators, site 
personnel, subjects, and site monitors until the last subject in Part II has completed the Week 24 
assessments and the Sponsor unblinds the study. This measure will mitigate the potential bias in 
the remaining investigator and subject assessments.
Data that may potentially unblind the treatment assignment (ie, study drug serum concentrations, 
anti-drug antibodies, treatment allocation, and study drug preparation/accountability data) will be 
handled with special care to ensure that the integrity of the blind is maintained and the potential 
for bias is minimized. In particular, before unblinding, this information will be available only to 
a limited number of data management staff for purposes of data cleaning, and if applicable, to 
quality assurance representatives for the purposes of conducting independent drug audits.
The SNP status and postbaseline results of CRP, fecal lactoferrin, and fecal calprotectin tests will 
be blinded to the investigative site. If an investigative site requests these data, it will be provided 
to them after the final analyses have been completed.
The designated pharmacists, or other appropriately licensed and authorized personnel, and 
independent drug monitors will be unblinded to study agent. Placebo infusions/injections will
have the same appearance as the ustekinumab infusions/JNJ-64304500 injections. Under no 
circumstances should unblinded personnel reveal the treatment assignment for a subject.
For bioanalytical purposes, before the PK, anti-drug antibody, and PD bioanalyses are initiated, 
the unblinded data management team will provide the sponsor bioanalysts with the information 
about which treatment (JNJ-64304500, ustekinumab, or placebo) the subjects received, but not 
the dose level to which the subjects are randomized. For the purpose of performing PK, 
immunogenicity, and PD bioanalyses, bioanalysts in Biologics Clinical Pharmacology at Janssen 
will be unblinded to treatment-level data (JNJ-64304500, ustekinumab, or placebo) at the time of 
analyzing serum samples for the determination of drug concentrations, detection of antibodies to 
study agents, or PD assessments. Samples will be separated based on treatment administered; 
subject identification and dose given will not be disclosed.
Additionally, a given subject’s treatment assignment may be unblinded to the sponsor, 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), and site personnel to 
fulfill regulatory reporting requirements for suspected unexpected serious adverse reactions 
(SUSARs).
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.
Under normal circumstances, the blind should not be broken until the final analyses have been 
completed for all subjects. 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 


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such cases, the investigator may in an emergency determine the identity of the treatment by 
contacting the IWRS. It is recommended that the investigator contact the sponsor or its designee 
if possible to discuss the particular situation, before breaking the blind. Telephone contact with 
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the 
blind is broken, the sponsor must be informed as soon as possible. The date, time, and reason for 
the unblinding must be documented by the IWRS, 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 so as to not unblind the 
study site monitor. The investigators are advised not to reveal the study treatment assignment to 
the study site monitor or to sponsor personnel.
A separate code-break procedure will be available for use by the Janssen Global Medical Safety 
group to allow for unblinding of individual subjects to comply with specific requests from 
regulatory or health authorities.
Subjects who have had their treatment assignment unblinded will be discontinued from further 
study agent administration but should continue to return for scheduled evaluations (Section 10).
6.
DOSAGE AND ADMINISTRATION
Subcutaneous injections of study agent should be administered at different locations at each visit 
at which study agent is administered to allow for assessment of potential injection-site reactions.
6.1.
Part I
In Part I of the study (Figure 2), all subjects will receive either placebo SC or JNJ-64304500 
400 mg SC at Week 0 and placebo SC or JNJ-64304500 200 mg SC at Weeks 2, 4, 6, 8, 10, 12, 
14, 16, 18, 20, and 22, with the exception of placebo nonresponders at Week 12. Placebo 
nonresponders will receive JNJ-64304500 400 mg SC at Week 12 and JNJ-64304500 200 mg SC 
at Weeks 14, 16, 18, 20, and 22. Study drug concentration in Part I is 100 mg/mL.
To maintain the blind in Part I, all subjects will receive 4 SC injections at Weeks 0 and 12, and 
2 SC injections at Weeks 2, 4, 6, 8, 10, 14, 16, 18, 20, and 22.
6.2.
Part II
In Part II of the study (Figure 3), subjects will be randomly assigned in equal proportions to 
receive placebo, 1 of 3 dose regimens of JNJ-64304500, or ustekinumab, as follows:

Placebo: Placebo SC at Weeks 0, 2, 4, 8, 12, 16, and 20. Placebo nonresponders at Week 12 
will receive JNJ-64304500 150 mg SC at Week 12 and JNJ-64304500 75 mg SC at 
Weeks 14, 16, and 20.

JNJ-64304500 high dose: 400 mg SC at Week 0 and 200 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20 (study drug concentration=100 mg/mL).

JNJ-64304500 middle dose: 150 mg SC at Week 0 and 75 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20 (study drug concentration=75 mg/mL).


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
JNJ-64304500 low dose: 50 mg SC at Week 0 and 25 mg SC at Weeks 2, 4, 8, 12, 16, 
and 20 (study drug concentration=25 mg/mL).

Ustekinumab: tiered doses approximating 6 mg/kg IV (Section 3.1.2) at Week 0 and 90 mg 
SC at Weeks 8 and 16.
Administration of IV study agent at Week 0 should occur over a period of not less than 1 hour. 
The infusion should be completed within 5 hours of preparation. Detailed instructions on the 
administration of study agent are provided in the Study Reference Manual.
To maintain the blind in Part II, all subjects will receive 4 SC injections plus an IV infusion at 
Week 0, 2 SC injections at Weeks 2, 4, 12, and 20, 3 SC injections at Weeks 8 and 16, and one 
SC injection at Week 14.
6.3.
Part II Long-term Extension
After Protocol Amendment 5 is implemented, subjects who complete Part II Week 24 
assessments, and who may benefit from continued treatment in the opinion of the investigator, 
are eligible to enter the Part II LTE. In the Part II LTE, each subject will be eligible to receive up 
to 52 weeks of additional study drug (for a total of up to 72 weeks of study drug in Part II). The 
first dose of study drug within the Part II LTE will be administered after the Week 24 
assessments have been completed. The dose may be administered on the same day as the 
Week 24 assessments, or may be administered on a later date, as long as the dose is administered 
within the Week 24 visit window.
Subjects will continue to receive the same treatment regimen during the Part II LTE that they 
were receiving between Week 12 and Week 20 in the main study phase of Part II (placebo, high, 
middle, low dose JNJ-64304500, or ustekinumab). To maintain the study blind, all patients, 
investigators, and sites will remain blinded to treatment allocation during the Part II LTE until 
the last subject in the Part II main study phase has completed the Week 24 assessments and the 
Sponsor unblinds the study.
The timing of the Week 24 data analysis is dependent upon the timing and completion of Part II 
enrollment. An individual subject’s unblinding during the Part II LTE will depend upon his/her 
Part II enrollment date. Therefore, a portion of subjects will complete the entire Part II LTE in a 
blinded fashion before study unblinding, while other subjects could be unblinded to treatment 
allocation during their participation in the Part II LTE.
On 15 March 2021, sites were informed that due to lack of sufficient efficacy of JNJ-64304500, 
subjects who were receiving JNJ-64304500 or placebo in the LTE were discontinued, subjects 
receiving ustekinumab in countries where ustekinumab is not commercially available were 
continued in the LTE.
Any subject who withdraws from the Part II LTE prior to study unblinding will return for a final 
safety follow-up visit 16 weeks after the last dose of study drug. For subjects that remain in the 
Part II LTE at the time of study unblinding, continuation of study drug during the Part II LTE 
will be dependent upon treatment allocation as follows:


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
JNJ-64304500: Subjects receiving JNJ-64304500 during the LTE will stop receiving study 
drug and will have a final safety follow-up visit 16 weeks after the last dose of study drug.

Placebo: Subjects receiving placebo who remain in the Part II LTE at the time of study 
unblinding will have their final safety follow-up visit subsequent to unblinding and will be 
discontinued from the study. No further follow-up visits will be performed.

Ustekinumab: Subjects receiving ustekinumab will continue to receive it during the Part II 
LTE until unblinding occurs. After unblinding, based on the treating physician’s clinical 
judgment, subjects may receive ustekinumab in a manner dependent on the country in which 
they are located:
o
If a subject is not continuing on ustekinumab after unblinding, the subject will need 
to return for a final safety follow-up visit that will be performed 16 weeks after the 
final dose of study ustekinumab.
o
If a subject continues on ustekinumab in a country where commercial ustekinumab 
is available and approved for the treatment of adult Crohn’s disease, the treating 
physician is responsible for providing the subject with commercial ustekinumab, 
which should be administered according to the approved dosing regimen in each 
country. The final safety follow-up visit should be performed after unblinding but 
before receiving the first dose of commercial ustekinumab.
o
If a subject continues on ustekinumab in countries where commercial ustekinumab 
is not available or approved for adult Crohn’s disease, ustekinumab will continue to 
be provided to subjects through Week 72.
For eligible Part II subjects, participation in the Part II LTE is entirely voluntary. Eligible 
subjects who do not wish to enter the Part II LTE will complete the Part II Week 24 safety and 
efficacy assessments, followed by the final efficacy and safety assessments at Week 36.
During the Part II LTE, all concomitant medications, including Crohn’s disease-specific 
medications (except for the prohibited medications listed in Section 8.2) may be administered at 
the discretion of the investigator.
All subjects in the Part II LTE (before unblinding for JNJ-64304500, ustekinumab, and placebo 
and after unblinding for JNJ 64304500) will be assessed according to the Time & Events 
Schedule (Table 3), which includes assessments, AEs, laboratory analyses, and PK and 
immunogenicity samples. Ustekinumab subjects in the Part II LTE (after unblinding for 
ustekinumab subjects in countries where ustekinumab is not commercially available) will be 
assessed according to the Time & Events Schedule (Table 4), which includes assessments and 
AEs.
7.
TREATMENT COMPLIANCE
Study agent will be administered as an IV infusion or SC injection by qualified staff. The details 
of each administration will be recorded in the CRF. For IV infusions, this will include date and 
start and stop times of the IV infusion and volume infused; for SC injections, this will include 
date and time of SC injection.


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8.
PRESTUDY AND CONCOMITANT THERAPY
Concomitant therapies must be recorded throughout the study, from signing of the informed 
consent to the last study visit.
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. Recorded 
information will include a description of the type of therapy, treatment period, dosage, route of 
administration, and indication. Modification of an effective pre-existing therapy should not be 
made for the explicit purpose of entering a subject into the study.
8.1.
Concomitant Medications
Subjects who are receiving oral 5-ASA compounds, oral corticosteroids, conventional 
immunomodulators (ie, AZA, 6-MP, or MTX), enteral therapy, and/or antibiotics for the 
treatment of Crohn’s disease at baseline should maintain a stable dose for a specified period 
before baseline, as defined in the Inclusion Criteria (Section 4.1).
With the exception of oral corticosteroids, subjects who are receiving these medications for 
Crohn’s disease at baseline should maintain a stable dose through the final efficacy and safety 
visit. Corticosteroids must be maintained at baseline doses through Week 12 (see Section 8.1.1).
Randomized subjects should not initiate any of the following Crohn’s disease-specific medical 
therapies during their participation in the study:

Oral or rectal 5-ASA compounds.

Immunomodulators (ie, AZA, 6-MP, or MTX).

Oral, parenteral, or rectal corticosteroids.

Antibiotics as a treatment for Crohn’s disease.

Total (complete) or partial (supplemental) parenteral nutrition administered through an 
indwelling catheter as a treatment for Crohn’s disease.

Enteral therapy (liquid nutritional formula comprising ≥80% of total caloric intake) as 
treatment for Crohn’s disease.
If the above medications are initiated or medication doses are changed, subjects should continue 
to attend all study visits and have all assessments. If due to medical necessity in the opinion of 
the investigator, the above medications are initiated or medication doses are changed, this does 
not represent a deviation from the study protocol but may be considered a treatment failure.
After Week 12, subjects may transiently use (ie, for <4 weeks) increased doses of corticosteroids 
for reasons other than worsening of Crohn’s disease (eg, stress doses of corticosteroids for 
surgery, asthma, adrenocortical insufficiency).


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Subjects participating in the Part II LTE may continue receiving concomitant medications they 
were receiving at the time of Part II Week 24, including aminosalicylates, immunomodulatory 
agents (including 6-MP/AZA, MTX), enteral therapy, and corticosteroids. During the Part II
LTE, these medications may be initiated, discontinued, or dose adjusted at the investigator’s 
discretion.
8.1.1.
Corticosteroid Tapering
In Part I and Part II, subjects who are receiving corticosteroids at Week 0 and who are in clinical 
response at Week 12 are encouraged to initiate corticosteroid tapering at the Week 12 visit, using 
the tapering schedules described below. Other subjects should remain on their original 
corticosteroid dose through Week 24 unless a change in corticosteroid dose is considered 
medically necessary (eg, for corticosteroid side effects).
For subjects who experience a worsening of disease activity while tapering, further dose 
decreases may be suspended and/or their oral corticosteroid dose increased if deemed necessary 
by the investigator. The oral corticosteroid dose, however, may not be increased above the 
baseline dose unless due to medical necessity (Section 8.1).
During the Part II LTE, corticosteroids may be initiated, discontinued, or dose adjusted at the 
investigator’s discretion.
Tapering Schedule for Oral Prednisone (or Equivalent)

Dose >15 mg/day prednisone or equivalent: taper daily dose by 5 mg/week until receiving 
10 mg/day, then continue tapering at 2.5 mg/week until 0 mg/day.

Dose 11 to 15 mg/day prednisone or equivalent: taper daily dose to 10 mg/day for 1 week, 
then continue tapering at 2.5 mg/week until 0 mg/day.

Dose ≤10 mg/day prednisone or equivalent: taper daily dose by 2.5 mg/week until 0 mg/day.
Tapering Schedule for Oral Budesonide or Beclomethasone

Tapering of budesonide or beclomethasone dipropionate should follow local clinical 
practice.
8.2.
Prohibited Medications
Randomized subjects must not initiate any of the following prohibited medications at any time 
during Part I, Part II, or the Part II LTE:

Immunomodulatory agents other than 6-MP/AZA or MTX (including but not limited to 
6-TG, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, tofacitinib, and other 
JAK inhibitors).

Immunomodulatory biologic agents (including but not limited to tumor necrosis factor 
[TNF] antagonists, natalizumab, abatacept, vedolizumab).

Experimental Crohn’s disease medications (including but not limited to thalidomide, 
briakinumab, traficet, brodalumab [AMG 827]). Ustekinumab is permitted in Part II of this


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protocol only in subjects randomly assigned to ustekinumab and only as stipulated per 
protocol.
Because protection of human research subjects is paramount, it is recognized that initiating such 
therapies may rarely be required due to medical necessity. However, initiation of these
prohibited medications should be documented as a deviation from the study protocol, and 
subjects will be discontinued from receiving further study agent.
Subjects must not participate in any other clinical study with an investigational agent while in 
this study and must terminate study participation if they do. A subject who intends to participate 
in any other clinical study with an investigational agent should undergo an early termination visit 
before he or she withdraws from study participation.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedules summarize the frequency and timing of efficacy, PK, 
immunogenicity, PD, pharmacogenomic, medical resource utilization, and safety measurements 
applicable to this study (Table 1, Table 2, Table 3). The Time and Events Schedules for the LTE 
after unblinding for ustekinumab subjects in countries where ustekinumab is not commercially 
available (Table 4) includes safety assessments.
It is recommended that all visit-specific PRO assessments be conducted before any tests, 
procedures, or other consultations to prevent influencing subject perceptions.
The maximum amount of blood drawn from each subject in this study will be approximately 
330 mL.
9.1.2.
Screening Period
At the screening visit, written informed consent must be obtained from the subject for this study 
by the principal investigator or designee before performing any protocol-specific procedure.
Procedures to be performed at the screening visit are outlined in the Time and Events Schedules
(Table 1, Table 2).
The CDAI diary will be completed by subjects during the screening period. The investigator or 
appropriate site personnel will use the hematocrit value obtained during screening to calculate 
the CDAI score at Week 0.
The screening period should be a minimum of 7 days to allow for collection of CDAI data. 
Subjects who are rescreened do not need to have a minimum of 7 days, provided that they have 
enough data to support CDAI calculation.


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Women of childbearing potential must have a negative serum β-hCG pregnancy test result at 
screening. Subjects must be reminded that they are required to use a highly effective method of 
contraception during the study (as described in Inclusion Criterion 13) and must continue taking 
such precautions for 16 weeks after receiving the last administration of study agent. The 
method(s) of contraception used by each subject must be documented.
Subjects must undergo testing for TB (Attachment 3) and their medical history assessment must 
include specific questions about a history of TB or known occupational or other personal 
exposure to individuals with active TB. The subject should be asked about past testing for TB, 
including chest radiograph results and responses to tuberculin skin or other TB testing.
Subjects with a negative QuantiFERON-TB test result (and a negative tuberculin skin test result 
in countries in which the QuantiFERON-TB test is not approved/registered or the tuberculin skin 
is mandated by local health authorities) are eligible to continue with prerandomization 
procedures. A tuberculin skin test is recommended but not required for study centers in countries
where tuberculin is not available. Subjects with a newly identified positive QuantiFERON-TB 
(or tuberculin skin) test result must undergo an evaluation to rule out active TB and initiate 
appropriate treatment for latent TB. Appropriate treatment for latent TB is defined according to 
local country guidelines for immunocompromised patients. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed, or the subject will be 
excluded from the study. Note: Subjects in countries with high multidrug-resistant TB burden 
(eg, Brazil, China, India, the Russian Federation, and South Africa) identified with latent TB at 
screening will be excluded from participating in the study.
A subject whose first QuantiFERON-TB test result is indeterminate should have the test 
repeated. In the event that the second QuantiFERON-TB test result is also indeterminate, the 
subject may be randomized without treatment for latent TB if his/her chest radiograph shows no 
abnormality suggestive of TB (active or old, inactive TB) and the subject has no additional risk 
factors for TB as determined by the investigator and medical monitor.
Note: Subjects in countries with high multidrug-resistant TB burden (eg, Brazil, China, India, 
the Russian Federation, and South Africa) with a repeat indeterminate QuantiFERON-TB test 
result will be excluded from participating in the study, unless his/her chest radiograph shows no 
abnormality suggestive of TB (active or old, inactive TB), there are no additional risk factors for 
TB as determined by the investigator and medical monitor, and he/she has a negative tuberculin 
skin test result within the 2 months before baseline, in which case he/she may be randomized 
without treatment for latent TB.
An assessment of all screening laboratory test results, clinical data, and concomitant medication 
data will be made by the principal investigator or designee to confirm that the subject satisfies all 
inclusion criteria and does not violate any exclusion criteria.
9.1.3.
Double-Blind Treatment Period
In Part I, the visit window should be ±4 days for each visit. In Part II, the visit window should be 
±4 days, from the Week 0 visit up to and including the Week 12 visit, and ±7 days from Week 16 


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until the end of the study. Procedures to be performed at each visit are outlined in the Time and 
Events Schedules (Table 1, Table 2). Unless otherwise specified, all procedures are to be 
conducted before study agent administration.
Study agent should not be administered to a subject with a clinically important, active infection.
Each subject must be instructed to complete the CDAI diary card daily during the study, except 
during the Part II LTE.
9.1.4.
Final Efficacy and Safety Follow-up Visit
Subjects in Part I should complete the final efficacy and safety follow-up visit approximately 16
weeks after the last study agent administration (Table 1). Subjects in Part II who are not 
continuing into the Part II LTE should complete the final efficacy and safety follow-up visit 
approximately 16 weeks after receiving the last dose of study drug (Table 2). Subjects in the 
Part II LTE should complete the final safety follow-up visit approximately 16 weeks after 
receiving the last dose of study drug (Table 3). Subjects in the Part II LTE on ustekinumab after 
unblinding will not require a safety follow-up visit. Placebo subjects who remain in the Part II
LTE at the time of study unblinding will have their final safety follow-up visit subsequent to 
unblinding and will be discontinued from the study.
9.2.
Efficacy Evaluations
The CDAI will be the primary tool for assessing disease activity response to JNJ-64304500, 
along with PRO-2, PRO-3, Bristol stool form scale, abdominal pain based on NRS 0-10 scale, 
PGIS of Crohn’s disease, and PGIC of severity of Crohn’s disease. The degree of inflammation 
will be assessed by measuring serum CRP concentrations. Stool samples will be collected and 
analyzed to evaluate changes in markers that may reflect JNJ-64304500 or ustekinumab 
treatment. The well-being of subjects will be measured using the IBDQ and the SF-36. 
Endoscopic improvement will be assessed by ileocolonoscopy. For subjects with fistulizing 
disease, fistula closure will also be assessed.
9.2.1.
Crohn’s Disease Activity Index
The CDAI will be assessed by collecting information on 8 different Crohn’s disease-related 
variables (Attachment 4):1 extra-intestinal manifestations, abdominal mass, weight, hematocrit, 
total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or 
opiates, and general well-being. The last 4 variables are scored over 7 days by the subject on a 
diary card. The PRO-2 score is based on the CDAI components of the total number of liquid 
stools and abdominal pain/cramping. The PRO-3 score, which is also based on the CDAI,
comprises the PRO-2 components plus general well-being. Subjects are to complete a daily diary 
entry and bring the diary to each visit.
9.2.2.
Bristol Stool Form Scale
The Bristol stool form scale is a medical aid to classify the form (or consistency) of human feces
into 7 categories.8 It has been used as a research tool to evaluate the effectiveness of treatments 


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for various diseases of the bowel (eg, irritable bowel syndrome).4 Subjects will complete the 
Bristol stool form scale as a daily diary entry and bring the diary to each visit up to Week 12.
9.2.3.
Abdominal Pain Numerical Rating Scale
The NRS for pain is a unidimensional measure of pain intensity in adults.5 An 11-point (0-10) 
NRS will be used to evaluate abdominal pain. The score of 0 represents “no abdominal pain” and 
the score of 10 represents the “worst possible abdominal pain”, with greater scores indicating 
greater pain severity and intensity. Subjects will select only one number that best reflects their 
pain at its worst in the past 24 hours. The abdominal pain NRS will be assessed daily. Subjects 
will complete the NRS at approximately the same time each day before going to bed and bring 
the diary to each visit.
9.2.4.
Patient’s Global Impression of Severity of Crohn’s Disease
The PGIS of Crohn’s disease is a 5-point scale (“None”, “Mild”, “Moderate”, “Severe” and 
“Very Severe”) to rate Crohn’s disease intensity. Subjects will rate their PGIS of Crohn’s disease
at Weeks 0, 4, 8, 12, and 24.
9.2.5.
Patient’s Global Impression of Change of Severity of Crohn’s Disease
The PGIC of severity of Crohn’s disease is a 7-point scale ranging from “a lot better now” to “a 
lot worse now” with a neutral center point (“neither better nor worse”) to measure perceived 
change (improvement or deterioration) in severity of Crohn’s disease. Subjects will assess their 
PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.
9.2.6.
C-Reactive Protein
C-reactive protein has been demonstrated to be useful as a marker of inflammation in patients 
with inflammatory bowel disease (IBD). In Crohn’s disease, elevated CRP concentrations have 
been associated with severe clinical activity, elevated sedimentation rate, and active disease as 
detected by colonoscopy.10,11 Blood samples for the measurement of CRP will be collected from 
all subjects at visits indicated in the Time and Events Schedule. CRP will be assayed using a 
validated, high sensitivity CRP assay. Results of postbaseline CRP measurement will not be 
released to the investigators by the central laboratory.
9.2.7.
Fecal Lactoferrin and Calprotectin
Fecal lactoferrin and fecal calprotectin have been demonstrated to be sensitive and specific 
markers in identifying intestinal inflammation and response to treatment in patients with IBD.2,3,7
Stool samples for fecal lactoferrin and calprotectin concentrations will be collected from all 
subjects at visits indicated in the Time and Events Schedules. Assays for fecal lactoferrin and 
calprotectin concentrations will be performed using a validated method. Additional tests may 
also be performed on the stool samples for additional markers related to intestinal inflammation 
and treatment response such as the microbiome. Results of postbaseline fecal lactoferrin and 
calprotectin tests will not be released to the investigators by the central laboratory.


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9.2.8.
Inflammatory Bowel Disease Questionnaire
The IBDQ6 is a 32-item self-report questionnaire for subjects with IBD to evaluate the PROs 
across 4 dimensions: bowel symptoms (loose stools, abdominal pain), systemic symptoms 
(fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), 
and emotional function (anger, depression, irritability). Scores range from 32 to 224 with higher 
scores indicating better outcomes.
9.2.9.
36-Item Short Form Health Survey
The SF-36 was developed to measure the general health status with 8 functional domain scales.

Limitations in physical functioning due to health problems.

Limitations in usual role activities due to physical health problems.

Bodily pain.

General mental health (psychological distress and well-being).

Limitations in usual role activities due to personal or emotional problems.

Limitations in social functioning due to physical or mental health problems.

Vitality (energy and fatigue).

General health perception.
Based on the 8 scale scores, the PCS and the MCS can be derived. The scale scores and summary 
scores are converted into a score from 0 to 100 using a norm-based system where linear 
transformations are performed to transform scores to a mean of 50 and standard deviations (SD)
of 10, based on general US population norms.12 The concepts measured by the SF-36 are not 
specific to any age, disease, or treatment group, allowing comparison of relative burden of 
different diseases and the relative benefit of different treatments.13
9.2.10.
Fistula Assessment
Subjects will be assessed for fistulas. For subjects with fistulizing disease, fistula closure will be 
assessed. Enterocutaneous fistulas (eg, perianal and abdominal) will be considered no longer 
draining (ie, closed) when there is absence of drainage despite gentle compression. Rectovaginal 
fistulas will be considered closed based on either physical examination or absence of relevant 
symptoms (eg, passage of rectal material or flatus from the vagina).
9.2.11.
Endoscopic Endpoints
Endoscopic improvement will be assessed during endoscopy (ileocolonoscopy). A video 
ileocolonoscopic examination will be performed to determine the presence or absence of 
mucosal inflammation and ulceration at screening and Week 12, and Week 24 (optional in 
Part I), according to the Study Reference Manual provided to each site; if the video 
ileocolonoscopic examination is not performed on the day of the visit, it must be performed at 
least 8 days before the Week 0 visit and no more than 8 days before the Week 12 visit. The 
Week 24 video ileocolonoscopy in Part I is suggested but not required; if performed, it should 


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occur not more than 8 days before the Week 24 visit. The video ileocolonoscopy will not be 
performed at Week 24 in Part II. Video endoscopies will be assessed by a central facility that 
will be blinded to treatment group and study visit. A complete video endoscopic examination 
does not require assessment of the terminal ileum if it cannot be visualized.
The SES-CD score is based on the evaluation of 4 endoscopic components (presence/size of 
ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface affected 
by any other lesions, and presence/type of narrowing/strictures) across 5 ileocolonic segments. 
Each endoscopic component is scored from 0 to 3 for each segment, and a total score is derived 
from the sum of all the component scores (range, 0 to 56). The SES-CD score will be evaluated 
by a central reader.
In addition to the evaluation of the SES-CD score, endoscopic healing, which is traditionally 
defined as the resolution (absence) of mucosal ulcers in response to a therapeutic intervention, 
will also be assessed by the central reader.
9.2.12.
Histologic Assessment
Histologic assessment will be performed using biopsy samples collected during endoscopy. 
Biopsy samples will be collected at screening, Week 12, and Week 24 from each of 3 predefined 
anatomic locations: the terminal ileum, splenic flexure, and rectum. The biopsy samples 
collected at Week 12 and Week 24 will be obtained near where the biopsy samples at screening 
were collected from each of the 3 predefined locations. Histologic assessment will be conducted 
by a central reader who is blinded to treatment groups. The GHAS will be used to evaluate 
histologic improvement. Additional details will be provided in the Study Reference Manual.
9.3.
Pharmacokinetics and Immunogenicity Evaluations
9.3.1.
Evaluations
Serum samples used to evaluate the PK and immunogenicity of JNJ-64304500 and ustekinumab 
(antibodies to JNJ-64304500 and antibodies to ustekinumab) will be collected according to the 
Time and Events Schedules. Samples collected for analyses of serum concentration of 
JNJ-64304500 and ustekinumab and antibodies to JNJ-64304500 or ustekinumab may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period, for further characterization of immunogenicity or for the evaluation of 
relevant biomarkers. Genetic analyses will not be performed on these serum samples. Subject 
confidentiality will be maintained. The exact dates and times of sample collection must be 
recorded on the laboratory requisition form.
At visits where only serum concentration of study agent will be evaluated (ie, no antibodies to 
study agent will be evaluated), 1 venous blood sample of sufficient volume should be collected, 
and each serum sample should be divided into 2 aliquots (1 for serum concentration of study 
agent, and a back-up). At visits where serum concentration of study agent and antibodies to study 
agent will be evaluated, 1 venous blood sample of sufficient volume should be collected. Each 


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serum sample will be divided into 3 aliquots (1 each for serum concentration of study agent,
antibodies to study agent, and a back-up).
9.3.2.
Serum Concentration
Serum samples will be analyzed to determine concentrations of JNJ-64304500 and ustekinumab 
using a validated, specific, and sensitive method by or under the supervision of the sponsor.
9.3.3.
Immunogenicity Assessments (Antibodies to Study Agent)
The detection and characterization of antibodies to JNJ-64304500 and ustekinumab will be 
performed using a validated assay method by or under the supervision of the sponsor. All 
samples collected for detection of antibodies to JNJ-64304500 or ustekinumab will also be 
evaluated for JNJ-64304500 or ustekinumab serum concentration to enable interpretation of the 
antibody data.
Serum samples will be screened for antibodies binding to JNJ-64304500 or ustekinumab and the 
titer of confirmed positive samples will be reported. Other analyses may be performed to verify 
the stability of antibodies to JNJ-64304500 or ustekinumab and/or further characterize the 
immunogenicity of JNJ-64304500 or ustekinumab. Antibodies to JNJ-64304500 or ustekinumab 
will be evaluated on blood drawn from all subjects according to the Time and Events Schedule. 
Additionally, samples should also be collected at the final visit for subjects who terminate from 
the study. These samples will be tested by the sponsor or sponsor's designee.
9.4.
Biomarker and Other Pharmacodynamic Evaluations
Biomarker assessments will be made to examine the biological response to treatment and to 
identify biomarkers that are relevant to JNJ-64304500 treatment and/or Crohn’s disease. 
Assessments will include the evaluation of relevant biomarkers in serum, whole blood, stool, and 
mucosal biopsy samples collected according to the Time and Events Schedule.
9.4.1.
Serum-based Biomarkers
Blood samples for serum-based biomarker analyses will be collected from all subjects. Assays to 
be performed may include the following: measurement of proteins associated with the NKG2D 
pathway, including but not limited to, MICA, MICB, and UBPs 1-6, as well as proteins 
associated with Crohn’s disease such as serum amyloid A, interferon gamma, or matrix 
metalloproteinases.
9.4.2.
Whole Blood-based Biomarkers
Whole blood samples will be collected from all subjects to study the effect of study agent on 
RNA expression. Whole blood analyses may also examine RNA expression associated with the 
pathogenesis of Crohn’s disease. An additional blood sample will be obtained for analysis of the 
T-cell receptor repertoire.


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9.4.3.
Biopsy-based Biomarkers
Mucosal biopsy samples will be collected during video ileocolonoscopy to study the effect of 
study agent on gene and protein expression and for the histologic assessment of disease and 
healing (refer to Study Reference Manual for further details). Mucosal biopsy analyses may also 
examine gene and protein expression associated with the pathogenesis of Crohn’s disease.
9.4.4.
NKG2D Receptor Occupancy
NKG2D RO assessments will be performed at the time points specified in the Time and Events 
Schedule. NKG2D RO will be determined using a validated flow cytometry assay.
9.4.5.
Immunophenotyping
Immunophenotyping assessments (including NK cells and CD8+ T cells) will be performed at 
the time points specified in the Time and Events Schedule. Immunophenotyping will be 
performed using flow cytometry.
9.5.
Pharmacogenomic (DNA) Evaluations
All subjects will be tested for the NKG2D SNP rs2255336 and the MICB (NKG2D ligand) SNP 
rs2239705 at screening. For subjects who have signed a separate ICF, complete genomic testing 
will be done to search for links of specific genes to disease or response to drug. Only DNA 
research related to JNJ-64304500 or ustekinumab or to the diseases for which this drug is 
developed will be performed. A 10 mL blood sample will be collected from all subjects for this 
testing; in the event of DNA extraction failure, a replacement pharmacogenomic blood sample 
will be requested from the subject.
Further, a subject may withdraw his/her optional DNA consent for complete genomic testing at 
any time without affecting their participation in other aspects of the study, or their future 
participation in the study.
9.6.
Medical Resource Usage
Crohn's disease-related hospitalizations and Crohn’s disease-related surgeries will be collected in 
the study.
9.7.
Safety Evaluations
Details regarding the DMC are provided in Section 11.11.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedules:


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Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the Adverse Event section of the CRF. Clinical hematology and 
chemistry laboratory test results will be graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) toxicity criteria. The laboratory reports 
must be filed with the source documents.
The following tests will be performed by the central laboratory unless otherwise specified or 
approved by the medical monitor:

Hematology assessments: hematocrit, hemoglobin, platelet count, total and differential 
white blood cell count.

Blood chemistry assessments: ALT, AST, alkaline phosphatase, albumin, total and direct 
bilirubin, blood urea nitrogen, calcium, chloride, creatinine, phosphate, potassium, total 
protein, and sodium.
A medical monitor or delegate and the clinical site will be notified if prespecified abnormal 
laboratory values defined in the Laboratory Manual are identified in any subject during the 
conduct of the study.

Pregnancy testing: Female subjects of childbearing potential will undergo a serum β-hCG 
pregnancy test at screening, and a urine pregnancy test before each study agent 
administration visit, at an early termination visit, and at the final efficacy and safety visit.

Serology (HIV antibody, HBsAg, and HCV antibody)

Abnormal liver function tests: If laboratory testing for a subject randomized in the study 
and receiving study drug reveals an increase of serum aminotransferases (ALT or AST) to 
>3x the ULN and an increase of bilirubin to >2x ULN, study agent should be suspended 
immediately. In addition, laboratory tests for ALT, AST, alkaline phosphatase, and total 
bilirubin should be confirmed by a retest within 24 hours if possible, but no later than 
72 hours following notification of test results. See Attachment 5 (Liver Safety Monitoring 
and Assessment) for additional information on monitoring and assessment of abnormal liver 
function tests.
Electrocardiogram (ECG)
A 12-lead ECG will be performed at screening.


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Vital Signs
Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure will be 
collected at all study visits before and 30 minutes after each SC study agent administration. In 
Part II, vital signs will also be measured at Week 0 before the IV infusion, approximately every 
30 minutes during the infusion, and twice after completion of the infusion (at approximately 
30-minute intervals).
Physical Examination
Physical examinations will be performed as specified in the Time and Events Schedules. Height 
and weight will be recorded at screening; weight will also be recorded at timepoints specified in 
the Time and Events Schedules.
Early Detection of Active Tuberculosis
To aid in the early detection of TB reactivation or new TB infection during study participation, 
subjects must be evaluated for signs and symptoms of active TB at scheduled visits (refer to 
Time and Events Schedule). The following series of questions is suggested for use during the 
evaluation:

“Have you had a new cough of >14 days’ duration or a change in a chronic cough?”

“Have you had any of the following symptoms:

Persistent fever?

Unintentional weight loss?

Night sweats?”

“Have you had close contact with an individual with active TB?” (If there is uncertainty as 
to whether a contact should be considered “close,” a physician specializing in TB should be 
consulted.)
If the evaluation raises suspicion that a subject may have TB reactivation or new TB infection, 
an immediate investigation should be undertaken, including, where possible, consultation with a 
physician specializing in TB.
Investigators should be aware that TB reactivation in immunocompromised subjects may present 
as disseminated disease or with extrapulmonary features. Subjects with evidence of active TB 
must discontinue further study agent administrations and should be referred for appropriate 
treatment.
Subjects who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QuantiFERON-TB test, a repeat 
tuberculin skin test in countries in which the QuantiFERON-TB test is not approved/registered, 
and, if possible, referral to a physician specializing in TB to determine the subject’s risk of 
developing active TB and whether treatment for latent TB is warranted. A tuberculin skin test is 
recommended but not required for study centers in countries where tuberculin is not available. A 
positive QuantiFERON-TB (or tuberculin skin) test result should be considered detection of 
latent TB. If the QuantiFERON-TB test result is indeterminate, the test should be repeated as 


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outlined in Section 9.1.2. If recommended, treatment for latent TB must be initiated before or 
simultaneously with the administration of further study agent. Subjects who discontinue 
treatment for latent TB prematurely or who are noncompliant with therapy must immediately 
discontinue further administration of study agent and be encouraged to return for all subsequent 
scheduled study visits.
Concomitant Medication Review
Concomitant medications will be reviewed at each visit.
Infusion Reactions
An infusion reaction (Part II of the study) is defined as an AE that occurs during or within 1 hour 
after the infusion of study agent, with the exception of laboratory abnormalities. Minor infusion 
reactions may be managed by slowing the rate of the IV infusion and/or treating with 
antihistamines and/or acetaminophen (paracetamol) as clinically indicated. If an IV infusion of 
study agent is stopped because of an infusion reaction and the reaction, in the opinion of the 
investigator, is not severe or does not result in a serious adverse event (SAE; Section 12.3.2), the 
infusion may be restarted with caution.
Injection-Site Reaction
An injection-site reaction (in Part I or Part II) is any adverse reaction at an SC study agent 
injection-site. Injection sites will be evaluated for reactions and any injection-site reactions will 
be recorded as an AE.
Allergic Reactions
Before any SC injection or IV infusion, appropriately trained personnel and medications must be 
available to treat allergic reactions, including anaphylaxis. Appropriate medical personnel must 
be in attendance at the time of the injection or infusion and for at least 30 minutes after the SC 
injection or for at least 1 hour after the start of the IV infusion.
Appropriate medical personnel must remain in close proximity to the infusion center for the 
remaining duration of the infusion, and for 1 hour after the end of the infusion in the event that 
emergency resuscitation is required. All subjects must be observed carefully for symptoms of an 
allergic reaction (eg, urticaria, itching, hives).
If a mild or moderate allergic reaction is observed, acetaminophen, nonsteroidal anti-
inflammatory drugs (NSAIDs), and/or diphenhydramine may be administered. In the case of a 
severe allergic reaction (eg, anaphylaxis), SC aqueous epinephrine, corticosteroids, respiratory 
assistance, and other proper resuscitative measures are essential and must be available at the 
study site where the injections or infusions are being given.
For severe reactions related to an injection or infusion, the subject may be permanently 
discontinued from further study injections at the discretion of the investigator (Section 10.2).


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Subjects who experience serious adverse reactions related to an injection or infusion should be 
discontinued from further study agent administrations (Section 10.2).
Subjects who experience reactions after an injection or infusion (Part II) that result in 
bronchospasm with wheezing and/or dyspnea that requires ventilatory support OR that 
result in symptomatic hypotension with a decrease in systolic blood pressure >40 mm Hg or 
blood pressure <90/60 mm Hg will not be permitted to receive additional study agent.
Infections
Study agent administration should not be given to a subject with a clinically important, active 
infection. Investigators are required to evaluate subjects for any signs or symptoms of infection, 
and also review subjects’ diary cards for signs of infection, at scheduled visits (see Time and 
Events Schedule). If a subject develops a serious infection, including but not limited to sepsis or 
pneumonia, discontinuation of study treatment (ie, no further study agent administrations) must 
be considered.
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
Main Study Phase (Part I and Part II)
A subject will be considered to have completed the study if he or she has completed assessments 
through the final efficacy and safety visit (ie, Week 38 in Part I and Week 36 in Part II), as 
specified in the Time and Events Schedules for Part I or Part II.
Subjects who prematurely discontinue study treatment for any reason can be considered to have 
completed the study if they have completed scheduled assessments as follows:

Subjects who discontinue study agent in Part I before Week 8 should return for the Week 8 
and Week 12 visit and a final efficacy and safety follow-up visit, which should occur 
16 weeks after receiving the last dose of study drug.


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
Subjects who discontinue study agent at or after Week 8 in Part I should complete the 
Week 12 and Week 24 visits and a final efficacy and safety follow-up visit, which should 
occur 16 weeks after receiving the last dose of study drug.

Subjects who discontinue study agent in Part II before Week 12 should return for the 
Week 12 visit and a final efficacy and safety follow-up visit, which should occur 16 weeks 
after receiving the last dose of study drug.

Subjects who discontinue study agent at or after Week 12 in Part II should complete the 
Week 24 visit and a final efficacy and safety follow-up visit, which should occur 16 weeks 
after receiving the last dose of study drug.
The final efficacy and safety follow-up visit for subjects who discontinue study agent is 
approximately 16 weeks after the last administration of study agent in both Part I and Part II.
Long-term Extension Phase
A subject will be considered to have completed the LTE phase of the study if he or she has 
completed the final safety follow-up visit in the Part II LTE.
The final safety follow-up visit will occur approximately 16 weeks after last study agent 
administration for all subjects who received JNJ-64304500 or ustekinumab. Following the study 
unblinding, any remaining ustekinumab subjects in the LTE (in countries were ustekinumab is 
not commercially available) will not have a final safety visit due to the well-known safety profile 
of ustekinumab. If the investigator decides that the patient should continue ustekinumab 
treatment after completing the Part II LTE, the investigator or the subject’s treating physician is 
responsible for providing the subject with commercial ustekinumab, which should be 
administered according to the approved dosing regimen in each country.
Subjects who received placebo will be considered to have completed the extension phase of the 
study if they complete 52 weeks of the Part II LTE and complete the final safety follow-up visit 
in the Part II LTE before study unblinding or if they have been discontinued from the study prior 
to the final safety visit due to study unblinding. After unblinding of the Part II Week 24 data, 
subjects who received placebo during the Part II LTE will have their final safety follow-up visit 
at the time of study unblinding and will then be discontinued from the study. Subjects who 
prematurely discontinue study treatment for any reason, other than study unblinding, before 
completion of the study extension will not be considered to have completed the extension phase 
of the study.
10.2.
Discontinuation of Study Treatment
A subject's study treatment must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, AE), it is in the 
best interest of the subject to discontinue study treatment.

The subject becomes pregnant or plans a pregnancy within the study period or within 
16 weeks after the last study agent administration.


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
The subject is deemed ineligible according to the following TB screening criteria:

A diagnosis of active TB is made.

A subject has symptoms suggestive of active TB based on follow-up assessment 
questions and/or physical examination, or has had recent close contact with a person 
with active TB, and cannot or will not continue to undergo additional evaluation.

A subject undergoing continued evaluation has a chest radiograph with evidence of 
current active TB and/or a positive QuantiFERON-TB test result and/or a positive 
tuberculin skin test result in countries in which the QuantiFERON-TB is not 
approved/registered (recommended but not required for study centers in countries where
tuberculin is not available) unless active TB can be ruled out and appropriate treatment 
for latent TB can be initiated either prior to or simultaneously with the next 
administration of study agent and continued to completion. (Note: Study agent must be 
discontinued for all subjects diagnosed with latent TB in countries with high 
multidrug-resistant TB burden [eg, Brazil, China, India, the Russian Federation, and 
South Africa]).

A subject receiving treatment for latent TB discontinues this treatment prematurely or is 
noncompliant with the therapy.

A serious adverse reaction occurs that is related to an injection or an infusion, including an 
injection-site or infusion reaction, resulting in bronchospasm with wheezing and/or dyspnea 
that requires ventilatory support OR that results in symptomatic hypotension with a decrease 
in systolic blood pressure >40 mm Hg or blood pressure <90/60 mm Hg. This may include 
events of NCI-CTCAE toxicity grade ≥3.

Adverse events of NCI-CTCAE grade ≥3 will be evaluated by the investigator and the study 
medical monitor to make a determination on discontinuation of study agent. Discontinuation 
of study agent should be considered in subjects with worsening Crohn’s disease where 
continuation of the study drug is not in the best interest of the subject.

Malignancy including squamous cell skin cancer. Consideration may be given to allowing 
subjects who develop ≤2 basal cell skin cancers that are adequately treated with no evidence 
of residual disease to continue to receive study agent.

Total (complete) or partial (supplemental) parenteral nutrition is initiated through an 
indwelling catheter at any time during the study.

The initiation of the following protocol-prohibited medications at any time during the study:

Immunomodulatory agents other than 6-MP, AZA, or MTX (including but not limited 
to 6-TG, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, tofacitinib, and 
other JAK inhibitors).

Immunomodulatory biologic agents (including but not limited to TNF antagonists, 
natalizumab, abatacept, vedolizumab).

Experimental Crohn’s disease medications (including but not limited to thalidomide, 
briakinumab, traficet, AMG-827). Ustekinumab is permitted in Part II of this study only 
in subjects randomly assigned to ustekinumab and only as stipulated per protocol.

A systemic opportunistic infection.


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
Severe hepatic function abnormalities as described in Section 9.7.

The subject (or the subject’s representative) withdraws consent for administration of study 
agent.

Crohn’s disease-related surgeries that represent a lack of efficacy of study agent or will 
preclude the future ability to assess efficacy through the CDAI.

Note: Other permitted Crohn’s disease-related surgeries (eg, to resolve long-standing 
complications such as strictures or for symptomatic nonhealing fistulas, in subjects 
experiencing improvement on study agent) other than minor procedures (eg, placement of a 
seton or cutaneous drainage of an abscess) should be postponed until after the final efficacy 
and safety visit, unless necessary to ensure subject well-being and/or safety.
In the event of any serious infection, severe injection-site or infusion reaction, the study drug 
must be held and dosing may not be resumed until the investigator has discussed the case with 
the study medical monitor.
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
treatment before the end of the treatment regimen. If a subject discontinues study treatment for 
any reason before the end of the treatment period, assessments should be obtained as specified in 
Section 10.1.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Sponsor decision (eg, participating in any other clinical study with an investigational agent)
Subjects who terminate study participation will not be required to return for any follow-up 
assessments; however, these subjects should complete the safety and efficacy evaluations 
specified for the Early Termination Visit in the appropriate Time and Events Schedule at the 
time they terminate study participation.
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 agent assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
10.4.
Withdrawal From the Use of Research Samples
A subject who withdraws from the study will have the following options regarding the optional
research samples:


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
The collected samples will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the samples
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research samples will be destroyed. The sample destruction process will 
proceed as described above.
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 main ICF and in the separate ICF for optional research samples.
10.5.
Withdrawal From Pharmacogenomic Research Only
The subject may withdraw from the optional consent for pharmacogenomic research related to 
the drug while remaining in the clinical study. As noted in Section 9.5, however, any testing to 
be performed on all subjects consented as part of the main study can only be withdrawn if the 
subject withdraws from the study. In the case of withdrawal from the optional 
pharmacogenomics testing and request for sample destruction, the investigator must notify the 
sponsor site contact to request sample destruction. The sponsor site contact will, in turn, contact 
the biomarker representative to execute sample destruction. If requested, the investigator will 
receive written confirmation from the sponsor that the sample has been destroyed.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the SAP.
Descriptive statistics (eg, mean, median, SD, interquartile range, minimum, and maximum) will 
be used to summarize continuous variables. Counts and percentages will be used to summarize 
categorical variables. Graphic data displays (eg, line plots) may also be used to summarize the 
data.
Analyses suitable for categorical data (eg, chi-square tests or Cochran-Mantel-Haenszel 
chi-square tests as appropriate) will be used to compare the proportions of subjects achieving 
selected endpoints (eg, clinical remission). In cases of rare events, Fisher’s exact test will be used 


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for treatment comparisons. Continuous response parameters will be compared using an analysis 
of variance or covariance (ANCOVA) model on the van der Waerden normal scores.
All statistical testing will be performed at a significance level of 0.05 (2-sided) unless otherwise 
specified. Nominal p-values will be displayed for all treatment comparisons.
11.1.
Sample Size Determination
Sample size calculations for Part I were determined by the power to detect a significant 
difference in the change from baseline in the CDAI score at Week 8 (primary endpoint for Part I)
between JNJ-64304500 and placebo using a 2-sample t-test. Sample size calculations for Part II 
were determined by the power to detect a dose-response signal for the change from baseline in 
CDAI at Week 12 (primary endpoint for Part II) using the Multiple Comparison Procedures with 
modeling techniques (MCP-Mod) method.
11.1.1.
Sample Size in Part I
Part I is powered based on the combined data from Study 1 and Study 2. Study 1 and Study 2 
were not individually powered to detect differences between JNJ-64304500 and placebo.
The assumptions for the sample size calculations in Part I were based on data from 
CNTO1275CRD3001 (a study conducted by the sponsor in subjects with Crohn’s disease who 
had failed or were intolerant to TNF-antagonist therapy) and CNTO1275CRD3002 (a study 
conducted by the sponsor in subjects with Crohn’s disease who had failed or were intolerant to 
corticosteroids or immunomodulators but who had not failed TNF-antagonist therapy). In 
CNTO1275CRD3001, the mean CDAI change from baseline at Week 8 was -25.1 (SD=91.41) 
and -78.7 (SD=91.79) for the placebo and ustekinumab 6 mg/kg groups, respectively. These 
assumptions incorporated the impact of 6% of subjects being noncompleters (in 
CNTO1275CRD3001). In CNTO1275CRD3002, the mean CDAI change from baseline at 
Week 8 was -66.3 (SD=97.81) and -116.3 (SD=102.88) for the placebo and ustekinumab 
6 mg/kg groups, respectively. These assumptions incorporated the impact of 4% of subjects 
being noncompleters (in CNTO1275CRD3002).
For Part I, assuming the mean CDAI change from baseline at Week 8 is -98 in the JNJ-64304500 
group and -46 in the placebo group with a common SD of 96 (these values are derived assuming 
1:1 ratio of Bio-IR and Bio-NF subjects), 60 subjects per treatment group (a total of 120 
subjects) will provide 84% power to detect a treatment difference between JNJ-64304500 and 
placebo at an overall Type 1 error of 0.05 (2-sided; Table 6).


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Table 6:
Power to detect a treatment difference and sample size combinations at an overall 
Type 1 error of 0.05 (2-sided) for Part I
Sample size per group
Placebo
JNJ-64304500
Difference
Power*
Mean change from baseline in CDAI score at Week 8
Based on data from CNTO1275CRD3001 and CNTO1275CRD3002 (assuming 1:1 of Bio-IR and Bio-NF 
subjects)
55
-46
-68
32
41%
55
-46
-78
42
62%
55
-46
-98
52
80%
55
-46
-108
62
92%
55
-46
-118
72
97%
60
-46
-68
32
44%
60
-46
-78
42
66%
60
-46
-98
52
84%
60
-46
-108
62
94%
60
-46
-118
72
98%
*Assuming a standard deviation of 96 (derived from CNTO1275CRD3001 and CNTO1275CRD3002) for each 
group. 
11.1.2.
Sample Size in Part II
The assumptions for the sample size calculations in Part II were based on the Part I Week 12 
analysis results. For Bio-IR subjects in Part I, the mean CDAI change from baseline at Week 12 
was -30.9 (SD=85.15) and -77.4 (SD=103.68) for the placebo and JNJ-64304500 groups, 
respectively. For Bio-NF subjects in Part I, the mean CDAI change from baseline at Week 12 
was -70.9 (SD=93.59) and -144.7 (SD=92.50) for the placebo and JNJ-64304500 groups, 
respectively.
For Part II, assuming the mean CDAI change from baseline at Week 12 is -111 in the 
JNJ-64304500 high dose group and -51 in the placebo group (these values are derived assuming
a 1:1 ratio of Bio-IR and Bio-NF subjects) with a common SD of 102, 50 subjects per treatment 
group will provide a mean power of 85% to detect a dose-response signal for the change from 
baseline in CDAI at Week 12 based on 7 candidate dose-response models (to be detailed in the 
SAP) at an overall Type 1 error rate of 0.05 (2-sided). Fifty subjects per treatment group will 
also provide 83% power to detect a treatment difference between the JNJ-64304500 treatment 
group with the highest dose and the placebo treatment group for change from baseline in CDAI 
at Week 12 based on a 2-sample t-test at a Type I error rate of 0.05 (2-sided; Table 7). This will 
result in a total sample size of 250 subjects in Part II (incorporating an additional 50 subjects for 
the ustekinumab treatment group).


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Table 7:
Power to detect a treatment difference and sample size combinations at an overall 
Type 1 error of 0.05 (2-sided) for Part II
Sample size per group
Placebo
JNJ-64304500 
high dose
Difference
Power*
Mean change from baseline in CDAI score at Week 12
Based on data from Part I (assuming 1:1 of Bio-IR and Bio-NF subjects)
45
-51
-91
40
45%
45
-51
-101
50
63%
45
-51
-111
60
79%
45
-51
-121
70
90%
45
-51
-131
80
96%
50
-51
-91
40
49%
50
-51
-101
50
68%
50
-51
-111
60
83%
50
-51
-121
70
92%
50
-51
-131
80
97%
*Assuming a standard deviation of 102 (based on JNJ-64304500 group at Week 12) for each group. 
11.2.
Efficacy Analyses
This protocol is comprised of 2 separate parts (Part I [Study 1: Bio-IR subjects and Study 2: Bio-NF 
subjects] and Part II [Bio-IR and Bio-NF subjects]). Part I and Part II will be analyzed separately 
with separate Type I error control for the primary endpoint (at the 0.05 level of significance). 
The other endpoints within each part will not be controlled for multiplicity.
For each part, the analysis set is all randomized subjects who received study agent. Efficacy 
analyses will be based on a modified intent-to-treat principle. Therefore, the efficacy data for 
each subject who received study agent will be analyzed according to the assigned treatment 
regardless of the actual treatment received.
11.2.1.
Part I
11.2.1.1.
Primary Endpoint Analysis
The primary endpoint for Part I is the change from baseline in the CDAI score at Week 8.
The change from baseline in the CDAI score will be compared between the JNJ-64304500 
treatment group and the placebo treatment group for all subjects in Part I. For the comparison, an 
ANCOVA model on the van der Waerden normal scores will be used with treatment as a fixed 
factor and baseline CDAI score, SNP-positive status (yes or no), and Bio-IR status (yes or no) as 
covariates. For this analysis, treatment failure rules and missing data rules as specified in 
Section 11.2.2.1 will be applied.
Part I will be considered to be positive if a significant improvement is detected in the change 
from baseline in the CDAI score at Week 8 in the JNJ-64304500 group compared with the 
placebo group at the 0.05 level of significance.


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11.2.1.2.
Other Efficacy Endpoint Analyses
The following endpoints will be compared between the JNJ-64304500 treatment group and the 
placebo treatment group for all subjects in Part I and by Bio-IR status (yes or no):

Change in CDAI from baseline at all postbaseline visits.

Clinical remission based on CDAI at all postbaseline visits.

Clinical response based on CDAI at all postbaseline visits.

Change in PRO-2 from baseline at all postbaseline visits.

Change in abdominal pain score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.

Change in stool frequency score (daily average based on the CDAI assessment) from 
baseline at all postbaseline visits.

Clinical remission based on PRO-2 at all postbaseline visits.

Clinical response based on PRO-2 at all postbaseline visits.

Change in PRO-3 from baseline at all postbaseline visits.

Clinical remission based on CDAI at Week 24 among subjects in clinical response at 
Week 12.

Clinical remission based on CDAI at Week 24 among subjects in clinical remission at 
Week 12.

Change in SES-CD score from baseline at Weeks 12 and 24.

Endoscopic improvement at Weeks 12 and 24 based on a reduction from baseline in 
SES-CD score ≥3.

At least 50% improvement from baseline in SES-CD at Weeks 12 and 24.

Endoscopic healing (defined as the absence of mucosal ulcerations) at Weeks 12 and 24.

Endpoint(s) for histologic assessment based on the GHAS (to be detailed in the SAP).

Fistula response at all postbaseline visits, defined as a ≥50% reduction from baseline in the 
number of draining fistulas.

Endpoint(s) based on Bristol stool form scale (to be detailed in the SAP).

Change in abdominal pain from baseline at all postbaseline visits based on a 0-10 NRS.

Change in IBDQ score from baseline at Weeks 8, 12, and 24.

Clinical remission based on IBDQ (≥170) at Weeks 8, 12, and 24.

A ≥16-point improvement in IBDQ from baseline at Weeks 8, 12, and 24.

Change from baseline in the PCS and MCS scores of the SF-36 at Weeks 8, 12, and 24.

A ≥5-point improvement in PCS or MCS scores of the SF-36 at Weeks 8, 12, and 24.


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
Change in biomarkers (CRP, fecal calprotectin, fecal lactoferrin) from baseline at Weeks 8, 
12, and 24.

Clinical remission based on CDAI at Week 12 by SNP status. Subjects who are positive in at 
least 1 of 2 SNPs (NKG2D or MICB) will be considered to be SNP-positive.
Other efficacy endpoints may be examined by SNP status (to be detailed in the SAP).
11.2.2.
Part II
11.2.2.1.
Primary Endpoint Analysis
The primary endpoint is the change from baseline in the CDAI score at Week 12.
A unified strategy that combines Multiple Comparison Procedures with modeling (MCP-Mod) 
techniques, will be used to analyze the dose-response relationship for the JNJ-64304500 doses 
(the efficacy measurement for the dose-response analysis is the change from baseline in the 
CDAI score at Week 12). This approach consists of 2 major steps. The first step consists of 
testing the dose-response signal via multiple contrast tests while controlling the overall Type 1 
error. If a dose-response signal is detected, the second step is to select a model that best describes 
the observed data and use it to estimate adequate doses with associated precision. The details of 
the dose-response analysis will be provided in the SAP.
Part II will be considered positive if a dose-response signal for the primary endpoint is detected.
In addition to the dose-response analysis, pairwise comparisons of the JNJ-64304500 treatment 
groups versus the placebo group will be performed for the change from baseline in the CDAI 
score at Week 12; these comparisons will not be adjusted for multiplicity. For these comparisons, 
an ANCOVA model on the van der Waerden normal scores will be used with treatment as a 
fixed factor and baseline CDAI score, SNP-positive status (yes or no), and Bio-IR status (yes or 
no) as covariates. Pairwise comparisons of the ustekinumab treatment group with the 
JNJ-64304500 treatment groups or with placebo are not planned; however, summary statistics 
will be provided for the ustekinumab treatment group.
For the analyses described above, subjects who meet 1 or more treatment failure rules before 
Week 12 will have their baseline value for the CDAI score carried forward to Week 12. Subjects 
who have any of the following events before the Week 12 visit will be considered to be treatment 
failures for the primary endpoint analysis, regardless of the actual CDAI score:

Specified changes in concomitant Crohn’s disease medications (to be detailed in the SAP).

A Crohn’s disease-related surgery (with the exception of drainage of an abscess or seton 
placement).

Discontinuation of study agent due to lack of efficacy or due to an AE of worsening Crohn’s 
disease.


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In addition, subjects who do not return for evaluation or have insufficient data to calculate their 
CDAI score at Week 12 (ie, <4 components of the CDAI are available) will have their last 
available CDAI score carried forward for Week 12.
To examine the robustness of the primary endpoint analysis, sensitivity analyses of the primary 
endpoint will be conducted using different missing data approaches; these analyses will be 
described in the SAP. In addition, sensitivity analyses excluding subjects who do not meet 
predefined threshold values of stool frequency and abdominal pain at study entry will be 
performed for the primary endpoint; the threshold values and analyses will also be described in 
the SAP.
To evaluate the consistency of the efficacy, subgroup analysis of the primary endpoint by Bio-IR 
status (yes or no) will be performed.
11.2.2.2.
Major Secondary Endpoint Analyses
The major secondary endpoints are:

Clinical remission at Week 12 as measured by CDAI (CDAI <150).

Clinical response at Week 12 as measured by CDAI (≥100-point reduction from baseline in 
CDAI or CDAI <150).

Change in PRO-2 from baseline at Week 12.

Clinical remission at Week 12 as measured by PRO-2 (PRO-2 <75).

Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from baseline in 
PRO-2 or PRO-2 <75).

Change in SES-CD from baseline at Week 12.
The major secondary endpoints of clinical remission and clinical response at Week 12 (defined 
by either CDAI or PRO-2) will be compared between each of the JNJ-64304500 treatment 
groups and the placebo group using the Cochran-Mantel-Haenszel chi-square test (2-sided) 
stratified by baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), and Bio-IR 
status (yes or no). In addition, for the endpoint of clinical remission at Week 12 as measured by 
CDAI, the MCP-MOD strategy will be used to examine the dose-response relationship for the 
JNJ-64304500 doses.
Subjects who meet 1 or more treatment failure rules (as specified for the primary endpoint) 
before Week 12 will be considered not to be in clinical remission or clinical response. Subjects 
who have a missing CDAI score (ie, <4 components of the CDAI score) at Week 12 will be 
considered not to be in clinical remission or clinical response, as measured by the CDAI score. 
Subjects who have a missing PRO-2 score (ie, at least one component score of the PRO-2 is 
missing) at Week 12 will be considered not to be in clinical remission or clinical response as 
measured by the PRO-2 score.
The change in PRO-2 from baseline at Week 12 will be compared between each of the 
JNJ-64304500 treatment groups and the placebo group using an ANCOVA model on the van der 


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Waerden normal scores with treatment as a fixed factor and baseline PRO-2 score, SNP-positive 
status (yes or no), and Bio-IR status (yes or no) as covariates.
Subjects who meet 1 or more treatment failure rules before Week 12 will have their baseline 
PRO-2 score carried forward to Week 12. Subjects who do not return for evaluation or who have 
a missing PRO-2 score at Week 12 will have their last available PRO-2 score carried forward to 
Week 12.
The change in SES-CD score from baseline at Week 12 will be compared between each of the 
JNJ-64304500 treatment groups and the placebo group using an ANCOVA model on the van der 
Waerden normal scores with treatment as a fixed factor and baseline SES-CD score, SNP-
positive status (yes or no), and Bio-IR status (yes or no) as covariates. Data-handling rules for 
the SES-CD score will be provided in the SAP.
For the major secondary endpoints, pairwise comparisons of the ustekinumab treatment group 
with the JNJ-64304500 treatment groups or with placebo are not planned; however, summary 
statistics will be provided for the ustekinumab treatment group.
Sensitivity analyses excluding subjects who do not meet predefined threshold values of stool 
frequency and abdominal pain at study entry will be performed for the major secondary 
endpoints; the threshold values and analyses will be described in the SAP.
To evaluate the consistency of the efficacy, subgroup analyses of the major secondary endpoints 
by Bio-IR status (yes or no) will be performed.
No adjustments for multiple comparisons will be made for the major secondary endpoints.
11.2.2.3.
Other Efficacy Endpoint Analyses
Comparisons between each of the JNJ-64304500 treatment groups and the placebo treatment 
group will also be made for each of the endpoints specified in Section 11.2.1.2 and for the 
following endpoints.

Change in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12 and 24.

A ≥1-point improvement in PGIS of Crohn’s disease from baseline at Weeks 4, 8, 12, 
and 24.

Improvement in PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.
Pairwise comparisons of the ustekinumab treatment group with the JNJ-64304500 treatment 
groups or with placebo are not planned for these endpoints, however summary statistics will be 
provided for the ustekinumab group.
11.3.
Pharmacokinetic Analyses
Descriptive statistics of the serum JNJ-64304500 and ustekinumab concentrations will be 
calculated at each sampling time point. Serum JNJ-64304500 and ustekinumab concentrations 
over time will be summarized for each treatment group.


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Concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics.
A population PK analysis approach for JNJ-64304500 using nonlinear mixed-effects modeling 
will be used to evaluate PK parameters. The influence of important covariates on the population 
PK parameter estimates may be evaluated. Details will be provided in a population PK analysis 
plan and the results of the population PK analysis will be presented in a separate technical report.
11.4.
Immunogenicity Analyses
The incidence and titers of antibodies to JNJ-64304500 and antibodies to ustekinumab will be 
summarized for all subjects who receive a dose of JNJ-64304500 or ustekinumab and have 
appropriate samples for detection of antibodies to JNJ-64304500 or antibodies to ustekinumab 
(ie, subjects with at least 1 sample obtained after their first dose of JNJ-64304500 or 
ustekinumab).
A listing of subjects who are positive for antibodies to JNJ-64304500 or ustekinumab will be 
provided. The maximum titers of antibodies to JNJ-64304500 or ustekinumab will be provided 
for subjects who are positive for antibodies to JNJ-64304500 or ustekinumab.
The incidence of neutralizing antibodies to JNJ-64304500 or ustekinumab will be summarized 
for subjects who are positive for antibodies to JNJ-64304500 or ustekinumab and have samples 
evaluable for neutralizing antibodies to JNJ-64304500 or ustekinumab.
11.5.
Biomarker Analyses
Biomarker analyses will characterize the effects of JNJ-64304500 on the measured biomarkers to 
identify biomarkers relevant to treatment and to determine if these biomarkers can predict 
response to JNJ-64304500. Biomarker analyses of ustekinumab will be performed as 
comparisons but not to identify novel biomarkers for ustekinumab.
Results of serum, whole blood analyses, stool, and mucosal biopsy analyses will be reported in 
separate technical reports.
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between serum concentrations of JNJ-64304500 and PD and/or clinical 
endpoints will be examined.
NKG2D RO (%) over time will be summarized for each treatment group.
The absolute numbers and percentages of peripheral blood NK cells and T cells (including CD4+ 
and CD8+) over time will be summarized for each treatment group.
11.7.
Pharmacogenomic Analyses
Exploratory genetic analyses on DNA collection from subjects who signed the optional DNA 
consent will be presented in a separate technical report.


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11.8.
Medical Resource Utilization
Crohn’s disease-related hospitalizations and Crohn’s disease-related surgeries will be 
descriptively summarized by treatment group.
11.9.
Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities. Treatment-emergent AEs are AEs with onset 
during the treatment phase or that are a consequence of a pre-existing condition that has
worsened since baseline. All reported treatment-emergent AEs will be included in the analysis. 
For each AE, the percentage of subjects who experience at least 1 occurrence of the given event 
will be summarized by treatment group.
The following analyses of AEs will be used to assess the safety of subjects:

The incidence and type of AEs.

The incidence and type of SAEs.

The incidence and type of reasonably related AEs.

The incidence and type of AEs leading to discontinuation of study agent.

The incidence and type of infections.

The incidence and type of infusion or injection-site reactions.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue study agent due to an AE, or who experience a severe or a 
serious AE.
Clinical Laboratory Tests
The following summaries of clinical laboratory tests will be used to assess the safety of subjects:

Laboratory parameters and change from baseline in laboratory parameters (hematology and 
chemistry).

Summary of maximum NCI-CTCAE toxicity grade for postbaseline laboratory values
(hematology and chemistry).
Listings of subjects with any abnormal postbaseline laboratory values of CTCAE grade ≥2 will 
also be provided.
11.10. Interim Analysis
An interim analysis is planned in Part I when 100 randomized subjects (Study 1: Bio-IR and 
Study 2: Bio-NF) have completed their Week 12 visit or have terminated their study participation
before Week 12. This interim analysis will allow for uninterrupted patient enrollment through a 
seamless transition from Part I to Part II of the trial. As this interim analysis does not affect the 


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conduct or completion of Part I, it will be considered administrative and will not require 
multiplicity adjustment for the final Part I analysis.
The primary efficacy evaluation is the comparison between JNJ-64304500 and placebo with 
respect to the change in CDAI from baseline (in the combined Bio-IR and Bio-NF subjects). 
Other selected efficacy analyses (eg, clinical remission, clinical response, and change in 
SES-CD) will also been performed; details will be provided in the Interim Analysis Plan.
A sponsor committee independent of the study team will be established to review the interim 
data and formulate recommended decisions/actions in accordance with predefined decision rules
that will be defined in the Interim Analysis Plan.
11.11. Data Monitoring Committee
An external DMC will be established to monitor safety data on an ongoing basis to ensure the 
continuing safety of the subjects randomized in Part I and Part II. The committee will meet 
periodically to review interim data. After the review, the DMC will make recommendations 
regarding the continuation of these studies. The details will be provided in a separate DMC
charter.
The DMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one 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 in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE 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]).


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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 AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For JNJ-64304500 and for ustekinumab, the expectedness 
of an adverse event will be determined by whether or not it is listed in the IB for JNJ-64304500 
or for ustekinumab, respectively.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
Adverse Events Associated with the Study Population
Anticipated events will be recorded and reported as described in Attachment 6.


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12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE 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 AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE 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 AE 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
as outlined in Section 12.1.3.1 and by NCI-CTCAE toxicity grade outlined in Section 12.1.3.2.
12.1.3.1.
Severity Criteria: 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).
Note: Seriousness and severity should not be confused. A subject could experience a severe 
headache that would not qualify as a SAE, while another might experience a mild stroke that, 
while not severe, would be considered serious.


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12.1.3.2.
Severity Criteria Based on National Cancer Institute Common 
Terminology Criteria for Adverse Events Toxicity Grade
An assessment of severity grade will also be made using the following NCI-CTCAE categorical 
descriptors. The NCI-CTCAE Grade refers to the severity of the AE. The NCI-CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2:
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
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

Accidental or occupational 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)

Exposure to a sponsor study drug from breast-feeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of an 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 AEs and special reporting situations, whether serious or nonserious, will be reported from the 
time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure, which may include contact for follow-up of safety. Serious AEs, including those 
spontaneously reported to the investigator within 16 weeks after the last dose of study drug, must 
be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
this protocol.
All events that meet the definition of an 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 6.
All AEs, 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 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all SUSARs. The investigator (or sponsor where required) must report SUSARs 
to the appropriate 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, subjects must be provided 
with a "wallet (study) card" and instructed to carry this card with them for the duration of the 
study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind


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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 Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an 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 an 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 an SAE, except hospitalizations 
for the following:

Social reasons in the absence of an AE.

Hospitalizations not intended to treat an acute illness or AE (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 AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
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 


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abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs 
and must be reported using the Serious Adverse Event Form. Any subject who becomes pregnant 
during the study must discontinue further study treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.3.4.
Events of Special Interest
Any newly identified malignancy or case of active TB occurring after the first administration of 
study agent in subjects participating in this clinical study must be reported by the investigator 
according to the procedures in Section 9.1.2. Investigators are also advised that active TB is 
considered a reportable disease in most countries. These events are to be considered serious only 
if they meet the definition of an SAE.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an 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.


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13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
In Part I and Part II, the JNJ-64304500 supplied for this study is a lyophilized drug product 
which, upon reconstitution with 1.1 mL of water for injection, contains 100 mg/mL 
JNJ-64304500 in 34 mM L-histidine, 8.6% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, pH 
6.0 in a 10 mL glass vial. It will be manufactured and provided under the responsibility of the 
sponsor. Refer to the IB for a list of excipients.
Placebo for JNJ-64304500 consists of a 9 mL solution of 34 mM L-histidine, 8.6% (w/v) sucrose, 
and 0.03% (w/v) polysorbate 80, pH 6.0 in a 10 mL glass vial.
In Part II, ustekinumab 5 mg/mL final vialed product for IV infusion and placebo to match will be 
supplied as a single-use, sterile solution in 30 mL vials with 1 dose strength (ie, 130 mg in 26 mL 
nominal volume).
Ustekinumab SC will be supplied as a sterile solution in a single-use prefilled syringe (PFS) at a 
volume of 1 mL (90 mg dose) that contains ustekinumab 90 mg, L-histidine, L-histidine 
monohydrochloride monohydrate, sucrose, and polysorbate 80 at pH 6.0 in 1.0 mL nominal 
volume. No preservatives are present. The needle cover on the PFS contains dry natural rubber 
(a derivative of latex), which may cause allergic reactions in individuals sensitive to latex. Liquid 
placebo will be supplied in a 1 mL PFS.
Placebo administrations will have the same appearance as the respective JNJ-64304500 or 
ustekinumab administrations.
14.2.
Packaging
The investigational supplies will be uniquely packaged to assure that they are appropriately 
managed throughout the supply chain process.
The study drug will be packaged in individual subject kits. Each kit will consist of one vial or 
one PFS of study agent packaged inside a protective outer carton. Each carton will be uniquely 
labeled with a medication identification number.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study drug must be stored at controlled temperatures ranging from 2°C to 8°C (36°F to 46°F).


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Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
14.5.
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 study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes, and vials containing 
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. The immediate destruction of these drug supplies 
should be documented in the drug accountability records on-site.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Site File (includes protocol and IB)

Investigational Product Binder

Central Laboratory Manual

CRF completion instructions

Patient recruitment materials

Subject study information

Informed consent form

CDAI diary


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
Bristol stool form scale diary

Abdominal pain NRS diary

IWRS Manual

Worksheets for data collection
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 AEs of the study, and provide their consent voluntarily will be randomized.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of the 
American Red Cross (1 pint/473 mL of blood for donation).
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials


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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs 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


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For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her Crohn’s disease. Subjects 
will be told that alternative treatments are available if they refuse to take part and that such 
refusal will not prejudice future treatment. Finally, they will be told that the investigator will 
maintain a subject identification register for the purposes of long-term follow-up if needed and 
that their records may be accessed by health authorities and authorized sponsor personnel
without violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF, the subject is authorizing such access, and agrees to 
allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for consent to provide optional samples for research where local 
regulations permit). After informed consent for the study is appropriately obtained, the subject 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the subject.


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Subjects must be able to read and write and give informed consent without assistance. A subject 
who is unable to read or write is not eligible to participate in the study.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects randomized in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, PD, biomarker, PK, and immunogenicity 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-64304500 and 
ustekinumab, to understand Crohn’s disease, to understand differential drug responders, and to 
develop tests/assays related to JNJ-64304500 and ustekinumab and Crohn’s disease. 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 10.4, Withdrawal From the Use of Research Samples).


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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 if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for 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 changes involve only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 


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protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.


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17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of
AEs; 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.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study 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).
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 an electronic source is utilized, references made to the CRF 
in the protocol include the electronic source system but information collected through the 
electronic source 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 prepared and provided by the sponsor for each subject in electronic format.
All data relating to the study must be recorded in the CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.


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The study data will be transcribed by study site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to 
a CRF are needed after the initial entry into the CRF, this can be done in either of the following
ways:

Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory 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 CRF 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 CRF 
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, as allowed by 
local regulation. 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 CRF with the 
source documents (eg, hospital/clinic/physician’s office medical records). The nature and 
location of all source documents will be identified to ensure that all sources of original data 
required to complete the 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 documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study site personnel. The sponsor expects that, during 
monitoring visits, the relevant study site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study site personnel will be available to provide an update on the progress 
of the study at the site.


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17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last efficacy and safety follow-up visit for the last 
subject participating in the study. The final data from the study site will be sent to the sponsor
(or designee) after completion of the final subject visit at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. 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-64304500 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 pharmacogenomic or exploratory biomarker


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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-64304500, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. 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.


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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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REFERENCES
1.
Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National 
Cooperative Crohn’s Disease Study. Gastroenterology. 1976; 70(3):439-444.
2.
Buderus S, Boone J, Lyerly D, Lentze MJ. Fecal lactoferrin: a new parameter to monitor infliximab therapy. 
Dig Dis Sci. 2004; 49(6):1036-1039.
3.
Costa F, Mumolo MG, Ceccarelli L, et al. Calprotectin is a stronger predictive marker of relapse in ulcerative 
colitis than in Crohn’s disease. Gut. 2005; 54:364-368.
4.
Dove LS, Lembo A, Randall CW, et al. Eluxadoline benefits patients with irritable bowel syndrome with 
diarrhea in a Phase 2 study. Gastroenterology. 2013; 145:329–338.
5.
Hawker GA, Mian S, Kendzerska T, et al. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), 
Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain 
Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), 
and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011; 
63: S240–S252.
6.
Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the 
treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. 
Gastroenterology. 1994; 106(2):287-296.
7.
Kane SV, Sandborn WJ, Rufo PA et al. Fecal lactoferrin is a sensitive and specific marker in indentifying 
intestinal inflammation. Am J Gastroenterol. 2003; 98(6);1309-1314.
8.
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 
1997; 32(9):920–924.
9.
Shah DK, Betts AM. Antibody biodistribution coefficients: inferring tissue concentrations of monoclonal 
antibodies based on the plasma concentrations in several preclinical species and human. mAbs. 2013; 
5(2):297–305.
10.
Solem CA, Loftus EV, Tremaine WJ, et al. Correlation of C-reactive protein with clinical, endoscopic, 
histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis. 2005; 11(8):707-712.
11.
Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as a marker of inflammatory bowel disease. 
Inflamm Bowel Dis. 2004; 10(5):661-665.
12.
Ware JE, Kosinski M, Keller SD. Interpretation: Norm-Based. In: SF-36 Physical and Mental Health Summary 
Scales: A User’s Manual. Boston, MA: The Health Institute; 1994; 8:1-8:42.
13.
Ware JE Jr, Sherbourne CD. The MOS 36 item short form health survey (SF 36), I. Conceptual framework and 
item selection. Med Care. 1992; 30(6):473 483.


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ATTACHMENTS
Attachment 1: Definition of Inadequate Initial Response, Loss of Response, or Intolerance to TNF-
Antagonist Therapies (Infliximab, Adalimumab, or Certolizumab Pegol) or
Vedolizumab
The criteria for inadequate initial response, response followed by loss of response, or intolerance 
to infliximab, adalimumab, certolizumab pegol, or vedolizumab are described in items I, II, and 
III, below.
I.
Inadequate initial response to current or prior therapy with infliximab, 
adalimumab, certolizumab pegol (primary nonresponse), or vedolizumab (primary 
nonresponse)
Eligible subjects must satisfy criteria A, B, and C.
A.
Have received induction doses of:

Infliximab (2 or 3 doses of 5 mg/kg)
or

Adalimumab (at a dose of 160 mg followed by a dose 80 mg or at a 
dose of 80 mg followed by a dose 40 mg)
or

Certolizumab pegol (2 or 3 doses of 400 mg)
or

Vedolizumab (3 or 4 doses of 300 mg)
AND
B.
Did not initially respond to these induction doses of infliximab, adalimumab, 
certolizumab pegol, or vedolizumab, as evidenced by the presence of at least 
1 of the following signs or symptoms related to persistence of Crohn’s 
disease, as assessed by a treating physician:

Lack of improvement or worsening in stool frequency

Lack of improvement or worsening in daily abdominal pain

Occurrence, lack of improvement, or worsening of fever thought to be 
related to Crohn’s disease

Lack of improvement or worsening in a draining fistula or development of 
a new draining fistula

Lack of improvement or worsening in rectal bleeding

Initiation or increase in antidiarrheal medication


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These signs and symptoms of Crohn’s disease must have occurred 2 weeks after 
receiving the last induction dose of infliximab, adalimumab, certolizumab pegol, 
or vedolizumab, and are offered only as a benchmark of the minimally acceptable 
criteria required to designate a subject as having had an inadequate initial 
response to infliximab, adalimumab, certolizumab pegol, or vedolizumab therapy. 
This benchmark acknowledges that the CDAI is not routinely recorded in clinical 
practice.
AND
C.
Have documentation available to the investigator that meets the following 2 
requirements:

Provide the dates and doses of the failed infliximab, adalimumab, 
certolizumab pegol, or vedolizumab induction therapy.

Documents that the subject had persistence of disease activity following 
infliximab, adalimumab, certolizumab pegol, or vedolizumab induction
therapy.
Examples of acceptable documents include: medical records, letter provided by a 
referring physician, or other “reason for referral” documents (eg, insurance 
authorization form).
II.
Initial response followed by loss of response to current or prior therapy with 
infliximab, 
adalimumab, 
certolizumab 
pegol, 
or 
vedolizumab
(secondary 
nonresponse)
Eligible subjects must satisfy criteria A, B, C, and D.
A.
Initially responded to induction therapy
AND
B.
Have received at least 2 maintenance doses of:

Infliximab (at a dose of 5 mg/kg)
or

Adalimumab (at a dose of 40 mg)
or

Certolizumab pegol (at a dose of 400 mg)
or

Vedolizumab (at a dose of 00 mg)


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AND
C.
Have or had at least 1 of the following signs or symptoms related to 
recurrence of Crohn’s disease, as assessed by a treating physician:

Worsening in stool frequency

Worsening in daily abdominal pain

Occurrence or worsening in fever thought to be related to Crohn’s disease

Recurring drainage from a previously nondraining fistula or development 
of a new draining fistula

Worsening in rectal bleeding

Initiation or increase in antidiarrheal medication
These signs and symptoms of Crohn’s disease must have occurred 2 weeks after 
receiving the last maintenance dose of infliximab, adalimumab, certolizumab 
pegol, or vedolizumab, and are offered only as a benchmark of the minimally 
acceptable criteria required to designate a subject as having lost response to 
infliximab, adalimumab, certolizumab pegol, or vedolizumab therapy. This 
benchmark acknowledges that the CDAI is not routinely recorded in clinical 
practice.
AND
D.
Have documentation available to the investigator that meets the following 2 
requirements:

Provide the dates and doses of the failed infliximab, adalimumab, 
certolizumab pegol, or vedolizumab maintenance therapy.

Documents that the subject had recurrence of disease activity despite 
infliximab, adalimumab, certolizumab pegol, or vedolizumab maintenance 
therapy.
Examples of acceptable documents include: medical records, letter provided by a 
referring physician, or other “reason for referral” documents (eg, insurance 
authorization form).
III.
Current or prior intolerance to therapy with infliximab, adalimumab, certolizumab 
pegol, or vedolizumab
Eligible subjects must satisfy criteria A and B.
A.
Have had an adverse reaction that meets 1 of the following 3 criteria: 1) 
significant acute infusion/administration reaction; 2) significant delayed 
infusion/administration reaction (for example, delayed hypersensitivity or 
serum-sickness like reaction); or 3) significant injection-site reaction. 
Definitions of these 3 criteria are provided below. Adverse reactions also 


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must have followed 1 dose of infliximab, adalimumab, certolizumab pegol, 
or vedolizumab, and, in the treating physician’s opinion, precluded 
continued use of the therapy.
1)
A significant acute infusion/administration reaction is defined as an 
adverse reaction that was:

Manifested through 1 of the following symptoms.
a.
Fever greater than 100F (37.8C)
b.
Chills or rigors
c.
Itching
d.
Rash
e.
Flushing
f.
Urticaria or angioedema
g.
Breathing difficulties (dyspnea, chest paint or tightness, 
shortness of breath, wheezing, stridor)
h.
Clinical 
hypotension 
(pallor, 
diaphoresis, 
faintness, 
syncope), blood pressure less than 90 mm Hg systolic and 
60 mm Hg diastolic, or a systemic or orthostatic drop in 
systolic blood pressure of greater than 20 mm Hg
AND

Occurred 24 hours after infusion/administration of infliximab, 
adalimumab, certolizumab pegol, or vedolizumab
AND

Was considered related to the infusion/administration of 
infliximab, adalimumab, certolizumab pegol, or vedolizumab.
2)
A significant delayed infusion/administration reaction is defined as an 
adverse reaction that:

Was manifested through 1 or more of the following symptoms:
a.
Myalgias
b.
Arthralgias
c.
Fever greater than 100F (37.8C)
d.
Malaise
e.
Rash
AND


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
Occurred >24 hours and <15 days after infusion/administration of 
infliximab, adalimumab, certolizumab pegol, or vedolizumab
AND

Was considered related to the infusion/administration of 
infliximab, adalimumab, certolizumab pegol, or vedolizumab.
3)
A significant injection-site reaction is defined as an adverse reaction 
that:

Was manifested through 1 or more of the following symptoms:
a.
Significant bruising
b.
Erythema
c.
Hemorrhage
d.
Irritation
e.
Pain
f.
Pruritus
g.
“Injection-site reaction”
AND

Occurred within 24 hours of an SC injection of adalimumab or 
certolizumab pegol.
AND

Was considered related to the injection.
B.
Have documentation available to the investigator that meets the following 2 
requirements:

Provides the date of discontinuation of infliximab, adalimumab, 
certolizumab pegol, or vedolizumab.

Documents that the subject had intolerance to infliximab, adalimumab, 
certolizumab pegol, or vedolizumab.
Examples of acceptable documents include: medical records, letter provided by a 
referring physician, or other “reason for referral” documents (eg, insurance 
authorization form).


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Attachment 2: Definitions of Inadequate Response to or Intolerance of Corticosteroids or 
AZA/6-MP/MTX and Corticosteroid Dependence
CORTICOSTEROIDS
Subjects have failed to respond to corticosteroids if they have had evidence of an initial inadequate 
response, recurrent disease, or a relapse despite receiving at least 0.75 mg/kg/day or >40 mg/day of 
prednisone (or corticosteroid equivalent, given orally or intravenously) for 2 weeks; or ≥9 mg/day of 
budesonide or ≥5 mg/day of beclomethasone dipropionate given orally for at least 4 weeks.
Subjects are intolerant of corticosteroids if:

They have developed clinically significant adverse events (eg, osteonecrosis or osteoporosis, 
psychosis, uncontrolled diabetes) unresponsive to dose reduction that, in the judgment of the 
investigator, precluded the use of corticosteroids to treat Crohn’s disease.

OR

They have a medical condition that precludes the use of corticosteroids as a treatment for Crohn’s 
disease.
Subjects are corticosteroid dependent if they have failed to successfully taper their corticosteroid (ie, 
had a flare of disease) within 3 months of starting therapy, or if a relapse occurs within 3 months after 
stopping corticosteroids or if they are unable to discontinue these agents without flare within 3 months 
after starting them.
6-MERCAPTOPURINE (6-MP), AZATHIOPRINE (AZA), OR METHOTREXATE 
(MTX):
Subjects have failed to respond to 6-MP, AZA, or MTX if they have had evidence of an initial 
inadequate response, recurrent disease, or a relapse despite receiving:

At least 3 months of therapy with 1 mg/kg/day of 6-MP, 2 mg/kg/day of AZA, or 25 mg/week 
(intramuscular or subcutaneous) of MTX.
OR

A lower dosage of 6-MP, AZA, or MTX when country or local guidelines specify a different 
treatment regimen. (In such an event, the country or local guidelines needs to be included in the 
source document).
OR

The dosage of 6-MP, AZA, or MTX confirmed to be therapeutic for the subject with whole blood 
thioguanine nucleotide levels >200 pmole/8x108 red blood cells.
OR

The highest tolerated dosage due to leukopenia, elevated liver enzymes, or nausea.
Subjects are intolerant of 6-MP, AZA, or MTX if:

They have developed clinically significant adverse events (eg, pancreatitis, arthritis accompanied by 
high fever and/or rash, leukopenia, or persistently elevated liver enzymes) unresponsive to dose 
reduction that, in the judgment of the investigator, precluded the use of 6-MP, AZA, or MTX to treat 
Crohn’s disease within the past 5 years.


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OR

They have a medical condition that precludes the use of 6-MP, AZA, or MTX.


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Attachment 3: Tuberculin Skin Testing
Administering the Mantoux Tuberculin Skin Test
The Mantoux tuberculin skin test (CDC, 2000) is the standard method of identifying persons infected with 
Mycobacterium tuberculosis. Multiple puncture tests (Tine and Heaf) should not be used to determine whether a 
person is infected because the amount of tuberculin injected intradermally cannot be precisely controlled. Tuberculin 
skin testing is both safe and reliable throughout the course of pregnancy. The Mantoux tuberculin test is performed 
by placing an intradermal injection of 0.1 mL of tuberculin into the inner surface of the forearm. The test must be 
performed with tuberculin that has at least the same strength as either 5 tuberculin units (TU) of standard purified 
protein derivative (PPD)-S or 2 TU of PPD-RT 23, Statens Seruminstitut, as recommended by the World Health 
Organization. PPD strengths of 1 TU or 250 TU are not acceptable (Menzies, 2000). Using a disposable tuberculin 
syringe with the needle bevel facing upward, the injection should be made just beneath the surface of the skin. This 
should produce a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter. To prevent needle-stick 
injuries, needles should not be recapped, purposely bent or broken, removed from disposable syringes, or otherwise 
manipulated by hand. After they are used, disposable needles and syringes should be placed in puncture-resistant 
containers for disposal. Institutional guidelines regarding universal precautions for infection control (eg, the use of 
gloves) should be followed. A trained health care worker, preferably the investigator, should read the reaction to the 
Mantoux test 48 to 72 hours after the injection. Subjects should never be allowed to read their own tuberculin skin 
test results. If a subject fails to show up for the scheduled reading, a positive reaction may still be measurable up to 
1 week after testing. However, if a subject who fails to return within 72 hours has a negative test, tuberculin testing 
should be repeated. The area of induration (palpable raised hardened area) around the site of injection is the reaction 
to tuberculin. For standardization, the diameter of the induration should be measured transversely (perpendicular) to 
the long axis of the forearm. Erythema (redness) should not be measured. All reactions should be recorded in 
millimeters, even those classified as negative.
Interpreting the Tuberculin Skin Test Results
In the US and many other countries, the most conservative definition of positivity for the tuberculin skin test is 
reserved for immunocompromised patients, and this definition is to be applied in this study to maximize the 
likelihood of detecting latent TB, even though the subjects may not be immunocompromised at baseline.
In the US and Canada, an induration of 5 mm or greater in response to the intradermal tuberculin skin test is 
considered to be a positive result and evidence for either latent or active TB.
In countries outside the US and Canada, country-specific guidelines for immunocompromised patients should be 
consulted for the interpretation of tuberculin skin test results. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed.
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable antituberculous 
treatment regimens for latent TB. If no local country guidelines for immunocompromised patients exist, US 
guidelines must be followed.
NOTE: The tuberculin skin test is recommended but not required in countries where tuberculin is not available.
References
Centers for Disease Control and Prevention. Core curriculum on tuberculosis: What the clinician should know 
(Fourth Edition). Atlanta, GA: Department of Health and Human Services; Centers for Disease Control and 
Prevention; National Center for HIV, STD, and TB Prevention; Division of Tuberculosis Elimination; 2000:25-86.
Menzies RI. Tuberculin skin testing. In: Reichman LB, Hershfield ES (eds). Tuberculosis, a comprehensive 
international approach. 2nd ed. New York, NY: Marcel Dekker, Inc; 2000:279-322.


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Attachment 4: Crohn’s Disease Activity Index
       DISEASE ACTIVITY INDEX              
  SUM  
X FACTOR
    SUBTOTAL      
Total number of liquid or very soft stools in the 
previous 7 days
x
2
=
Sum abdominal pain/cramps ratings
(total for previous 7 days):
x
5
=
0 = none
2 = moderate
1 = mild
3 = severe
General well-being (total for previous 7 days):
x
7
=
0 = generally well
3 = very poor
1 = slightly under par
4 = terrible
2 = poor
Categories currently present and
presumed to be related to Crohn’s disease: 0 = no; 1 = yes 
 =
arthritis/arthralgia
x
20
=
 =
iritis/uveitis
x
20
=
 =
erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
x
20
=
 =
anal fissure, fistula or abscess
x
20
=
 =
other fistula
x
20
=
 =
fever over 100° F (37.8° C) during the 
previous 7 days.
x
20
=
During the previous 7 days has subject received 
antidiarrheal therapy at least once:
OR
x
30
=
During the previous 7 days has subject received
opiate therapy on each of the 7 days:
0 = no
1 = yes
Abdominal mass:
x
10
=
0 = none
2 = questionable
5 = definite
Hematocrit:
x
6
=
Males: (47-Hct) = SUM
(add or subtract by sign)
Females: (42-Hct) = SUM
(Standard Weight - Actual Body Weight)
x 100 =
*
x
1
=
Standard Weight
(add or subtract by sign, round to 3 decimal places)
* If this value is less than -10 then enter -10 here.
Standard weight and actual weight must be in same units (kg or lb)
TOTAL = 
(round total to integer)


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Attachment 5: Liver Safety Monitoring and Assessment
If laboratory testing for a subject enrolled in study and receiving study drug reveals an increase 
of serum aminotransferases (ALT or AST) to >3X ULN and bilirubin >2X ULN, laboratory tests 
for ALT, AST, alkaline phosphatase, and total bilirubin should be confirmed by a retest within 
24 hours if possible, but no later than 72 hours following notification of test results. Testing 
should be repeated within 24 hours but no later than 72 hours following notification of the test 
results. For studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and marked liver abnormality to inform the investigator, study 
monitor, and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
DEFINITION OF LIVER ABNORMALITIES
Confirmed abnormalities will be characterized as moderate and marked where ULN:
ALT or AST
Total Bilirubin
Moderate
>3x ULN 
or 
>2x ULN
Marked
>3x ULN 
and 
>2x ULN
In addition, the subject should be considered to have marked hepatic abnormalities for any of the 
following:

ALT or AST >8x ULN.

ALT or AST >5x ULN for more than 2 weeks.

ALT or AST >3x ULN and international normalized ratio (INR) >1.5.

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or marked abnormalities and require additional monitoring and 
follow-up.
FOLLOW-UP PROCEDURES
Confirmed moderate and marked abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination, and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF). Subjects with confirmed abnormal liver function testing should be followed as 
described below.


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Confirmed moderately abnormal liver function tests (LFTs) should be repeated 2 to 3 times 
weekly then weekly or less if abnormalities stabilize or the trial drug has been discontinued and 
the subject is asymptomatic.
Marked hepatic liver function abnormalities, in the absence of another etiology, may be 
considered an important medical event and reported as an SAE. The medical monitor should be 
contacted and informed of all subjects for whom marked hepatic liver function abnormalities 
possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:

Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms and 
new onset-diseases should be recorded as ‘adverse events’ on the AE sheet. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease than may lead to 
secondary liver abnormalities should be noted. Non-alcoholic steatohepatitis (NASH) is seen 
in obese hyperlipoproteinemic, and/or diabetic patients and may be associated with 
fluctuating aminotransferase levels. The investigator should ensure that the medical history 
form captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.

Obtain a history of concomitant drug use (including nonprescription medication, 
complementary, and alternative medications), alcohol use, recreational drug use, and special 
diets. Medications, including dose, should be entered on the concomitant medication form. 
Information on alcohol, other substance use, and diet should be entered on the LA-CRF.

Obtain a history of exposure to environmental chemical agents.

Based on the subject’s history, other testing may be appropriate including:

acute viral hepatitis (A, B, C, D, E or other infectious agents).

ultrasound or other imaging to assess biliary tract disease.

other laboratory tests including INR, direct bilirubin.

Consider gastroenterology or hepatology consultations.

Submit results for any additional testing and possible etiology on the LA-CRF.
STUDY AGENT SUSPENSION and/or DISCONTINUATION
If laboratory testing reveals an increase of serum aminotransferases (ALT or AST) to >3x ULN 
and an increase of bilirubin to >2x ULN, study agent should be suspended immediately. 
Suspension of study agent should also be considered if:

ALT or AST >8x ULN.

ALT or AST >5x ULN for more than 2 weeks.

ALT or AST >3x ULN and INR >1.5.

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).


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In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute 
liver disease, or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study agent. The investigator may determine that it is not in the subject’s 
best interest to continue study agent.
In addition, if close monitoring for a subject with moderate or marked hepatic laboratory tests is 
not possible, study agent should be discontinued.
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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Attachment 6: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or nonserious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease-related) or background regimen.
For the purposes of this study the following events will be considered anticipated events:

Adverse events related to symptoms of Crohn’s disease

Adverse events related to worsening or progression of Crohn’s disease
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities. However, if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of prespecified
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).


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INVESTIGATOR AGREEMENT
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 27 April 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Protocol to Evaluate the Safety and Efficacy of JNJ-64304500 
in Subjects with Moderately to Severely Active Crohn’s Disease
TRIDENT
Protocol 64304500CRD2001; Phase 2b
JNJ-64304500
*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 Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; 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.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).]
Status:
Approved  
Date:
27 April 2020
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-38074, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF 
PROTOCOL 64304500CRD2001
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT02877134


COVID-19 Appendix
JNJ-64304500
Clinical Protocol 64304500CRD2001
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Status: Approved,  Date: 27 April 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, 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 subject management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government guidelines or requirements or the clinical 
judgement of the investigator to protect the health and well-being of subjects and site staff. If, at 
any time, a subject’s safety is considered to be at unacceptable 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, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects 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 subjects on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation between the participant and investigator, 
and with the agreement of the sponsor (see below). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.
If a subject has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.


COVID-19 Appendix
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Status: Approved,  Date: 27 April 2020
ADDITIONAL ELEMENTS, WHERE APPLICABLE:

Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of subject care and study integrity. Certain 
measures, such as those listed below, may be necessary and should be instituted in accordance 
with applicable (including local) laws, regulations, guidelines, and procedures:
o
remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and participants for study procedures, eg, those related 
to safety monitoring / efficacy evaluation / study intervention storage and 
administration (including training where pertinent)
o
laboratory assessments using a suitably accredited local laboratory; for selected 
measures (eg, urine pregnancy), home testing may be employed

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).  
o
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 detailed sponsor guidance. These may include missed / delayed / 
modified study visits / assessments / dosing, and instances where temporary 
measures such as those above are implemented.  

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study 
data and additional data analyses will be outlined in study SAP(s). 

Exclusion: a potential subject with the following features will be excluded from 
participating in the study protocol:
o
During the 6 weeks prior to baseline, have had ANY of (a) confirmed SARS-CoV-2 
(COVID-19) infection (test positive), OR (b) suspected SARS-CoV-2 infection 
(clinical features without documented test results), OR (c) close contact with a 
person with known or suspected SARS-CoV-2 infection 

Exception: may be included with a documented negative result for a 
validated SARS-CoV-2 test
(i) obtained at least 2 weeks after conditions (a), (b), (c) above (timed from 
resolution of key clinical features if present, eg, fever, cough, dyspnea)
AND


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Status: Approved,  Date: 27 April 2020
(ii) with absence of ALL conditions (a), (b), (c) above during the period 
between the negative test result and the baseline study visit 

NOTES on COVID-related exclusion:
1. If a participant is excluded due to recent COVID-19-related features, the reason for 
screen failure should be documented in the case report form under the exclusion 
criterion of having a condition for which participation would not be in the participant’s 
interest or could confound study assessments. 
2. The field of COVID-related testing (for presence of, and immunity to, the SARS-
CoV-2 virus) is rapidly evolving. Additional testing may be performed as part of 
screening and/or during the study if deemed necessary by the investigator and in 
accordance with current regulations / guidance from authorities / standards of care. 

Precaution: for those who may carry a higher risk for severe COVID-19 illness (eg, those 
aged over 65 years), follow guidance from local health authorities when weighing the 
potential benefits and risks of enrolling in the study, and during participation in the study. 


COVID-19 Appendix
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Status: Approved,  Date: 27 April 2020
INVESTIGATOR AGREEMENT
PPD

SAP_001.pdf: 
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Status: Approved, Date: 26 August 2020
Janssen Research & Development
Statistical Analysis Plan
(Part II)
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Protocol to Evaluate the Safety and Efficacy of JNJ-64304500 in Subjects with Moderately 
to Severely Active Crohn’s Disease
Protocol 64304500CRD2001; Phase 2b
JNJ-64304500 (TRIDENT)
Status:
Approved
Date:
26 August 2020
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-134274
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT02877134


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Status: Approved, Date: 26 August 2020
TABLE OF CONTENTS
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.5.
Randomization and Blinding .......................................................................................................... 12
1.5.1.
Randomization and Treatment Allocation................................................................................... 12
1.5.2.
Blinding ....................................................................................................................................... 12
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 14
2.1.
Visit Windows................................................................................................................................. 14
2.2.
Analysis Sets.................................................................................................................................. 14
2.2.1.
Randomized Analysis Set........................................................................................................... 14
2.2.2.
Efficacy Analysis Set .................................................................................................................. 14
2.2.3.
Safety Analysis Set..................................................................................................................... 14
2.2.4.
Pharmacokinetics Analysis Set .................................................................................................. 14
2.2.5.
Immunogenicity Analysis Set...................................................................................................... 14
2.3.
Definition of Subgroups.................................................................................................................. 15
2.4.
Study Day and Relative Day .......................................................................................................... 16
2.5.
Baseline ......................................................................................................................................... 16
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 16
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 17
4.
SUBJECT INFORMATION................................................................................................................ 18
4.1.
Demographics and Baseline Characteristics ................................................................................. 18
4.2.
Disposition Information................................................................................................................... 18
4.3.
Treatment Compliance................................................................................................................... 19
4.4.
Extent of Exposure......................................................................................................................... 19
4.5.
Protocol Deviations ........................................................................................................................ 19
4.6.
Prior and Concomitant Medications ............................................................................................... 20
5.
EFFICACY ......................................................................................................................................... 20
5.1.
General Method of Analysis........................................................................................................... 20
5.2.
Analysis Specifications................................................................................................................... 20
5.2.1.
Level of Significance................................................................................................................... 20
5.3.
Primary Efficacy Endpoint.............................................................................................................. 21
5.3.1.
Definition..................................................................................................................................... 21
5.3.2.
Primary Estimand (Estimand 1).................................................................................................. 21
5.3.3.
Analysis Methods for the Primary Estimand............................................................................... 22
5.3.3.1.
Estimator (Analysis) for the Primary Estimand........................................................................ 22
5.3.3.1.1.
Pairwise Comparisons ......................................................................................................... 25
5.3.3.2.
Subgroup Analyses ................................................................................................................. 26
5.3.4.
Supplementary Estimands for the Primary Endpoint.................................................................. 26
5.3.4.1.
Estimand 2............................................................................................................................... 26
5.3.4.2.
Estimand 3............................................................................................................................... 27
5.3.5.
Estimator (Analysis) for the Supplementary Estimands of the Primary Endpoint ...................... 27
5.3.6.
Summary of Analyses Related to the Primary Endpoint ............................................................ 28
5.4.
Major Secondary Endpoints........................................................................................................... 29
5.4.1.
Definitions ................................................................................................................................... 29
5.4.2.
Main Estimands for the Major Secondary Endpoints ................................................................. 31
5.4.3.
Analysis Methods for the Main Estimands for the Major Secondary Endpoints......................... 33
5.4.3.1.
Estimators (Analyses) for the Main Estimands........................................................................ 33


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5.4.3.1.1.
Additional Missing Data Rules for the Main Estimands ....................................................... 34
5.4.4.
Supplementary Estimands for the Major Secondary Endpoints................................................. 34
5.4.5.
Estimators for the Supplementary Estimands of the Major Secondary Endpoints..................... 35
5.4.6.
Summary of Analyses Related to Major Secondary Endpoints.................................................. 35
5.5.
Other Endpoints ............................................................................................................................. 36
5.5.1.
Definitions ................................................................................................................................... 41
5.5.2.
Analysis Methods........................................................................................................................ 46
6.
SAFETY............................................................................................................................................. 48
6.1.
Adverse Events .............................................................................................................................. 48
6.2.
Clinical Laboratory Tests................................................................................................................ 49
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 50
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 50
7.1.
Pharmacokinetics........................................................................................................................... 50
7.1.1.
Serum Concentrations................................................................................................................ 50
7.1.1.1.
Data Handling Rules................................................................................................................ 51
7.1.2.
PK vs Efficacy............................................................................................................................. 51
7.1.3.
Population PK Analysis............................................................................................................... 52
7.2.
Immune Response......................................................................................................................... 52
7.2.1.
Antibodies to Study Agents ........................................................................................................ 52
7.2.1.1.
Neutralized Antibodies to Study Agents .................................................................................. 52
7.2.2.
Antibodies vs Efficacy/PK........................................................................................................... 52
7.2.3.
Antibodies vs Safety ................................................................................................................... 52
7.3.
Receptor Occupancy and Immunophenotyping............................................................................. 53
7.4.
Pharmacodynamic/Biomarker Analyses ........................................................................................ 53
7.5.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 53
7.6.
Pharmacogenomic Analyses ......................................................................................................... 53
8.
HEALTH ECONOMICS ..................................................................................................................... 54
REFERENCES............................................................................................................................................ 55
ATTACHMENTS......................................................................................................................................... 56
Attachment 1  Detailed prohibited changes in CD medication (category 2 of the Intercurrent 
events)........................................................................................................................ 56
Attachment 2:  Grading Criteria for Clinical Laboratory Tests [CTCAE Version 4.03]................................ 58


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ABBREVIATIONS
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
analysis of covariance
AST
Aspartate aminotransferase
AZA
Azathioprine
BDS
Biologics Development Sciences
Bio-IR
biologic intolerant or refractory
Bio-NF
biologic nonfailure, i.e., inadequate response to or failed to tolerate corticosteroids or 
immunomodulators, but not a biologic
BSFS
Bristol Stool Form Scale
CDAI
Crohn’s Disease Activity Index
CI
confidence interval
CRF
case report form
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DPS
Data presentation specifications
ECG
electrocardiogram
GHAS
Global Histology Activity Score
GMS
Global Medical Safety
IBD
Inflammatory Bowel Disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web response system
LLN
lower limit of normal
LOCF
last observation carried forward
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities
MITT
modified intent-to-treat
MTX
Methotrexate
NAbs
neutralizing antibodies
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NKG2D
natural killer group 2 member D
NRS
numerical rating scale
PCS
Physical Component Summary
PD
pharmacodynamic
PK
pharmacokinetic(s)
PRO
patient-reported outcome(s)
RNA
ribonucleic acid
RO
receptor occupancy
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SF-36
36-item Short Form Health Survey
SNP
Single Nucleotide Polymorphism
SSG
Statistical Support Group
SUSAR
suspected unexpected serious adverse reaction


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TNF
tumor necrosis factor
TNFα
tumor necrosis factor alpha
ULN
upper limit of normal


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Status: Approved, Date: 26 August 2020
1.
INTRODUCTION
The protocol 64304500CRD2001 is comprised of 2 parts, Part I and Part II. Except for trial 
objectives and trial design sections, all other sections in this SAP will be focused on Part II. The 
planned analyses for Part I were specified in a separate SAP. This Statistical Analysis Plan (SAP) 
contains definitions of analysis sets, derived variables, and statistical methods for all planned 
analyses for Part II. 
1.1.
Trial Objectives
The objectives are the same in Part I and Part II.
Primary Objectives

To evaluate the efficacy of JNJ-64304500 to reduce the Crohn’s Disease Activity Index 
(CDAI) score from baseline. 

To evaluate the safety of JNJ-64304500.
Secondary Objectives

To evaluate the efficacy of JNJ-64304500 to induce clinical remission, clinical response, and 
endoscopic healing of the mucosa, and to maintain remission.

To evaluate the relationship between efficacy and the presence of the natural killer group 2 
member D (NKG2D) and/or major histocompatibility class I chain-related protein B (MICB)
single-nucleotide polymorphism (SNP) biomarkers.

To evaluate the efficacy of JNJ-64304500 to improve general and disease-specific health-
related quality of life and to reduce Crohn’s disease-related hospitalizations and surgeries.

To evaluate the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and 
biomarkers (i.e., reductions in CRP, fecal calprotectin, and fecal lactoferrin) of JNJ-64304500 
therapy.
1.2.
Trial Design
This protocol is comprised of 2 parts (Part I and Part II) that are designed to evaluate the efficacy 
and safety of JNJ-64304500 in subjects with moderately to severely active Crohn’s disease.  Both 
parts of the protocol will enroll Bio-IR and Bio-NF subjects, as defined below.
In Part I, the following 2 studies were conducted:

Study 1: A study in subjects who are biologic intolerant or refractory (Bio-IR);

Study 2: A study in subjects who have not previously failed a biologic therapy 
(Biologic nonfailure [Bio-NF]).
In Part II, the following study will be conducted:

Study 3: A dose-ranging study in subjects who are Bio-IR or Bio-NF.


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Figure 1:
Schematic representation of 64304500CRD2001
The target population for each part of the protocol consists of men or women ≥18 years of age with 
moderately to severely active Crohn’s disease (of at least 3 months’ duration), defined as a CDAI 
score ≥220 but ≤450 at Week 0, with elevated CRP (>3.0 mg/L) and/or fecal calprotectin 
(>250 mg/kg) at screening. Subjects must have colitis, ileitis, or ileocolitis previously confirmed 
at any time in the past by radiography, histology, and/or endoscopy.
Additionally, subjects must have previously failed or been intolerant to 1 or more approved 
biologic agents (ie, TNFα-antagonists or vedolizumab, hereafter referred to as biologic intolerant 
or refractory subjects) or have demonstrated an inadequate response to or failed to tolerate 
corticosteroids or immunomodulators (ie, 6-mercaptopurine [6-MP], azathioprine [AZA], or
methotrexate [MTX]) but not a biologic agent (hereafter referred to as biologic nonfailure 
subjects). These 2 populations are described below: 
Biologic intolerant or refractory (Bio-IR) subjects are defined as those who have received an 
advanced therapy, including infliximab (or a biosimilar for infliximab), adalimumab (or a 
biosimilar for adalimumab), certolizumab pegol, or vedolizumab at a dose approved for the 
treatment of Crohn’s disease, and either did not respond initially, responded initially but then lost 
response, or were intolerant to the medication. Bio-IR subjects must allow a ≥8-week washout for 
prior TNFα antagonist use and a 16-week washout period for prior vedolizumab use.
Biologic nonfailure (Bio-NF) subjects are defined as those who have demonstrated an inadequate 
response to or have failed to tolerate corticosteroids or the immunomodulators 6-MP, AZA, or 
MTX. Subjects who have demonstrated corticosteroid dependence (ie, an inability to successfully 
taper corticosteroids without a return of the symptoms of Crohn’s disease) are also eligible. Bio-
NF subjects may also have received biologic therapy but only if it was discontinued for reasons 
other than lack of efficacy or intolerance (eg, drug holiday).


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Part I studied the safety and efficacy of a high dose regimen of JNJ-64304500 (400 mg SC at 
Week 0 then 200 mg SC q2w through Week 22) compared with placebo. All planned analyses for 
Part I were defined in the SAP for Part I.
Part II will study the efficacy and safety of multiple dose regimens of JNJ-64304500 compared 
with placebo, and with ustekinumab (STELARA®) as a reference arm. In Part II, approximately
250 Bio-IR or Bio-NF subjects will be randomly assigned to receive placebo or ustekinumab or 1 
of 3 dose levels of JNJ-64304500 in a ratio of 1:1:1:1:1 using permuted block randomization, 
stratified by baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), and Bio-IR 
status (yes or no). The maximum proportion of either Bio-NF or Bio-IR subjects will be 60%.
The treatment groups in Part II will be as follows:

Placebo SC at Weeks 0, 2, 4, and 8; from Week 12, these subjects will receive additional doses 
as follows:

Placebo-treated subjects who are in clinical response at Week 12 (≥100-point reduction 
from baseline in CDAI or CDAI <150) will continue to receive placebo at Weeks 12, 14, 
16, and 20.

Placebo-treated subjects who are not in clinical response at Week 12 will receive 
JNJ-64304500 150 mg SC at Week 12 and then JNJ-64304500 75 mg SC at Weeks 14, 
16, and 20.

High dose: JNJ-64304500 400 mg SC at Week 0 and 200 mg SC at Weeks 2 and 4, then 
200 mg SC every 4 weeks (q4w) through Week 20.

Middle dose: JNJ-64304500 150 mg SC at Week 0 and 75 mg SC at Weeks 2 and 4, then 
75 mg SC q4w through Week 20.

Low dose: JNJ-64304500 50 mg SC at Week 0 and 25 mg SC at Weeks 2 and 4, then 25 mg 
SC q4w through Week 20.

Ustekinumab (tiered doses approximating 6 mg/kg intravenously [IV]) at Week 0 (as indicated 
in the bullets below), followed by 90 mg SC at Weeks 8 and 16.

Ustekinumab 260 mg (weight ≤55 kg).

Ustekinumab 390 mg (weight >55 kg and ≤85 kg).

Ustekinumab 520 mg (weight >85 kg);
Subjects who are receiving oral 5-ASA compounds, conventional immunomodulators (ie, AZA, 
6-MP, or MTX), enteral therapy, and/or antibiotics for the treatment of Crohn’s disease at baseline 
should maintain a stable dose through the final safety visit. Subjects who are receiving 
corticosteroids at baseline should maintain a stable dose through Week 12. Subjects who are 
receiving corticosteroids at Week 0 and who are in clinical response at Week 12 will be encouraged 
to initiate corticosteroid tapering at the Week 12 visit.
The primary endpoint for Part II is the change from baseline in the CDAI score at Week 12. 


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The main part of Part II of this protocol is through Week 24.  Initially, Part II of the protocol did 
not have a long-term extension (LTE), but it was subsequently added in Protocol Amendment 5.
After Protocol Amendment 5 was implemented, subjects who complete Part II Week 24 
assessments, and who may benefit from continued treatment in the opinion of the investigator, are 
eligible to enter the Part II LTE. In the Part II LTE, each subject will be eligible to receive up to 
52 weeks of additional study drug (for a total of up to 72 weeks of study drug in Part II). A 
schematic representation of the Part II (including the LTE) is shown in Figure 2.
Figure 2:
Schematic Overview of the 64304500CRD2001 Part II (including the Long-term Extension)


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1.3.
Statistical Hypotheses for Trial Objectives
The hypothesis for Part II is that there is dose-response for the JNJ-64304500 doses and placebo 
in inducing a reduction from baseline in CDAI at Week 12 in subjects with moderately to severely 
active Crohn’s disease. The null hypothesis to be tested is that there is no dose-response for the
JNJ-64304500 doses and placebo in inducing a reduction from baseline in CDAI at Week 12 in 
subjects with moderately to severely active Crohn’s disease.
1.4.
Sample Size Justification
Sample size and power to detect a dose response signal were evaluated using the Multiple 
Comparison Procedures with modeling techniques (MCP mod) method, assuming the true 
underlying dose-response curve is one of the shapes shown in Figure 3. Response is defined as the 
difference in the CDAI score between Week 0 and Week 12. For the sample size calculation, doses 
under consideration are placebo, JNJ-64304500 high dose, JNJ-64304500 middle dose, and 
JNJ-64304500 low dose. The ustekinumab dose is not used for sample size calculation since it is 
included in Part II as a reference arm.
Figure 3:
Dose-response shapes included in power calculation
The assumptions for the sample size calculations in Part II were based on the Part I Week 12 
analysis results. For Bio-IR subjects in Part I, the mean CDAI change from baseline at Week 12 
was -30.9 (SD=85.15) and -77.4 (SD=103.68) for the placebo and JNJ-64304500 groups (this 
corresponds to the high dose in Part II), respectively. For Bio-NF subjects in Part I, the mean CDAI 
change from baseline at Week 12 was -70.9 (SD=93.59) and -144.7 (SD=92.50) for the placebo 
and JNJ-64304500 groups, respectively.


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For Part II, assuming the mean CDAI change from baseline at Week 12 is -111 in the
JNJ-64304500 high dose group and -51 in the placebo group (these values are derived assuming a 
1:1 ratio of Bio-IR and Bio-NF subjects) with a common SD of 102, 50 subjects per treatment 
group will provide a mean power of 85% to detect a dose-response signal for change from baseline
in CDAI at Week 12 based on 7 candidate dose-response models (Figure 3, Table 1 and Table 2) 
at an overall Type 1 error rate of 0.05 (2-sided). For ease of interpretation, the reverse of the change 
from baseline in the CDAI at Week 12 (Week 0 – Week 12) will be used as the response variable 
in the dose response analysis so that larger values in response will indicate a better outcome in 
Figure 3. Table 1 gives the model specifications for the candidate models that have been selected 
for this study based on potential outcomes. Table 2 shows the power for detecting a dose response 
signal under the different shapes at an overall Type 1 error rate of 0.05 (2 sided).
Table 1:
Candidate Dose-responsea Models
Model Type
Model specificationb
Emax 1
dose/(50+dose)
Emax 2
dose/(150+dose)
Exponential
exp(dose/150)-1
Linear
dose
Logistic 1
1/{1+exp[(200 –dose)/40]}
Logistic 2
1/{1+exp[(100 –dose)/23]}
Quadratic
dose-0.002*(dose**2)
a Response is the difference in the CDAI score between Week 0 and Week 12 (Week 0 – Week 12).
bA standardized version of the dose response model 
Table 2:
Power for Detecting a Dose Response Signal Under Different Shape at an Overall Type 
1 Error of 0.05 (2 sided)
Sample size
Per Group
Emax 1
Emax2
Exponential
Linear
Logistic 1
Logistic 2
Quadratic
Mean 
Power
50
85%
85%
89%
86%
89%
95%
68%
85%
Fifty subjects per treatment group will also provide 83% power to detect a treatment difference 
between the JNJ-64304500 treatment group with the highest dose and the placebo treatment group 
for change from baseline in CDAI at Week 12 based on a 2-sample t-test at a Type 1 error rate of 
0.05 (2-sided; Table 3). This will result in a total sample size of 250 subjects in Part II 
(incorporating an additional 50 subjects for the ustekinumab treatment group).


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Table 3:
Power to detect a treatment difference and sample size combinations at an overall 
Type 1 error of 0.05 (2-sided) for Part II
Sample size per group
Placebo
JNJ-64304500 
high dose
Difference
Power*
Mean change from baseline in CDAI score at Week 12
Based on data from Part I (assuming 1: 1 of Bio-IR and Bio-NF subjects)
45
-51
-91
40
45%
45
-51
-101
50
63%
45
-51
-111
60
79%
45
-51
-121
70
90%
45
-51
-131
80
96%
50
-51
-91
40
49%
50
-51
-101
50
68%
50
-51
-111
60
83%
50
-51
-121
70
92%
50
-51
-131
80
97%
*Assuming a standard deviation of 102 (based on JNJ-64304500 group at Week 12) for each group. 
1.5.
Randomization and Blinding
1.5.1.
Randomization and Treatment Allocation
Central randomization will be implemented in Part II. Subjects will be randomly assigned to 1 of 
5 treatment groups (1:1:1:1:1 ratio), based on a 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 baseline CDAI score (≤300 
or >300), SNP-positive status (yes or no), and Bio-IR status (yes or no). 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. 
1.5.2.
Blinding
To maintain the study blind, the study agent container will have a label containing the study name 
and medication number or syringe number. The label will not identify the study agent in the 
container. The medication number or syringe number will be entered in the case report form (CRF) 
when the drug is dispensed. The study agents will be identical in appearance and packaging.
Planned efficacy and safety evaluations for Part II will be performed after the following planned 
database locks (DBLs) (additional database locks may be added as needed): 

Week 12 DBL for Part II:  Occurs when all Part II subjects have completed their Week 12 
visit or have terminated their study participation before Week 12. 

Week 24 DBL for Part II:  Occurs when all Part II subjects have completed their Week 24 
visit or have terminated their study participation before Week 24. 

Final DBL for Part II: Occurs when all Part II subjects who entered the Part II LTE have 
completed their final safety visit in the Part II LTE or have terminated their study participation 
before the final safety visit in the Part II LTE. For Part II subjects who did not enter the LTE, 
all their data (included data collected after Week 24) will be included in this lock.


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At the time of the Week 12 DBL for Part II, the sponsor, except for site monitors (who have 
interactions with the investigative sites), will become unblinded to treatment assignment. The 
study blind will be maintained for investigators, site personnel, subjects, and site monitors until 
the Week 24 analyses have been completed for Part II.
Data that may potentially unblind the treatment assignment (i.e., study drug serum concentrations, 
anti-drug antibodies, treatment allocation, and study drug preparation/accountability data) will be 
handled with special care to ensure that the integrity of the blind is maintained and the potential 
for bias is minimized. In particular, before unblinding, this information will be available only to a 
limited number of data management staff for purposes of data cleaning, and if applicable, to quality 
assurance representatives for the purposes of conducting independent drug audits. 
The SNP status and postbaseline results for CRP, fecal lactoferrin, and fecal calprotectin tests will 
be blinded to the investigative site.  If an investigative site requests these data, it will be provided 
to them after the final analyses based on final DBL for Part II have been completed.
The designated pharmacists, or other appropriately licensed and authorized personnel, and 
independent drug monitors will be unblinded to study agent. Placebo infusions/injections will have 
the same appearance as the ustekinumab infusions/JNJ-64304500 injections. Under no 
circumstances should unblinded personnel reveal the treatment assignment for a subject.
For bioanalytical purposes, before the PK, anti-drug antibody, and PD bioanalyses are initiated, 
the unblinded data management team will provide the sponsor bioanalysts with the information 
about which treatment (JNJ-64304500 or placebo) the subjects received. For the purpose of 
performing PK, immunogenicity, and PD bioanalyses, bioanalysts in Biologics Clinical 
Pharmacology at Janssen will be unblinded to treatment-level data (JNJ-64304500 or placebo) at 
the time of analyzing serum samples for the determination of drug concentrations, detection of 
antibodies to study agents, or PD assessments. Samples will be separated based on treatment 
administered; subject identification and dose given will not be disclosed.
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. 
Additionally, a given subject’s treatment assignment may be unblinded to the sponsor, Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and site personnel to fulfill regulatory 
reporting requirements for suspected unexpected serious adverse reactions (SUSARs).
A separate code-break procedure will be available for use by the Janssen Global Medical Safety 
group to allow for unblinding of individual subjects to comply with specific requests from 
regulatory or health authorities.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Actual scheduled visits will be used for all by-visit analyses in the study. Early termination visit 
and final efficacy and safety visit will be mapped to scheduled visits according to slotting rules 
that will be prespecified prior to the database lock. The study visits scheduled should occur at the 
times delineated in the Time and Events Schedule of the protocol. 
2.2.
Analysis Sets
2.2.1.
Randomized Analysis Set
The randomized analysis set includes all subjects who are randomized in the study. Subjects in the 
randomized analysis set will be analyzed according to the treatment group to which they were 
assigned regardless of the treatment they actually received.
2.2.2.
Efficacy Analysis Set
The efficacy analyses will be based on the full analysis set (FAS) and includes all randomized 
subjects in Part II who received at least one dose of study agent (Placebo or JNJ-64304500 or 
ustekinumab, including a partial dose). The efficacy data will be analyzed according to the 
treatment group to which they were assigned regardless of the treatment they actually received.
2.2.3.
Safety Analysis Set
The safety analysis set includes all randomized subjects in Part II who received at least one dose 
of study agent (Placebo or JNJ-64304500 or ustekinumab, including a partial dose). The safety 
data will be analyzed according to the treatment they actually received.
2.2.4.
Pharmacokinetics Analysis Set
The pharmacokinetics (PK) analysis set includes all randomized subjects in Part II who received 
at least one complete dose of JNJ-64304500 or ustekinumab and has at least 1 PK sample obtained 
after their first dose of JNJ-64304500 or ustekinumab. 
In the PK analyses, subjects will be analyzed according to the treatment they actually received. 
2.2.5.
Immunogenicity Analysis Set
The immunogenicity analysis set includes all subjects in Part II who received at least 1 (partial or 
complete) dose of JNJ-64304500 or ustekinumab and who have appropriate samples for detection 
of antibodies to JNJ-64304500 or ustekinumab (i.e., subjects with at least 1 sample obtained after 
their first dose of JNJ-64304500 or ustekinumab).
In the immunogenicity analyses, subjects will be analyzed according to the treatment they actually 
received.


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2.3.
Definition of Subgroups
Subgroups of interest in this study include but are not limited to:
1.
Demographics at baseline:
a.
Age (≤median age, >median age)
b.
Sex (male, female)
c.
Race (White, non-White)
d.
Weight at baseline (≤ median, > median; ≤ 1st quartile, >1st quartile and ≤ 2nd quartile, 
>2nd quartile and ≤ 3rd quartile, >3rd quartile) 
e.
Center location (Asia, Eastern Europe, Western Europe, North America)
2.
Disease characteristics at baseline:
a.
Crohn’s disease duration (5 years, > 5 years to 15 years, or > 15 years)
b.
Involved gastrointestinal areas (ileum only, colon only, ileum & colon)
c.
CDAI score (≤ 300, >
d.
CRP (≤ 3 mg/L, > 3 mg/L)
e.
Fecal Calprotectin (≤250 mg/kg, > 250 mg/kg)
3.
Concomitant Crohn’s-disease medication at baseline:
a.
Oral corticosteroids (including budesonide and beclomethasone dipropionate) 
(receiving, not receiving)
b.
Oral 5-ASA compounds (receiving, not receiving)
c.
Immunomodulators (6-MP/AZA/MTX) (receiving, not receiving)
d.
Oral corticosteroids (including budesonide and beclomethasone dipropionate) and 
Immunomodulators (receiving, not receiving)
e.
Oral corticosteroids (including budesonide and beclomethasone dipropionate) or 
Immunomodulators (receiving, not receiving)
4.
CD-related medication history:
a.
Refractory or intolerant to 6-MP/AZA/MTX (yes, no)
b.
Refractory, dependent on or intolerant to oral or IV corticosteroids (yes, no)
c.
Refractory, dependent on, or intolerant to oral or IV corticosteroids, but not refractory 
or intolerant to 6-MP/AZA/MTX (yes, no)
d.
Refractory, dependent on or intolerant to oral or IV corticosteroids, and refractory or 
intolerant to 6-MP/AZA/MTX (yes, no)
e.
Bio-IR status (yes, no)
f.
Subjects with biologic failure (ie, Primary nonresponse, secondary nonresponse, or 
intolerance) to:

One anti-TNF only without vedolizumab (yes, no)


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
Two or more anti-TNFs without vedolizumab (yes, no)

Vedolizumab only (yes, no)

Vedolizumab and one anti-TNF (yes, no)

Vedolizumab and two or more anti-TNFs (yes, no)

Two or more anti-TNFs regardless of vedolizumab (yes, no)

For subjects with biologic failure to at least one anti-TNF 

Primary nonresponse (yes, no)

Secondary nonresponse (yes, no)

Intolerance (yes, no)
g.
Subjects without biologic failure (bio-naïve, bio-experienced [but not documented 
failure])
5.
Other:
a.
SNP-positive status (yes, no)
b.
Current fistula at baseline (yes, no)
2.4.
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'.
2.5.
Baseline 
Baseline is defined as the last observation prior to the start of the first study agent administration.
2.6.
Imputation Rules for Missing AE Date/Time 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 date

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


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
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 AE 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 AE 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.
AE onset/resolution dates with missing times will be imputed as follows:

A missing time of onset of an AE will be set to the earlier of:

00:01 as long as the onset date is after the study agent start date

The time of the study agent start if this is the same day the AE occurred.

The missing time of resolution of an adverse event will be set to 23:59.
If a missing time is associated with a partial or missing date, the date will be imputed first prior to 
imputing the time.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis is planned for Part II. 
An external data monitoring committee (DMC), which consists of at least one medical expert in 
the relevant therapeutic area and at least one statistician, will be established to monitor safety data 
on an ongoing basis to ensure the continuing safety of the subjects randomized in Part II. Until 
study unblinding, the committee will meet periodically to review interim safety data and make 
recommendations regarding the continuation of these studies.


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4.
SUBJECT INFORMATION
The number of subjects in each analysis dataset will be summarized by treatment group, combined 
JNJ-64304500 treatment group, and overall. In addition, the distribution of subjects by center 
location, country, and site ID will be presented.
4.1.
Demographics and Baseline Characteristics
Demographic data and baseline Crohn’s disease characteristic data will be summarized by 
treatment group (Table 4) for the FAS.
Table 4:
Demographic and Baseline Crohn’s Disease Characteristic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Crohn’s Disease Duration (years)
CDAI
PRO-2 (defined as the sum of the abdominal pain and stool frequency 
subscores of the CDAI score)
PRO-3 (defined as the sum of abdominal pain, stool frequency, and 
general well-being subscores of the CDAI score)
SES-CD
CRP Concentration (mg/L)
Fecal Calprotectin (mg/kg)
Categorical Variables
Race ([White, Black or African American, Asian, American Indian or 
Alaska Native, Native Hawaiian or Other Pacific Islander, Other, Not 
Reported, and Unknown])
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex ([Male, Female])
Involved GI areas ([Ileum only, Colon only, Ileum and colon, Proximal 
gastrointestinal tract, and Perianal])
Extra intestinal manifestations ([Absent, Present])
Endoscopic disease severity (SES-CD score) ([Remission (0-2), Mild 
inflammation (3-6), Moderate inflammation (7-16) and Severe 
inflammation (>16)])
Abnormal CRP (>3 mg/L) ([Yes, No])
Abnormal fecal calprotectin (>250 mg/kg) ([Yes, No])
Crohn’s disease complications (Intra-abdominal abscess, Sinus tracts 
/perforation, Fistula, Bowel Stricturing]
SNP-positive status ([Yes, No])
4.2.
Disposition Information
The number of subjects in the following disposition categories will be summarized throughout the 
study by treatment group and overall based on the FAS:

Subjects randomized

Subjects receiving study agent

Subjects who discontinued study agent

Reasons for discontinuation of study agent


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
Subjects who terminated study prematurely

Reasons for termination of study
The above categories will include summaries through Week 12, through Week 24, and through the 
final safety visit. The reasons for discontinuation of study agent and termination of study due to 
COVID-19 will be included in the summary tables.
Listings of subjects will be provided for the following categories:

Subjects who discontinued study agent

Subjects who terminated study prematurely

Subjects who were unblinded during the study period

Subjects who were randomized yet did not receive study agent

Subjects who discontinued study agent due to COVID-19

Subjects who terminated study prematurely due to COVID-19
4.3.
Treatment Compliance
The number of subjects receiving each scheduled administration will be summarized by treatment 
group for the randomization analysis set. Compliance with randomized study agent versus actual 
received agent will be summarized by treatment group for the randomization analysis set.
In addition, a list of subjects who were assigned treatment but were never treated and a list of 
subjects who were unblinded during the study will be provided. 
4.4.
Extent of Exposure
The number and percentage of subjects who received study agent will be summarized by treatment 
group based on the efficacy analysis set.
The cumulative dose of JNJ-64304500 and ustekinumab received will be summarized by treatment 
group based on the safety analysis set.
In addition, the number of administrations of study agent and average duration of follow-up 
(weeks) will be summarized by treatment group.
4.5.
Protocol Deviations
Major protocol deviations will be summarized by treatment group based on the FAS. The major 
protocol deviations will include the following categories:

Subjects who entered the trial but did not satisfy entry criteria

Subjects who developed withdrawal criteria during the trial but were not withdrawn

Subjects who received the wrong medication or incorrect dose 


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
Subjects who received disallowed medication 

Other major protocol deviations  
In addition, a listing will be provided for subjects who had any major protocol deviations, who did 
not meet study inclusion/exclusion criteria by category, and who received wrong study agent. A 
listing will also be provided for subjects who had any COVID-19 related protocol deviations.
4.6.
Prior and Concomitant Medications
Summary of Crohn’s disease medication history (subjects who took medications for Crohn’s 
disease and their length of exposure prior to the study), CD-related conventional therapy 
(i.e., 6-MP, AZA, MTX, or corticosteroids) or advanced therapy (i.e., TNF antagonists
[infliximab, adalimumab, or certolizumab] or vedolizumab) history will be summarized by 
treatment group based on the FAS. Prior medications are defined as any therapy used before the 
day of first dose of study agent.
Crohn’s disease specific concomitant medications at baseline (including corticosteroids, 
immunomodulators, 5-aminosalicylates [5-ASAs], and antibiotics) will be summarized by 
treatment group based on the FAS. 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 on after the first dose of study agent.
5.
EFFICACY
5.1.
General Method of Analysis
Descriptive statistics (i.e., mean, median, standard deviation [SD], interquartile [IQ] range, 
minimum, and maximum) will be used to summarize continuous variables. Counts and percentages 
will be used to summarize categorical variables. Graphical data displays (e.g., line plots) may also 
be used to summarize the data.
Analyses suitable for categorical data (e.g., chi-square tests, Cochran-Mantel-Haenszel chi-square 
tests, or logistic regression, as appropriate) will be used to compare the proportions of subjects 
achieving selected endpoints (e.g., clinical response). In cases of rare events, Fisher’s exact test 
will be used for treatment comparisons. Continuous response parameters will be compared using 
Mixed-Effect Model Repeated Measure (MMRM) model. If the normality assumption is in 
question, an appropriate transformation may be implemented before fitting the MMRM model.
Analysis of covariance (ANCOVA) will be used if continuous data are collected at only one post-
baseline visit.
5.2.
Analysis Specifications
5.2.1.
Level of Significance
All statistical tests will be at a 2-sided 0.05 level of significance. A multiple comparisons procedure 
is specified to control the overall Type 1 error rate for the primary endpoint analysis; the analyses 
for major secondary endpoints and other endpoints are not adjusted for multiplicity.  Nominal 
p-values are provided for all analyses.


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5.3.
Primary Efficacy Endpoint
5.3.1.
Definition
The primary endpoint is change from baseline in the CDAI score at Week 12 (Week 12 minus
baseline).
The CDAI is a validated multi-item measure of severity of illness derived as a weighted sum of 
8 different Crohn’s disease-related variables. These 8 variables are: extra-intestinal manifestations, 
abdominal mass, weight, hematocrit, use of antidiarrheal drug(s) and/or opiates, total number of 
liquid or very soft stools, abdominal pain/cramps, and general well-being.  The last 3 variables are 
scored over 7 days by the subject on a diary card.  For the total number of liquid or very soft stools, 
abdominal pain/cramps, and general well-being, if only 5 days or 6 days of data are available for 
the calculation, the weights of 7/5 and 7/6, respectively, will be used for the calculation; if the 
values are recorded for less than 5 days, the components will not be calculated. The CDAI score 
calculation algorithm is presented in the protocol Attachment 4.  
The CDAI score will be calculated for a visit if 4 of the 8 components are available at that visit. 
When at least 4 of the 8 components are available, any missing components will be imputed by 
carrying forward the last non-missing component. If the CDAI score cannot be calculated 
(i.e., < 4 components available) at a visit, the CDAI score will be considered missing.
5.3.2.
Primary Estimand (Estimand 1)
The primary estimand, i.e. a precise definition of the primary targeted treatment effect, is defined 
by the following 5 attributes:
Treatment by Week 12:
Experimental:

Active dose 1: JNJ-64304500 400 mg SC at Week 0 and 200 mg SC at Weeks 2, 4, and 8  

Active dose 2: JNJ-64304500 150 mg SC at Week 0 and 75 mg SC at Weeks 2, 4, and 8

Active dose 3: JNJ-64304500 50 mg SC at Week 0 and 25 mg SC at Weeks 2, 4, and 8
Control: Placebo SC at Weeks 0, 2, 4, and 8
Note: Part II of this study also has an ustekinumab reference group which is not included in this 
Estimand.
Population: subjects 18 years or older with moderately to severely active Crohn’s disease.
Variable (Endpoint): change from baseline in the CDAI score at Week 12. Subjects who have 
intercurrent events in categories 1-3 (defined below) prior to the Week 12 visit will have a zero 
change from baseline in the CDAI score assigned, regardless of the observed data.


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Intercurrent Events and Corresponding Strategies: 
The following are the intercurrent events considered for this trial:
1.
A Crohn’s disease-related surgery (with the exception of drainage of an abscess or seton 
placement).
2.
A prohibited change in Crohn’s disease medication (described in Attachment 1).
3.
Discontinuation of study intervention due to lack of efficacy or an AE of worsening 
Crohn’s disease.
4.
Discontinuation of study intervention due to COVID-19 related reasons (excluding 
COVID-19 infection).
5.
Discontinuation of study intervention due to reasons other than lack of efficacy or an AE 
of worsening Crohn’s disease (including COVID-19 infection).
Intercurrent events (ICEs) in categories 1-3 will be handled by the composite strategy, and ICE 
category 4 will be handled by the hypothetical strategy (as if subjects would have not experienced 
this intercurrent event), and ICE category 5 will be handled by the treatment policy strategy.  This 
estimand acknowledges that having an intercurrent event in categories 1-3 is an unfavorable 
outcome. For subjects experiencing ICE 4, CDAI data at all visits after an ICE will be set to 
missing. For subjects experiencing ICE 5, observed values of the variable will be used, if available.
For subjects experiencing multiple ICEs, the overall strategy will be based on the first ICE.
Population-level summary: Difference in means between each JNJ-64304500 treatment group 
and the placebo treatment group.
5.3.3.
Analysis Methods for the Primary Estimand
5.3.3.1.
Estimator (Analysis) for the Primary Estimand
In the primary efficacy analysis (i.e. the main estimator for the primary estimand), data from all 
subjects 
in the FAS (Section 2.2.2) will be analyzed according to the randomized study 
intervention regardless of the study intervention they actually received.
The objective of the primary analysis is to detect a dose-response signal and then identify the 
minimum effective dose (MED).
Data used in the primary analysis includes all values for change from baseline in CDAI score 
collected up to and including Week 12 for all subjects in the FAS.  Any CDAI score collected 
after experiencing ICEs 1-3 will be replaced by the baseline observation for CDAI.  For example, 
if the ICE occurs between the Week 8 and Week 10 visit, the baseline CDAI will be used as the 
Weeks 10 and 12 CDAI scores. Any CDAI score collected after experiencing ICE 4 will be set to 
missing. A subject experiencing ICE 5 will use their observed data through Week 12 (if available), 
including those collected after the ICE; otherwise their data after the ICE will be missing. For 
subjects experiencing multiple ICEs, the overall strategy will be based on the first ICE. In addition, 
intermediate missing data is possible due to missed visits, missed data collections, etc.


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The Mixed-Effect Model Repeat Measures (MMRM) (see Section 5.3.3.1.1) will be used to 
estimate the mean change from baseline at Week 12 for each of the treatment arms (i.e., placebo 
and 3 active doses). This estimate will be used in MCP-Mod.
A unified dose-finding strategy called MCP-Mod that combines multiple comparison procedures 
with modeling techniques will be used to analyze the dose response data. This approach consists 
of 2 major steps. The first step consists of testing the dose response signal via multiple contrast 
tests while controlling the overall Type 1 error.  If a dose response signal is detected (i.e., statistical 
significance is observed in at least one of the contrast tests of the first step), the second step is to 
select a model that best describes the observed data and use it to estimate/select an adequate dose 
with associated precision. 
The road map for the MCP-Mod method is shown in Figure 4.
Step 1 starts with a set of candidate models (see Table 1 in Section 1.4) for representing the dose 
response relationship. For this step, doses under consideration are placebo, JNJ-64304500 high 
dose, JNJ-64304500 middle dose, and JNJ-64304500 low dose. 
Figure 4:
Process for the MCP-mod method
For each candidate model, its significance will be evaluated as follows: first, the optimum contrast 
coefficients will be computed; then a single contrast test for each model will be performed based 
on the optimal contrast coefficients applied to the estimated mean changes from baseline in CDAI 
score per dose, adjusting for baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), 
and Bio-IR status (yes or no). If the maximum of the contrast test statistics is larger than a 
computed critical value q, a significant dose-response signal is established. The critical value q 
will be calculated at the time of the analysis based on the multivariate t-distribution, so that the 
overall Type 1 error rate is controlled at the 0.05 (2-sided) level.


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If none of the contrast test statistics corresponding to the candidate models are significant, it will 
be concluded that no dose response signal is detected for the given sample size and candidate 
models, and the second step of the MCP-Mod procedure will not be undertaken. 
If at least 1 model contrast test statistic is significant, a reference set of good (statistically 
significant) models is obtained. The model associated with the minimum p value in the reference 
set may be selected as the most adequate dose response model unless there are issues with fitting 
this selected model in the second step (e.g., the fitted model is not convergent). Since each model 
in the reference set is statistically significant and may approximate the true model satisfactorily,
other models in the reference set may also be selected as the most adequate dose response model, 
giving consideration to other criteria such as model convergence and/or interpretation.
Once an adequate model has been selected, the next step of MCP-Mod consists of fitting the 
selected model to the data with baseline CDAI score (≤300 or >300), SNP-positive status (yes or 
no), and Bio-IR status (yes or no) as covariates and estimating the target dose of interest. For this 
step, data from all the doses will be used. The target dose will be based on the estimation of the 
MED, defined as the smallest dose within the dose range that shows a clinically relevant and 
statistically significant effect. The MED can be any value on a continuous scale.  To be more 
specific, the MED is defined as the smallest dose that meets both of the following criteria after 
adjusting for baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), and Bio-IR 
status (yes or no). Figure 5 illustrates the estimation of the target dose.

The estimated placebo-corrected treatment difference is at least 40 points (i.e., a clinically 
relevant treatment effect) above that of the placebo level.

The lower bound of the 80% confidence interval (CI) for the estimated placebo-corrected
response is greater than zero (i.e., a statistically significant effect).
If no dose meets both of these criteria, then the MED is not defined. If the MED can be estimated,
the target dose is chosen to be the smallest dose under study whose predicted treatment difference 
is greater than or equal to that of the MED.  By definition, the MED is ≤the target dose.  


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Figure 5:
Estimation of the target dose based on fitted model
If a dose-response relationship cannot be established (i.e. not achieving statistical significance) 
from the dose-response analysis, the totality of data (efficacy, safety, PK data from Part I, 
part II, as well as the available data for JNJ-64304500 from other indications) will be evaluated
and the reason for lack of a dose-response signal will be investigated to decide whether to 
proceed with the dose selection. 
Missing Data Handling Rules

To avoid the need for data imputation for subjects who have insufficient data to calculate 
their CDAI score at Week 12 (i.e. <4 components of the CDAI are available), the MMRM
will be used to estimate the mean change from baseline at Week 12 for each of the 
treatment arms (i.e., placebo and active doses) based on the observed data only. The 
generalized MCP-Mod procedure (Pinheiro et al, 2014)8 will be applied to estimated 
mean changes from baseline at Week 12, as previously described.
Part II will be considered positive if a dose-response signal for the primary endpoint is detected.
In addition, pooled Part I and Part II data might be used for the analyses.
5.3.3.1.1.
Pairwise Comparisons
In addition to the dose-response analysis, pairwise comparisons of each JNJ-64304500 treatment 
group versus the placebo group will be performed for the change from baseline in the CDAI score 
at Week 12 by MMRM. Pairwise comparisons will not be adjusted for multiplicity.


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Pairwise comparisons of the ustekinumab treatment group with each JNJ-64304500 treatment 
group or with placebo are not planned; however, summary statistics will be provided for the 
ustekinumab treatment group.
Missing data for CDAI scores will be addressed by MMRM. In MMRM, missing data for the 
CDAI scores will not be imputed but missing data will be accounted for through correlation of 
repeated measures in the model under the assumption of missing at random (MAR). The 
explanatory variables of the model will include treatment group, SNP-positive status (yes or no),
Bio-IR status (yes or no), baseline CDAI score, visit, and an interaction term of visit with treatment 
group. The model will include data from all 3 JNJ-64304500 treatment groups and placebo group
through Week 12. An unstructured covariance matrix for repeated measure within a subject will 
be used. The F-test will use Kenward-Roger’s approximation for degrees of freedom. In case of 
lack of convergence, empirical structured covariances will be used in the following order until 
convergence is reached: 1) Toeplitz 2) first order Autoregressive Moving Average.
The treatment difference between each JNJ-64304500 treatment group and the placebo group will 
be estimated by the difference in the least squares means (LSmeans). The 95% 2-sided confidence 
interval (CI) for the differences in LSmeans and p-values will be calculated based on the MMRM.
5.3.3.2.
Subgroup Analyses
The subgroup analyses for the primary endpoint will focus on the pairwise comparisons of each
JNJ-64304500 treatment group versus the placebo group.
To evaluate the consistency of the efficacy of the primary endpoint over different subgroups
(demographic, baseline disease characteristics, baseline concomitant medications, and history of 
CD-related medications), the change from baseline in CDAI at Week 12 will be analyzed for the 
subgroups defined in Section 2.3 when the number of subjects in the subgroups permits. The same 
analysis methods and same data handling rules as specified in Section 5.3.3.1.1 will be applied. 
The 95% 2-sided confidence interval (CI) for the differences in LSmeans and p-values will be 
calculated based on the MMRM.
5.3.4.
Supplementary Estimands for the Primary Endpoint
5.3.4.1.
Estimand 2
The components of this supplementary estimand are the same as those for the primary estimand 
with the exception of the Variable (Endpoint) and the ICE strategy, which are described as follows:  
Variable (Endpoint):  change from baseline in the CDAI score at Week 12. Subjects who have 
an intercurrent event described by categories 1-5 will have a zero change from baseline in the 
CDAI score assigned, regardless of the observed data.
ICE strategy: all ICEs are addressed by the composite strategy.


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5.3.4.2.
Estimand 3
The attributes of this supplementary estimand are the same as those for the primary estimand with 
the exception of Variable (Endpoint) and the ICE strategy, which are described as follows:
Variable (Endpoint):  Change from baseline in the CDAI score at Week 12.
ICE strategy: all intercurrent events are addressed by the hypothetical strategy: as if subjects 
would have not experienced these intercurrent events. This supplementary estimand defines the 
treatment effect as if the treatment was taken as directed and no intercurrent events would have 
occurred; therefore, CDAI data at all visits after an ICE will be set to missing.
5.3.5.
Estimator (Analysis) for the Supplementary Estimands of the Primary 
Endpoint
The same analysis methods for the primary Estimand (Estimand 1) described in Section 5.3.3.1
will be used for Estimands 2 and 3. The missing CDAI scores will be addressed by MMRM which 
is accounted for through correlation of repeated measures in the model under the assumption of 
missing at random (MAR).


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5.3.6.
Summary of Analyses Related to the Primary Endpoint 
Table 5:
Summary of Analyses Related to the Primary Endpoint of Change from Baseline in the CDAI 
Score at Week 12
Analysis 
(Analysis Set)
Missing data
Analysis method/Summary statistics
Analyses based on Primary Estimand (Estimand 1), where ICEs 1-3 (CD-related surgery, prohibited change in CD 
medication, and discontinuation of study intervention due to lack of efficacy or an AE of worsening Crohn’s disease) 
are handled by the composite strategy, ICE 4 (discontinuation of study intervention due to COVID-19) is handled by 
the hypothetical strategy, and ICE 5 (discontinuation of study intervention due to other reasons) is handled by the 
treatment policy strategy
Primary Analysis
(FAS)
Missing data due to missed visits or 
missed data collection, due to ICE 4, 
or due to ICE 5 in the absence of 
observed data.  Missing data is not 
imputed, but is handled through the 
MMRM assuming MAR. 

Descriptive summary statistics

MMRM model for
o
LS mean (SD) for each treatment group
o
Treatment differences in LS means (95% CI)
o
P-values for comparing LS means

MCP-MOD for 
o
List of contrasts for each pre-specified model
o
P-values for multiple contrast test
o
Dose-response curve to find MED based on 
selected model
Subgroup 
Analyses 
(Individual 
subgroup levels 
defined in 
Section 2.3, FAS)
Missing data due to missed visits or 
missed data collection, due to ICE 4, 
or due to ICE 5 in the absence of 
observed data.  Missing data is not 
imputed, but is handled through the 
MMRM assuming MAR. 

Descriptive summary statistics

MMRM model for
o
LS mean (SD) for each treatment group
o
Treatment differences in LS means (95% CI)
o
P-values for comparing LS means
Analyses based on Supplementary Estimand 2, where all ICEs are addressed by the composite strategy.
Supplementary
Analysis 1
(FAS)
Missing data due to missed visits or 
missed data collection. Missing data is 
not imputed, but is handled through 
the MMRM assuming MAR. 

Descriptive summary statistics

MMRM model for
o
LS mean (SD) for each treatment group
o
Treatment differences in LS means (95% CI)
o
P-values for comparing LS means

MCP-MOD for 
o
List of contrasts for each pre-specified model
o
P-values for multiple contrast test
o
Dose-response curve to find MED based on 
selected model
Analyses based on Supplementary Estimand 3, where all ICEs are handled by the hypothetical strategy.
Supplementary 
Analysis 2
(FAS)
Data is considered missing after the 
occurrence of an ICE and also due to 
missed visits or missed data 
collection. Missing data is not 
imputed, but is handled through the 
MMRM assuming MAR. 

Descriptive summary statistics

MMRM model for
o
LS mean (SD) for each treatment group
o
Treatment differences in LS means (95% CI)
o
P-values for comparing LS means

MCP-MOD for 
o
List of contrasts for each pre-specified model
o
P-values for multiple contrast test
o
Dose-response curve to find MED based on 
selected model


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5.4.
Major Secondary Endpoints
The testing of the major secondary endpoints will occur regardless of the significance of the 
primary endpoint.  The testing of these major secondary endpoints will not be adjusted for 
multiplicity, and statements of significance for these endpoints will be based on nominal p-values. 
A 2-sided significance level of 0.05 will be used. 
In the analysis of the major secondary endpoints, data from all subjects in the FAS will be analyzed 
according to the randomized study intervention regardless of the study intervention they actually 
received.
The major secondary endpoints are:

Clinical remission at Week 12 as measured by CDAI.

Clinical response at Week 12 as measured by CDAI.

Change from baseline in PRO-2 at Week 12.

Clinical remission at Week 12 as measured by PRO-2.

Clinical response at Week 12 as measured by PRO-2.

Change from baseline in SES-CD at Week 12 for subjects who had baseline SES-CD score 
≥3 (excluding the contribution of the narrowing component score).
5.4.1.
Definitions
Clinical remission as measured by CDAI
Clinical remission as measured by CDAI is defined as a CDAI score <150.
Clinical response as measured by CDAI
Clinical response as measured by CDAI is defined as a ≥100-point reduction from baseline in 
CDAI or clinical remission (CDAI<150).
PRO-2 score
PRO-2 score is defined as the sum of the abdominal pain and stool frequency components of the 
CDAI score (Note: these components have the weighting used in the calculation of the CDAI). If 
one of these two components cannot be evaluated, then the PRO-2 score will be set to missing.
Clinical remission as measured by PRO-2
Clinical remission as measured by PRO-2 is defined as a PRO-2 score <75.
Clinical response as measured by PRO-2
Clinical response as measured by PRO-2 is defined as a ≥50-point reduction from baseline in 
PRO-2 or PRO-2 <75.


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Simple endoscopic activity score for Crohn’s disease
The Simplified Endoscopic Activity Score for Crohn’s Disease (SES-CD) is a scoring system 
developed to provide a more granular evaluation of endoscopic disease severity in patients with 
Crohn’s disease. It is constructed based on the evaluation of 4 endoscopic components across 
5 predefined ileocolonic segments. The 4 endoscopic components within each segment are:  the 
presence and size of ulcers, the proportion of mucosal surface covered by ulcers, the proportion of 
mucosal surface affected by any other lesions, and the presence/ type of narrowing (also commonly 
referred to as strictures/stenosis clinically).  Each endoscopic component is scored from 0 to 3 for 
each segment, and a total score is calculated as a sum of all the component scores across all the
segments, as outlined in Table 6.  The total SES-CD score ranges from 0 to 56.
Calculation of the SES-CD score:
Main approach (SES-CD calculated based on all segments available):
The total SES-CD score at each visit will be calculated based on all segments scored at the visit. 
If the total SES-CD score cannot be calculated (i.e., no segment is scored) at a visit, the total 
SES-CD score will be considered missing.
Alternative approach (baseline segments matched approach):
To calculate the SES-CD score at a visit, the sum of the segments that were present at baseline 
will be used. For segments that were present at baseline but missing post-baseline, the last available
score for the missing segment(s) will be carried forward.  In the event that a segment is missing at 
baseline but non-missing at post-baseline, the non-missing post-baseline score is not used in the 
calculation of SES-CD.


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Table 6:
Sample score sheet and scoring definitions for the Simple Endoscopic Score for Crohn’s Disease 
(SES-CD)
Ileum
Right 
Colon
Transverse 
Colon
Left 
Colon
Rectum
Total
1. Presence and size of ulcers (0-3)
15 max
2. Extent of ulcerated surface (0-3)
15 max
3. Extent of affected surface (0-3)
15 max
4. Presence and type of narrowing (0-3)
11 max*
Total 1 + 2 + 3 + 4 =
SES-CD
(56 max)
Score = 0
Score = 1
Score = 2
Score = 3
Size of ulcers
None
Aphthous ulcers 
(ø 0.1 – 0.5 cm)
Large ulcers 
(ø 0.5 – 2.0 cm)
Very large ulcers
(ø > 2.0 cm)
Ulcerated surface
None
<10%
10-30%
>30%
Affected surface
Unaffected segment
<50%
50-75%
>75%
Narrowings
None
Single, can be passed
Multiple, can be passed
Cannot be passed
* The maximum sub-score for narrowings (i.e. stricturing) is 11 points. The presence of a narrowing that cannot be 
passed can be only observed once.
ø =Diameter.
5.4.2.
Main Estimands for the Major Secondary Endpoints
The following describes the attributes of the main estimands for the major secondary endpoints 
(corresponding to Estimands 4-9):
Treatment by Week 12: Same as Estimand 1, ie:
Experimental:

Active dose 1: JNJ-64304500 400 mg SC at Week 0 and 200 mg SC at Weeks 2, 4, and 8  

Active dose 2: JNJ-64304500 150 mg SC at Week 0 and 75 mg SC at Weeks 2, 4, and 8

Active dose 3: JNJ-64304500 50 mg SC at Week 0 and 25 mg SC at Weeks 2, 4, and 8
Control: Placebo SC at Weeks 0, 2, 4, and 8
Note: Part II of this study also has an ustekinumab reference group which is not included in this 
Estimand.
Population: subjects 18 years or older with moderately to severely active Crohn’s disease.


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Variables and Population-level Summary
Table 7:
Variables and Population-level Summary for the main estimand for each Major Secondary 
Endpoint
Estimand
Variable (Endpoint)
Population-level summary
4
Clinical remission at Week 12 as measured by 
CDAI (CDAI score <150 and no ICE 1-3 by 
Week 12).
Difference in percentage of subjects who achieved
clinical remission at Week 12 as measured by 
CDAI between each JNJ-64304500 treatment 
group and the placebo treatment group.
5
Clinical response at Week 12 as measured by CDAI
(≥100-point reduction from baseline in CDAI score 
or CDAI score <150 and no ICE 1-3 by Week 12).
Difference in percentage of subjects who achieved 
clinical response at Week 12 as measured by CDAI 
between each JNJ-64304500 treatment group and 
the placebo treatment group.
6
Change from baseline in PRO-2 at Week 12.
Subjects who have ICE 1-3 prior to the Week 12 
visit will have a zero change from baseline in the 
PRO-2 score assigned.
Difference in the mean change from baseline in 
PRO-2 at Week 12 between each JNJ-64304500 
treatment group and the placebo treatment group.
7
Clinical remission at Week 12 as measured by 
PRO-2 (PRO-2 score <75 and no ICE 1-3 by 
Week 12).
Difference in percentage of subjects who achieved 
clinical remission at Week 12 as measured by 
PRO-2 between each JNJ-64304500 treatment 
group and the placebo treatment group.
8
Clinical response at Week 12 as measured by PRO-
2 (≥50-point reduction from baseline in PRO-2 or 
PRO-2 <75 and no ICE 1-3 by Week 12).
Difference in percentage of subjects who achieved 
Clinical response at Week 12 as measured by 
PRO-2 between each JNJ-64304500 treatment 
group and the placebo treatment group.
9
Change from baseline in SES-CD at Week 12 for 
subjects who had baseline SES-CD score ≥3 
(excluding the contribution of the narrowing 
component score). Subjects who have ICE 1-3 prior 
to the Week 12 visit will have a zero change from 
baseline in the SES-CD score assigned.
Difference in the mean change from baseline in 
SES-CD at Week 12 between each JNJ-64304500 
treatment group and the placebo treatment group.
Intercurrent Events and Corresponding Strategies: 
The intercurrent events for all major secondary endpoints are the same as those used in the primary 
estimand, and are as follows: 
1.
A Crohn’s disease-related surgery (with the exception of drainage of an abscess or seton 
placement).
2.
A prohibited change in Crohn’s disease medication (described in Attachment 1).
3.
Discontinuation of study intervention due to lack of efficacy or an AE of worsening 
Crohn’s disease.


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4.
Discontinuation of study intervention due to COVID-19 related reasons (excluding 
COVID-19 infection).
5.
Discontinuation of study intervention due to reasons other than lack of efficacy or an AE 
of worsening Crohn’s disease (including COVID-19 infection).
ICEs 1-3 are handled by the composite strategy, and ICE category 4 is handled by the hypothetical
strategy (as if subjects would have not experienced these intercurrent events), and ICE 5 is 
addressed by the treatment policy strategy. If a subject had any of the ICE categories 1-3 prior to 
Week 12, the subject will be considered not to be in clinical remission at Week 12 as measured 
by CDAI, clinical response at Week 12 as measured by CDAI, clinical remission at Week 12 as 
measured by PRO-2, and clinical response at Week 12 as measured by PRO-2; in addition, a zero 
change from baseline in the PRO-2 and SES-CD scores will be assigned for subjects experiencing 
ICEs 1-3 and data at all visits after an ICE 4 will be set to missing. For subjects experiencing ICE 
5, observed values of the variable will be used for all major secondary endpoints, if available. For 
subjects experiencing multiple ICEs, the overall strategy will be based on the first ICE.
5.4.3.
Analysis Methods for the Main Estimands for the Major Secondary 
Endpoints
5.4.3.1.
Estimators (Analyses) for the Main Estimands
In the analysis of the major secondary endpoints, data from all subjects in the FAS will be analyzed 
according to the randomized study intervention regardless of the study intervention they actually 
received.
Descriptive statistics (i.e., mean, median, SD, IQ range, minimum, and maximum) will be used to 
summarize continuous variables. Counts and percentages will be used to summarize binary
variables.
The major secondary endpoints of clinical remission and clinical response at Week 12 (defined by 
either CDAI or PRO-2) will be compared between each of the JNJ-64304500 treatment groups 
and the placebo group using the Cochran-Mantel-Haenszel (CMH) chi-square test (2-sided) 
stratified by baseline CDAI score (≤300 or >300), SNP-positive status (yes or no), and Bio-IR 
status (yes or no). The adjusted treatment difference (with Cochran-Mantel-Haenszel weight) 
between each of the JNJ-64304500 treatment groups and the placebo group, as well as the 
associated 95% confidence interval, will be presented.
The change from baseline in PRO-2 at Week 12 will be compared between each of the 
JNJ-64304500 treatment groups and the placebo group using MMRM method. The explanatory 
variables of the model will include treatment group, SNP-positive status (yes or no), Bio-IR status 
(yes or no), baseline PRO-2 score, visit, and an interaction term of visit with treatment group.
The change from baseline in SES-CD score at Week 12 (this is the only scheduled post-baseline 
visit for SES-CD data collection) will be compared between each of the JNJ-64304500 treatment 
groups and the placebo group using an analysis of covariance (ANCOVA) with treatment as a 
fixed factor and respective baseline score and baseline CDAI score (≤300 or >300), Bio-IR status 


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(yes or no), and SNP-positive status (yes or no) as covariates. The main approach will be used to 
calculate the SES-CD. An analysis will also be performed using the alternative approach to 
calculate the SES-CD. 
For SES-CD analysis using ANCOVA, multiple imputation (imputed 200 times to generate 200 
complete data sets using the Markov chain Monte Carlo method, assuming missing at random and 
a multivariate normal distribution) will be used to impute the missing SES-CD data.

Weeks 0 and 12 SES-CD values and design variables (treatment assignment,baseline CDAI 
score (≤300 or >300), Bio-IR status (yes or no), and SNP-positive status (yes or no)) will be 
used to impute the missing SES-CD values.
For the major secondary endpoints, pairwise comparisons of the ustekinumab treatment group with 
each JNJ-64304500 treatment group or with placebo are not planned; however, summary statistics 
will be provided for the ustekinumab treatment group.
5.4.3.1.1.
Additional Missing Data Rules for the Main Estimands
After accounting for the intercurrent events, any missing data for the binary major secondary 
endpoints will be handled with nonresponder imputation. In particular, the following rules will be 
used: 

Subjects who have a missing CDAI score (i.e. <4 components of the CDAI score) at 
Week 12 will be considered not to be in clinical remission or clinical response, as measured 
by the CDAI score. 

Subjects who have a missing PRO-2 score (i.e. at least one component score of the PRO-2 
is missing) at Week 12 will be considered not to be in clinical remission or clinical response 
as measured by the PRO-2 score. 
Missing data for the change from baseline in the PRO-2 score will be addressed by MMRM. In 
MMRM, missing data for the scores will not be imputed but missing data will be accounted for 
through correlation of repeated measures in the model under the assumption of missing at random 
(MAR).
5.4.4.
Supplementary Estimands for the Major Secondary Endpoints
Supplementary estimands 10-15 will be used to complement Estimands 4-9. 
The attributes of the supplementary estimands are the same as those for the main estimands for the 
major secondary endpoints, with the exception of the variable (endpoint), which is described as 
follows:


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Variable (Endpoint):  
Estimand
Variable (Endpoint)
10
Clinical remission at Week 12 as measured by CDAI (CDAI score <150 and no ICE by Week 12).
11
Clinical response at Week 12 as measured by CDAI (≥100-point reduction from baseline in CDAI 
score or CDAI score <150 and no ICE by Week 12).
12
Change from baseline in PRO-2 at Week 12. Subjects who have any ICE prior to the Week 12 visit 
will have a zero change from baseline in the PRO-2 score assigned.
13
Clinical remission at Week 12 as measured by PRO-2 (PRO-2 score <75 and no ICE by Week 12).
14
Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from baseline in PRO-2 
or PRO-2 <75 and no ICE by Week 12).
15
Change from baseline in SES-CD at Week 12 for subjects who had baseline SES-CD score ≥3 
(excluding the contribution of the narrowing component score). Subjects who have any ICE prior to 
the Week 12 visit will have a zero change from baseline in the SES-CD score assigned.
All ICEs are handled by the composite strategy. If a subject had any ICEs prior to Week 12, the 
subject  will be considered not to be in clinical remission at Week 12 as measured by CDAI, 
clinical response at Week 12 as measured by CDAI, clinical remission at Week 12 as measured by 
PRO-2, and clinical response at Week 12 as measured by PRO-2. In addition, a zero change from 
baseline in the PRO-2 and SES-CD scores will be assigned for subjects experiencing any ICEs.
5.4.5.
Estimators for the Supplementary Estimands of the Major Secondary 
Endpoints
The same analysis methods for the main estimands described in Sections 5.4.3.1 and 5.4.3.1.1 will 
be used for the supplementary estimands of the major secondary endpoints. 
5.4.6.
Summary of Analyses Related to Major Secondary Endpoints
Table 8 below provides an overview of all the analyses related to the major secondary endpoints, 
the estimands, the analysis sets, the data handling rules to be used, and the analysis methods and 
summary statistics.   


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Table 8:
Summary of Analyses Related to Major Secondary Endpoints
Endpoints
(Analysis Set)
Missing data
Analysis method/Summary statistics
Analyses based on Main Estimands 4-9, where ICEs 1-3 are handled by the composite strategy, ICE 4 is handled by 
the hypothetical strategy, and ICE 5 is handled by the treatment policy strategy 

Clinical remission at Week 12 
as measured by CDAI (FAS)

Clinical response at Week 12 
as measured by CDAI (FAS)

Clinical remission at Week 12 
as measured by PRO-2 (FAS)

Clinical response at Week 12 
as measured by PRO-2 (FAS)
Missing data due to missed 
visits or missed data 
collection, due to ICE 4, or 
due to ICE 5 in the absence 
of observed data.  Subjects 
with missing data are 
considered to be non-
responders (NRI)

Summaries of the proportion of subjects who 
achieved the endpoint 

Treatment difference (JNJ-64304500 group-
placebo group) and 95% CI 

P-value from the CMH test stratified by baseline 
CDAI score (≤300 or >300), SNP-positive status 
(yes or no), and Bio-IR status (yes or no)

Change from baseline in 
PRO-2 at Week 12 (FAS)

Change from baseline in SES-
CD at Week 12 for subjects 
who had baseline SES-CD 
score ≥3 (excluding the 
contribution of the narrowing 
component score) (FAS)
Missing data due to missed 
visits or missed data 
collection, due to ICE 4, or 
due to ICE 5 in the absence 
of observed data.  Missing 
data is not imputed, but is 
handled through the 
MMRM assuming MAR.

Descriptive summary statistics

MMRM model for PRO-2; ANCOVA for 
SES-CD
o
LS mean (SD) for each treatment group
o
Treatment differences in LS means (95% 
CI)

P-values for comparing LS means
Analyses based on Supplementary Estimands 10-15, where all ICEs are addressed by the composite strategy.

Clinical remission at Week 12 
as measured by CDAI (FAS)

Clinical response at Week 12 
as measured by CDAI (FAS)

Clinical remission at Week 12 
as measured by PRO-2 (FAS)

Clinical response at Week 12 
as measured by PRO-2 (FAS)
Missing data due to missed 
visits or missed data 
collection.  Subjects with 
missing data are 
considered to be non-
responders (NRI)

Summaries of the proportion of subjects who 
achieved the endpoint 

Treatment difference (JNJ-64304500  group-
placebo group) and 95% CI 

P-value from the CMH test stratified by 
baseline CDAI score (≤300 or >300), SNP-
positive status (yes or no), and Bio-IR status 
(yes or no)

Change from baseline in PRO-
2 at Week 12 (FAS)

Change from baseline in SES-
CD at Week 12 for subjects 
who had baseline SES-CD 
score ≥3 (excluding the 
contribution of the narrowing 
component score) (FAS)
Missing data due to missed 
visits or missed data 
collection. Missing data is 
not imputed, but is handled 
through the MMRM 
assuming MAR.

Descriptive summary statistics

MMRM model for PRO-2; ANCOVA for SES-
CD
o
LS mean (SD) for each treatment group
o
Treatment differences in LS means (95% 
CI)

P-values for comparing LS means
5.5.
Other Endpoints
The testing of the other endpoints will occur regardless of the significance of the major secondary 
endpoints.  The testing of these endpoints will not be adjusted for multiplicity, and statements of 
significance for these endpoints will be based on nominal p-values. A 2-sided significance level 
of 0.05 will be used. 


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The endpoints in the following list will be analyzed. 

Change from baseline in CDAI at Week 12 for subjects who had baseline SES-CD ≥3 
(excluding the contribution of the narrowing component score), for subjects who had baseline 
SES-CD ≥6 (excluding the contribution of the narrowing component score), for subjects who 
had isolated ileal disease with baseline SES-CD ≥4 or subjects who had colonic or ileocolonic 
disease with baseline SES-CD ≥6, and for subjects who had baseline abdominal pain mean 
daily score ≥1 and stool frequency mean daily score ≥1.5.

Clinical remission at Week 12 as measured by CDAI (CDAI <150) for subjects who had 
baseline SES-CD ≥3 (excluding the contribution of the narrowing component score), for 
subjects who had baseline SES-CD ≥6 (excluding the contribution of the narrowing 
component score), for subjects who had isolated ileal disease with baseline SES-CD ≥4 or 
subjects who had colonic or ileocolonic disease with baseline SES-CD ≥6, and for subjects 
who had baseline abdominal pain mean daily score ≥1 and stool frequency mean daily score 
≥1.5.

Clinical response at Week 12 as measured by CDAI (≥100-point reduction from baseline in 
CDAI or CDAI <150) for subjects who had baseline SES-CD ≥3 (excluding the contribution 
of the narrowing component score), for subjects who had baseline SES-CD ≥6 (excluding the 
contribution of the narrowing component score), for subjects who had isolated ileal disease 
with baseline SES-CD ≥4 or subjects who had colonic or ileocolonic disease with baseline 
SES-CD ≥6, and for subjects who had baseline abdominal pain mean daily score ≥1 and stool 
frequency mean daily score ≥1.5.

Change from baseline in PRO-2 at Week 12 for subjects who had baseline SES-CD ≥3 
(excluding the contribution of the narrowing component score), for subjects who had baseline 
SES-CD ≥6 (excluding the contribution of the narrowing component score), for subjects who 
had isolated ileal disease with baseline SES-CD ≥4 or subjects who had colonic or ileocolonic 
disease with baseline SES-CD ≥6, and for subjects who had baseline abdominal pain mean 
daily score ≥1 and stool frequency mean daily score ≥1.5.

Clinical remission at Week 12 as measured by PRO-2 (PRO-2 <75) for subjects who had 
baseline SES-CD ≥3 (excluding the contribution of the narrowing component score), for 
subjects who had baseline SES-CD ≥6 (excluding the contribution of the narrowing 
component score), for subjects who had isolated ileal disease with baseline SES-CD ≥4 or 
subjects who had colonic or ileocolonic disease with baseline SES-CD ≥6, and for subjects 
who had baseline abdominal pain mean daily score ≥1 and stool frequency mean daily score 
≥1.5.

Clinical response at Week 12 as measured by PRO-2 (≥50-point reduction from baseline in 
PRO-2 or PRO-2 <75) for subjects who had baseline SES-CD ≥3 (excluding the contribution 
of the narrowing component score), for subjects who had baseline SES-CD ≥6 (excluding the 
contribution of the narrowing component score), for subjects who had isolated ileal disease 
with baseline SES-CD ≥4 or subjects who had colonic or ileocolonic disease with baseline 
SES-CD ≥6, and for subjects who had baseline abdominal pain mean daily score ≥1 and stool 
frequency mean daily score ≥1.5.

Change from baseline in CDAI at all postbaseline visits.


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
Change from baseline in CDAI at all postbaseline visits for subjects who had daily average
stool frequency score >=4 or daily average abdominal pain score >=2 at baseline based on the 
CDAI assessment.

Clinical remission based on CDAI at all postbaseline visits.

Clinical remission based on CDAI at all postbaseline visits for subjects who had daily average
stool frequency score >=4 or daily average abdominal pain score >=2 at baseline based on the 
CDAI assessment.

Clinical response based on CDAI at all postbaseline visits.

Clinical response based on CDAI at all postbaseline visits for subjects who had daily average
stool frequency score >=4 or daily average abdominal pain score >=2 at baseline based on the 
CDAI assessment.

Change from baseline in PRO-2 at all postbaseline visits.

Change from baseline in abdominal pain score (daily average based on the CDAI assessment) 
at all postbaseline visits.

Change from baseline in stool frequency score (daily average based on the CDAI assessment) 
at all postbaseline visits.

Clinical remission based on PRO-2 at all postbaseline visits.

Clinical response based on PRO-2 at all postbaseline visits.

Clinical remission based on unweighted PRO-2 (defined as daily average abdominal pain 
score ≤1 AND daily average stool frequency score ≤3) at all postbaseline visits.

Abdominal pain score (daily average based on the CDAI assessment) ≤1 at all postbaseline 
visits for subjects who had daily average abdominal pain score >1 at baseline.

Number of liquid or very soft stools (daily average based on the CDAI assessment) ≤3 at all 
postbaseline visits for subjects who had daily average number of liquid or very soft stools >3 
at baseline.

Change from baseline in PRO-3 (the sum of abdominal pain, stool frequency, and general 
well-being subscores of the CDAI score) at all postbaseline visits.

Change from baseline in weighted CDAI component scores at all postbaseline visits.

Clinical response based on CDAI at Week 24 among subjects in clinical response at Week 12.

Clinical remission based on CDAI at Week 24 among subjects in clinical response at Week 12.

Clinical remission based on CDAI at Week 24 among subjects in clinical remission at 
Week 12.

Change from baseline in SES-CD score at Week 12 for subjects who had baseline SES-CD 
score ≥6 (excluding the contribution of the narrowing component score). 

Endoscopic improvement at Week 12 based on a reduction from baseline in SES-CD score ≥3 
for subjects who had baseline SES-CD score ≥3 (excluding the contribution of the narrowing 
component score) and for subjects who had baseline SES-CD score ≥6 (excluding the 
contribution of the narrowing component score). 


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
Endoscopic response at Week 12 for subjects who had baseline SES-CD score ≥3 (excluding 
the contribution of the narrowing component score) and for subjects who had baseline SES-
CD score ≥6 (excluding the contribution of the narrowing component score). 

Endoscopic healing (defined as the absence of mucosal ulcerations) at Week 12 for subjects 
who had ulcerations at baseline and baseline SES-CD score ≥3 (excluding the contribution of 
the narrowing component score) and for subjects who had ulcerations at baseline and baseline 
SES-CD score ≥6 (excluding the contribution of the narrowing component score).

Endoscopic remission (defined as a SES-CD score of 0-2) at Week 12 for subjects who had 
baseline SES-CD score ≥3 (excluding the contribution of the narrowing component score) and 
for subjects who had baseline SES-CD score ≥6 (excluding the contribution of the narrowing 
component score).

Change from baseline in total GHAS at Week 12.

Histologic Response (≥ 50% reduction in total GHAS score from baseline) at Week 12.

Histo-Endoscopic Response (histologic response and endoscopic response) at Week 12 for 
subjects who had baseline SES-CD score ≥3 (excluding the contribution of the narrowing 
component score) and for subjects who had baseline SES-CD score ≥6 (excluding the 
contribution of the narrowing component score).

Fistula response at all postbaseline visits, defined as a ≥50% reduction from baseline in the 
number of draining for subjects with draining fistulas at baseline.

Complete fistula response at all post-baseline visits for subjects with draining fistulas at 
baseline.

Change from baseline in daily average number of BSFS types 6 and 7 stools through Week 12.

A ≥2 reduction in daily average number of BSFS types 6 and 7 stools from baseline through 
Week 12 for subjects who had baseline daily average number of BSFS types 6 and 7 stools 
>=2.

A ≥3 reduction in daily average number of BSFS types 6 and 7 stools from baseline through 
Week 12 for subjects who had baseline daily average number of BSFS types 6 and 7 stools
>=3.

Change from baseline in daily average number of BSFS types 5, 6, and 7 stools through 
Week 12.

A ≥2 reduction in daily average number of BSFS types 5, 6, and 7 stools from baseline through 
Week 12 for subjects who had baseline daily number of BSFS types 5, 6, and 7 stools >=2

A ≥3 reduction in daily average number of BSFS types 5, 6, and 7 stools from baseline through 
Week 12 for subjects who had baseline daily number of BSFS types 5, 6, and 7 stools >=3.

Change from baseline in abdominal pain score (daily average based on a 0-10 NRS) at all 
postbaseline visits.

A ≥2-point reduction in abdominal pain score (daily average based on a 0-10 NRS) from 
baseline at all postbaseline visits for subjects who had baseline daily average based on a 0-10 
NRS >=2.


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
A ≥3-point reduction in abdominal pain (daily average based on a 0-10 NRS) from baseline 
at all postbaseline visits for subjects who had baseline daily average based on a 0-10 NRS
>=3.

A ≥3-point reduction in abdominal pain score (daily average based on a 0-10 NRS) and a ≥3 
reduction in daily average number of BSFS types 6 and 7 stools from baseline through 
Week 12 for subjects who had baseline daily average based on a 0-10 NRS >=3 and baseline 
daily average number of BSFS types 6 and 7 stools >=3.

Subjects with abdominal pain score (daily average based on a 0-10 NRS) <3 and daily average 
number of BSFS types 6 and 7 stools <3 through Week 12.

Change from baseline in IBDQ score at Weeks 8, 12, and 24.

Clinical remission based on IBDQ (≥170) at Weeks 8, 12, and 24. 

A ≥16-point improvement in IBDQ from baseline at Weeks 8, 12, and 24. 

Change from baseline in the Physical Component Summary (PCS) and Mental Component 
Summary (MCS) scores of the 36-item Short Form Health Survey (SF-36) at Weeks 8, 12, 
and 24. 

A ≥5-point improvement in PCS or MCS scores of the SF-36 at Weeks 8, 12, and 24. 

Change from baseline in CRP at all postbaseline visits.

Normalization in CRP at all postbaseline visits for subjects with abnormal CRP at baseline.

Change from baseline in fecal calprotectin at Weeks 2, 8, 12, and 24.

Normalization in fecal calprotectin at Weeks 2, 8, 12, and 24 for subjects with abnormal fecal 
calprotectin at baseline.

Change from baseline in fecal lactoferrin at Weeks 2, 8, 12, and 24.

Normalization in fecal lactoferrin at Weeks 2, 8, 12, and 24 for subjects with abnormal fecal 
lactoferrin at baseline.

Clinical-biomarker response at Week 12.

Change from baseline in the CDAI at all postbaseline visits by SNP status.

Clinical remission based on CDAI at all postbaseline visits by SNP status.

Clinical response based on CDAI at all postbaseline visits by SNP status.

Change from baseline in SES-CD score at Week 12 by SNP status for subjects who had 
baseline SES-CD score ≥3 (excluding the contribution of the narrowing component score) and 
for subjects who had baseline SES-CD score ≥6 (excluding the contribution of the narrowing 
component score).

Change from baseline in PGIS of Crohn’s disease at Weeks 4, 8, 12, and 24.

A ≥1-point improvement from baseline in PGIS of Crohn’s disease or PGIS=1 (absent) at 
Weeks 4, 8, 12, and 24.

A ≥2-point improvement from baseline in PGIS of Crohn’s disease or PGIS=1 (absent) at 
Weeks 4, 8, 12, and 24.


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
Agreement between PGIS (absent: yes or no) and clinical remission based on CDAI (yes or 
no) at Week 12.

Agreement between PGIS (absent or mild: yes or no) and clinical remission based on CDAI 
(yes or no) at Week 12.

Agreement between clinical remission based on unweighted PRO-2 (defined as daily average 
abdominal pain score ≤1 AND daily average stool frequency score ≤3 based on CDAI 
assessment) and subjects with abdominal pain score (daily average based on a 0-10 NRS) <3 
and daily average number of BSFS types 6 and 7 stools <3 at Week 12.

Empirical Cumulative Distribution Function (eCDF) curves of change from baseline in 
abdominal pain score (daily average based on a 0-10 NRS) at Week 12 by change in PGIS of 
Crohn’s disease at Week 12.

Empirical Cumulative Distribution Function (eCDF) curves of change from baseline in daily 
average number of BSFS types 6 and 7 stools at Week 12 by change in PGIS of Crohn’s 
disease at Week 12.

PGIS of Crohn’s disease in each category at Weeks 0, 4, 8, 12, and 24.

A ≥1-point improvement (a little better now, somewhat better now, or a lot better now) in 
PGIC of severity of Crohn’s disease at Weeks 4, 8, 12, and 24.

A ≥2-point improvement (somewhat better now or a lot better now) in PGIC of severity of 
Crohn’s disease at Weeks 4, 8, 12, and 24.

PGIC of severity of Crohn’s disease in each category at Weeks 4, 8, 12, and 24.
5.5.1.
Definitions
Daily average abdominal pain score
Daily average abdominal pain score is defined as: the sum of abdominal pain/cramps ratings in 
previous 7 days in a dairy card ÷ total days assessment performed. Daily average abdominal pain 
score at a scheduled visit will not be calculated if total days of assessment is less than 5.
Daily average stool frequency score
Daily average stool frequency score is defined as: total number of liquid or very soft stools in 
previous 7 days in a dairy card ÷ total days assessment performed. Daily average stool frequency 
score at a scheduled visit will not be calculated if total days of assessment is less than 5.
Daily average abdominal pain score based on a 0-10 NRS
Daily average abdominal pain score based on a 0-10 NRS is defined as: the sum of abdominal pain 
score based a 0-10 NRS in previous 7 days in a dairy card ÷ total days assessment performed. 
Daily average abdominal pain score at a scheduled visit will not be calculated if total days of 
assessment is less than 5.
Average number of BSFS types 6 and 7 stools per day
Average number of BSFS types 6 and 7 stools per day is defined as: the sum of number of BSFS 
types 6 and 7 stools in previous 7 days in a dairy card ÷ total days assessment performed. Average 


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number of BSFS types 6 and 7 stools per day at a scheduled visit will not be calculated if total 
days of assessment is less than 5.
Clinical remission as measured by unweighted PRO-2
Clinical remission as measured by unweighted PRO-2 is defined as the unweighted CDAI 
component of daily average abdominal pain (AP) score at or below 1 AND the unweighted CDAI 
component of daily average stool frequency (SF) score at or below 3, ie, AP ≤1 and SF ≤3.
PRO-3 score
PRO-3 score is defined as: the sum of abdominal pain, stool frequency, and general well-being
components of the CDAI score (Note: these components have the weighting used in the calculation 
of the CDAI). If one of these three components cannot be evaluated, then the PRO-3 score will be 
set to missing.
Clinical-biomarker response
Clinical-biomarker response at Week 12 is defined as clinical response based on CDAI score and 
≥50% reduction from baseline in CRP or fecal calprotectin
Fistula response 
Fistula response is defined as: ≥50% reduction from baseline in the number of draining fistulas.
Complete Fistula response
Complete fistula response is defined as the complete absence of draining fistulas.
Endoscopic improvement
Endoscopic improvement is defined as ≥3 points reduction from baseline in SES-CD score.
Endoscopic response 
Endoscopic response is defined as a reduction from baseline in SES-CD score of ≥50% or a SES-
CD score ≤2.
Endoscopic healing 
Endoscopic healing is defined as the complete absence of mucosal ulcerations in any ileocolonic 
segment among subjects who presented with ulceration in at least one ileocolonic segment at 
baseline.
Endoscopic remission 
Endoscopic remission is defined as a SES-CD score ≤2.
IBDQ
The Inflammatory Bowel Disease Questionnaire (Irvine et al, 1994)4 is a 32-item questionnaire
specifically designed for subjects with IBD. The range of the IBDQ score is 32 to 224. Higher 
scores indicate better quality of life. The IBDQ has 4 dimension scores (bowel, systemic, social, 


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and emotional). Each of the individual IBDQ dimensions will be calculated when ≤ 1 item is 
missing in the dimension. The missing item will be estimated using the average value across the 
nonmissing items. If any one of the dimensions within the IBDQ cannot be calculated, then the 
total IBDQ score cannot be calculated.
SF-36
The SF-36 was developed as part of the Rand Health Insurance Experiment and consists of 8 multi-
item scales: 

Limitations in physical functioning due to health problems

Limitations in usual role activities due to physical health problems

Bodily pain

General mental health (psychological distress and well-being) 

Limitations in usual role activities due to personal or emotional problems 

Limitations in social functioning due to physical or mental health problems

Vitality (energy and fatigue)

General health perception 
These scales are scored from 0 to 100 with higher scores indicating better health. Another 
algorithm yields 2 summary scores, the Physical Component Summary (PCS) and the Mental 
Component Summary (MCS). These summary scores are also scaled with higher scores indicating 
better health but are scored using a norm-based system where linear transformations are performed 
to transform scores to a mean of 50 and standard deviation of 10, based upon general US population 
norms (Ware et al, 1994).9 The concepts measured by the SF-36 are not specific to any age, disease, 
or treatment group, allowing comparison of relative burden of different diseases and the relative 
benefit of different treatments (Ware and Sherbourne, 1992).10 Eight subscales are calculated 
whenever ≥50% of the items that comprise the individual subscale are available (nonmissing).
Any missing items will be estimated using the average value across the nonmissing items for that 
subscale. If < 50% of the items that comprise the subscale is available, the subscale will not be 
calculated. If any of the individual subscales that comprise the physical component summary score 
or the mental component summary score are missing, then the physical or mental component 
summary scores cannot be calculated.
Histologic assessment and Global Histology Activity Score
Histologic assessment will be performed using biopsy samples collected during endoscopy. Up to 
2 biopsy samples will be collected at screening and Week 12 from each of 3 predefined anatomic 
locations: the terminal ileum, splenic flexure, and rectum. Biopsies will be collected from 
representative areas from each of the predefined locations that are consistent with the inflammation 
status visually observed during endoscopy. Histologic assessment will be conducted by a single 
central reader who is blinded to treatment assignment and visit information. The modified Global 
Histology Activity Score (GHAS) will be used to evaluate histologic improvement.


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Global Histology Activity Score
The Global Histology Activity Score was first described in 1998, and has been subsequently 
utilized in a number of studies resulting in peer-reviewed publications (DHaens, 1998; 
DHaens, 1999; Mojtahed, 2014; Baert, 1999; Laharie, 2011; Mantzaris, 2009).2,3,7,1,5,6 The GHAS 
components and related scores are listed in Table 9.
All biopsies will be scored in a blinded manner using GHAS for each region, with minor 
adaptations for the circumstances of this study:

At each time point, all biopsies (up to 2 biopsies per region) obtained from each of the 
predefined anatomic regions will be scored separately for each of the 6 histological 
features: epithelial damage, architectural changes, infiltration of mononuclear cells into 
the lamina propria, polymorphonuclear cells in the lamina propria (all scored 0-2); 
polymorphonuclear cells in the epithelium (scored 0-3); the presence of erosions/ulcers 
(1 for presence and 0 for absence)

The component of presence of granulomas in the original GHAS will be excluded due to 
the rarity and potentially sporadic nature of granulomas, particularly in individual biopsy 
specimens (prevalence ~2%)

The component of number of biopsies affected in the original GHAS will also be excluded 
because only up to 2 biopsies will be taken from each anatomic region in this study, while 
the component score was constructed based on the assumption that 6 biopsies per region 
are available

The single highest scoring biopsy from each of the anatomic regions will be used as the 
final score for that region.
At each visit, the overall total histologic score will be derived based on the sum of the 3 regional 
scores. The overall GHAS can be calculated when all 3 regional scores are available. A regional 
score for a biopsy will be missing if any of the 6 histological features is missing.


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Table 9:
Scoring System for Histologic Abnormalities in Crohn’s Disease Mucosal Biopsy Specimens
Patient’s Global Impression of Severity (PGIS) of Crohn’s disease
The PGIS of Crohn’s disease is a 5-point scale (“None”, “Mild”, “Moderate”, “Severe” and “Very 
Severe”) to rate Crohn’s disease intensity.    
Patient’s Global Impression of Change (PGIC) of Severity of Crohn’s disease
The PGIC of severity of Crohn’s disease is a 7-point scale ranging from “a lot better now” to “a 
lot worse now” with a neutral center point (“neither better nor worse”) to measure perceived 
change (improvement or deterioration) in severity of Crohn’s disease. 


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SNP-positive
Subjects who are positive in at least 1 of 2 SNPs (NKG2D or MICB) will be considered to be SNP-
positive. Otherwise subjects are SNP-negative.
Abnormal CRP
Abnormal CRP is defined as CRP concentration >3.0 mg/L.
Abnormal fecal lactoferrin
Abnormal fecal lactoferrin is defined as fecal lactoferrin concentration >7.24 mg/kg.
Abnormal fecal calprotectin
Abnormal fecal calprotectin is defined as fecal calprotectin concentration > 250 mg/kg.
5.5.2.
Analysis Methods
Other endpoints listed and defined in Section 5.5 and Section 5.5.1 will be analyzed based on the 
FAS according to randomized treatment group regardless of the treatment actually received.
Descriptive statistics (i.e., mean, median, SD, IQ range, minimum, and maximum) will be used to 
summarize continuous variables. Counts and percentages will be used to summarize categorical 
variables. Graphical data displays (e.g., line plots) may also be used to summarize the data.
In general, for the analyses through Week 12, comparisons between each JNJ-64304500 treatment 
group and the placebo treatment group will be performed based on the overall efficacy analysis set 
and by Bio-IR status (yes or no) (i.e., Bio-IR and Bio-NF). Pairwise comparisons of the 
ustekinumab treatment group with the each JNJ-64304500 treatment group or with placebo are not 
planned. In addition, for the efficacy analyses beyond Week 12, only descriptive statistics will be 
provided.
The main estimand approach as defined above for the major secondary endpoints (Section 5.4.3) 
will also be used for these endpoints. 
Binary Endpoints
Subjects who have an intercurrent event in categories 1-3 (as specified in Section 5.3.2) will be 
considered to not have achieved the binary endpoints. For subjects experiencing an intercurrent 
event category 4, data at all visits after an ICE 4 will be set to missing. For subjects experiencing 
an intercurrent event in category 5, their observed values will be used, if available. For subjects 
experiencing multiple ICEs, the overall strategy will be based on the first ICE. In addition, for 
endpoints beyond Week 12, subjects in the placebo group who crossover to JNJ-64304500 
treatment group will be considered to have not achieved the binary endpoints. Subjects with 
missing data for an endpoint will be considered to have not achieved the associated binary 
endpoint.


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For endpoints through Week 12, the proportion of subjects achieving each endpoint will be 
compared between each JNJ-64304500 treatment group and the placebo group using the Cochran-
Mantel-Haenszel (CMH) chi-square test (2-sided) stratified by baseline CDAI score (≤300 or 
>300), Bio-IR status (yes or no), and SNP-positive status (yes or no). 
Additional analysis based on observed data (after the intercurrent event rules applied) will be 
performed for histologic assessment.
Continuous Endpoints
Baseline values (at Week 0) will be assigned from the point of an intercurrent event categories 1-3 
onward, regardless of the observed data if a subject has an intercurrent event in categories 1-3 (as 
specified in Section 5.3.2).  For subjects experiencing an intercurrent event category 4, data at all 
visits after an ICE 4 will be set to missing. For subjects experiencing an intercurrent event category 
5, their observed values will be used, if available. In addition, for analyses beyond Week 12, 
baseline values (at Week 0) will be assigned from the point of crossover for subjects in the placebo 
group who crossover to the JNJ-64304500 treatment group.
To account for the missing data for continuous endpoints of change from baseline, the MMRM 
method will be used, under the assumption of missing at random (MAR), to test the difference 
between each JNJ-64304500 treatment group and placebo group. In MMRM, missing data will not 
be imputed but rather missing data will be accounted for through correlation of repeated measures 
in the model. Additionally, if the MMRM normality assumption is in question, an appropriate 
transformation may be implemented before fitting the MMRM model. The explanatory variables 
of the model will include treatment group, baseline CDAI score (≤300 or >300), SNP-positive 
status (yes or no), Bio-IR status (yes or no), respective baseline score, visit, and an interaction term 
of visit with treatment group. For CDAI-related endpoints (CDAI, PRO-2, PRO-3, abdominal pain 
score based on the CDAI assessment, and stool frequency score based on the CDAI assessment), 
baseline CDAI score (≤300 or >300) will not be included as an explanatory variable.
Endpoints based on SES-CD and GHAS that are measured at only one post-baseline visit will be 
compared between each JNJ-64304500 treatment group and placebo group using an analysis of 
covariance (ANCOVA) with treatment as a fixed factor and respective baseline score and baseline 
CDAI score (≤300 or >300), Bio-IR status (yes or no), and SNP-positive status (yes or no) as 
covariates.
For analyses using ANCOVA, multiple imputation (imputed 200 times to generate 200 complete 
data sets using the Markov chain Monte Carlo method, assuming missing at random and a 
multivariate normal distribution) will be used to impute the missing data.

Weeks 0 and 12 values and design variables (treatment assignment，baseline CDAI score 
(≤300 or >300), Bio-IR status (yes or no), and SNP-positive status (yes or no)) will be used 
to impute the missing values.


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6.
SAFETY
All safety analyses will be based on the safety analysis set. In general, subjects will be analyzed 
according to the treatment they actually received. 
The safety of JNJ-64304500 in subjects with Crohn’s disease will be assessed by summarizing the 
frequency and type of AEs and changes from baseline in clinical laboratory parameters for 
hematology and chemistry. 
6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study agent is considered to be treatment emergent (ie, TEAE). If the event 
occurs on the day of the initial administration of study agent, and either event time or time of 
administration are missing, 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 will be included in 
the analysis.  For each adverse event, the number and percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. 
The following analyses of AEs will be used to assess the safety of subjects:

Frequency and type of AEs

Frequency and type of SAEs

Frequency and type of reasonably related AEs as assessed by the investigator

Frequency and type of AEs leading to discontinuation of study intervention

Frequency and type of infections, including serious infections and infections requiring oral or 
parenteral antimicrobial treatment.

Frequency and type of AEs temporally associated with infusion. 

Frequency and type of injection-site reactions.
These summary tables will provide the count and percentage of subjects with 1 or more of the 
specified TEAEs (including COVID-19 related TEAEs) by treatment group, system-organ class 
and preferred term. 
Tables that summarize key safety events (AEs, SAEs, reasonably related AEs, AEs leading to 
discontinuation of study intervention, infections, and serious infections) will also be provided for 
frequency of events, events per 100 subject years of follow-up,  and subjects with events per 100 
subject years of follow-up.  


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In addition to the summary tables, listings of subjects with SAEs and TEAEs leading to 
discontinuation of study intervention will be provided. Any deaths, possible anaphylactic or 
serum-sickness like reactions, or malignancies, will either be presented in a listing or described in 
the clinical study report.
Definitions

A reasonably related AE is defined as any event with a relationship to study intervention 
of ‘Very likely’, ‘Probable’, or ‘Possible’ on the AE eCRF page or if the relationship to 
study agent is missing. 

An infection is defined as any AE that was recorded as an infection by the investigator 
on the eCRF.

An AE that is temporally associated with the infusion of study intervention is one that 
occurs during or within 1 hour of completion of the infusion, with the exception of 
laboratory abnormalities.  

A study intervention injection-site reaction is any reaction at an SC study intervention 
injection site that was recorded as an injection-site reaction by the investigator on the 
eCRF.
6.2.
Clinical Laboratory Tests
Clinical laboratory values are to be graded using National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03. The laboratory data to be summarized 
are as follows:

Hematology assessments: hematocrit, hemoglobin, platelet count, total (leukocytes) and 
differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), and WBC 
count

Blood chemistry assessments: ALT, AST, alkaline phosphatase, albumin, total and direct 
bilirubin, blood urea nitrogen, calcium, chloride, creatinine, phosphate, potassium, total 
protein, and sodium.
The following data analyses will be performed:

Summary of maximum NCI-CTCAE toxicity grade for postbaseline laboratory values through 
Week 12, through Week 24, and through the final efficacy and safety visit for clinical 
laboratory parameters listed in Attachment 2.

Shift tables for selected clinical laboratory parameters (ALT, AST, alkaline phosphatase and 
total bilirubin) at Week 12.

Summary of maximum postbaseline measurement through Week 12, through Week 24, and 
through the final efficacy and safety visit for ALT, AST and alkaline phosphatase and total 
bilirubin relative to ULN.
Listings of subjects with any abnormal postbaseline laboratory values of CTCAE grade ≥2 will 
also be provided. 


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The baseline value for a subject is the value closest to but prior to the first dose of study agent 
(Week 0). Change from baseline is defined to be the assessment at the postbaseline visit minus the 
assessment at baseline. Summaries of laboratory data will be completed using all the available 
laboratory data at the time point of interest without imputing missing data. Shift tables summarize 
the number of subjects with low, normal, and high values (determined by the laboratory normal 
ranges) at the post baseline visit for each of the classifications of low, normal, and high at baseline. 
6.3.
Vital Signs and Physical Examination Findings
Vital signs are measured at every visit. However, since vital signs and physical examination data 
were not collected on the eCRF, no summaries will be provided for vital signs and physical 
examination findings.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
7.1.
Pharmacokinetics 
PK analyses will be based on the pharmacokinetics analysis set (Section 2.2.4). 
7.1.1.
Serum Concentrations
Blood samples for determining the serum JNJ-64304500 and ustekinumab concentrations will be 
drawn from all subjects according to the schedule in the Protocol Time and Events Schedule. 
Serum JNJ-64304500 and ustekinumab concentrations will be used to evaluate various PK 
parameters.
Serum JNJ-64304500 and ustekinumab concentrations will be summarized using descriptive 
statistics (i.e., n, arithmetic mean, standard deviation [SD], coefficient of variation [%CV],
median, range [minimum and maximum], and interquartile [IQ] range) at each visit. PK data may 
be displayed graphically. 
The following analyses will be performed for each treatment group.

Summary of serum JNJ-64304500 and ustekinumab concentrations over time by treatment 
group

Proportion of subjects with serum JNJ-64304500 and ustekinumab concentrations below the 
lowest quantifiable concentration in a sample at each visit by treatment group.   

Summary of serum JNJ-64304500 and ustekinumab concentrations over time by treatment 
group and by baseline body weight (quartiles). Additional analyses by Bio-IR status (yes or 
no; i.e. Bio-IR and Bio-NF), immunomodulator use (yes or no), and ileal dominant Crohn’s 
disease (yes or no) will also be performed.

Plots of median serum JNJ-64304500 concentrations over time by treatment group.

Plots of median serum JNJ-64304500 concentrations over time by treatment group and by 
baseline body weight (≤median, >median).


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7.1.1.1.
Data Handling Rules
Unless otherwise specified, the following data handling rules will apply to PK analyses:

Serum concentration summaries will be based on the actual treatment received. 

All serum concentration summaries for a particular timepoint will include data obtained from 
treated subjects at the timepoint of interest without imputing any missing data. 

A concentration not quantifiable (below the lower limit of quantification) will be treated as 0 
in the summary statistics and shown as the lower limit of quantification (< LLOQ) in the data 
listings. 

The data from a subject who meets at least 1 of the following dosing deviation criteria will be 
excluded from the by-visit data analyses from the point of the dosing deviation onwards:

Discontinued study agent administrations

Skipped an administration

Received an incomplete/ incorrect dose 

Received an incorrect study agent

Received an additional dose

Received an administration outside the dosing window specified in Table 10.
Table 10:
Dosing Window
Visit
Window
Week 0 through Week 24
± 5 days from scheduled visit day
Final Safety/Efficacy Follow-up visits
± 14 days from scheduled visit day
7.1.2.
PK vs Efficacy
To explore the relationship between JNJ-64304500 serum concentrations and efficacy endpoints, 
the following analyses will be explored: 

The relationship between JNJ-64304500 serum concentrations (quartiles) at Week 12 and 
change from baseline in CDAI score, clinical response and clinical remission status (based on 
CDAI), endoscopic response and remission status, and PRO-2 change from baseline at 
Week 12 will be explored. 

The relationship between JNJ-64304500 serum concentrations (quartiles) at Week 24 and 
change from baseline in CDAI score, clinical response and clinical remission status (based on 
CDAI), endoscopic response and remission status, and PRO-2 change from baseline at 
Week 24 will be explored.

Summaries by Bio-IR status (yes or no, i.e., Bio-IR and Bio-NF) will also be provided.


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7.1.3.
Population PK Analysis
When appropriate, population PK analysis will be performed using serum concentration-time data 
of JNJ-64304500 in all randomized subjects with the nonlinear mixed-effects modeling 
(NONMEM) approach.  Details will be provided in a separate technical report.
7.2.
Immune Response
Immune response analyses will be based on the immunogenicity analysis set (Section 2.2.5).
7.2.1.
Antibodies to Study Agents 
The antibodies to JNJ-64304500 and antibodies to ustekinumab status (positive at any time, 
negative) and titers will be summarized by treatment group for subjects who receive a dose of 
JNJ-64304500 or ustekinumab and have appropriate samples for detection of antibodies to 
JNJ-64304500 or antibodies to ustekinumab (ie, subjects with at least 1 sample obtained after their 
first dose of JNJ-64304500 or ustekinumab). The maximum titers of antibodies to JNJ-64304500
or antibodies to ustekinumab will be provided for subjects who are positive for antibodies to
JNJ-64304500 or ustekinumab respectively.
A listing of subjects who are positive for antibodies to JNJ-64304500 or ustekinumab will be 
provided. The sample antibodies status, the titer, and the neutralizing antibodies status to 
JNJ-64304500 or ustekinumab will be listed by visit. This listing will also provide information 
regarding immunomodulator use at baseline, dose administered, injection-site/infusion reactions, 
JNJ-64304500 or ustekinumab serum concentration, and CDAI for all visits. In addition, a list of 
antibodies status in subjects who discontinued study agent (JNJ-64304500 or ustekinumab) early 
will be provided.
7.2.1.1.
Neutralized Antibodies to Study Agents 
The incidence of neutralizing antibodies (NAbs) to JNJ-64304500 or ustekinumab will be 
summarized for subjects who are positive for antibodies to JNJ-64304500 or ustekinumab and 
have samples evaluable for NAbs to JNJ-64304500 or ustekinumab.
7.2.2.
Antibodies vs Efficacy/PK
Serum JNJ-64304500 concentrations, clinical remission/response status, and change from baseline 
in the CDAI score over time may be summarized by antibodies to JNJ-64304500 status if sufficient 
numbers of subjects are positive for antibodies. Serum ustekinumab concentrations may also be 
summarized by antibodies to ustekinumab status if sufficient numbers of subjects are positive for 
antibodies. Plots of median serum JNJ-64304500 concentrations over time by antibodies to 
JNJ-64304500 status and treatment group may also be provided.
7.2.3.
Antibodies vs Safety
Injection site reactions will be summarized by antibodies to JNJ-64304500 or ustekinumab status 
if sufficient numbers of subjects are positive for antibodies.


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7.3.
Receptor Occupancy and Immunophenotyping
NKG2D Receptor occupancy (RO%) over time will be summarized for each treatment group 
(excluding ustekinumab treatment group) using descriptive statistics (number of observations, 
mean, SD, %CV, median, minimum and maximum, IQR). Plots for NKG2D RO percentage 
(median) over time by treatment will be produced.  Plots by Bio-IR status (yes or no) (i.e., Bio-IR 
and Bio-NF) over time may also be provided. 
The absolute numbers and percentages of peripheral blood NK cells and T cells (including CD4+ 
and CD8+) expressing NKG2D receptor over time will be summarized for each treatment group 
(excluding ustekinumab treatment group) using descriptive statistics (number of observations, 
mean, SD, %CV, median, minimum and maximum, IQR). Plots for immunophenotyping results 
(median) over time by treatment will be produced. Plots by Bio-IR status (yes or no) (i.e., Bio-IR 
and Bio-NF) over time may also be provided.
7.4.
Pharmacodynamic/Biomarker Analyses
Biomarker assessments will be made to examine the biological response to treatment and to 
identify biomarkers that are relevant to JNJ-64304500 treatment and/or Crohn’s disease. 
Assessments include the evaluation of relevant biomarkers in serum, whole blood (for RNA 
analysis), stool, and mucosal biopsy samples (for RNA and histology analysis) collected according 
to the Time and Events Schedule.
Biomarker analyses will characterize the effects of JNJ-64304500 on the measured biomarkers to 
identify biomarkers relevant to treatment and to determine if these biomarkers can predict response 
to JNJ-64304500. Results will be reported in separate technical reports.
CRP, fecal lactoferrin and fecal calprotectin are included in the efficacy analysis Section 5.5.
7.5.
Pharmacokinetic/Pharmacodynamic Relationships
The relationship between serum concentration of JNJ-64304500 and PD will be analyzed 
graphically. For example, individual NKG2D RO% measurements may be plotted against serum 
JNJ-64304500 concentration data at the corresponding nominal sampling time. If any visual trend 
is observed, a suitable PK/PD model may be developed to describe the exposure-response
relationship. In the latter case, the results of the PK/PD modeling analysis will be presented in a 
separate technical report. PK/PD relationships for clinical efficacy endpoints will also be 
investigated, including but not limited to, clinical response and clinical remission (based on 
CDAI). Results of the PK/PD modeling analysis for the efficacy endpoints will be presented in the 
separate technical report.
7.6.
Pharmacogenomic Analyses
Whole blood sample collection for SNPs and DNA analysis will be collected from all subjects at 
Screening. All subjects will be tested for the NKG2D SNP rs2255336 and the MICB (NKG2D 
ligand) SNP rs2239705 at screening. Selected efficacy endpoints will be assessed by SNP status, 
which are included in the efficacy analysis Section 5.3. For subjects who have signed an optional
pharmacogenomics consent form, DNA testing will be done to search for links of specific genes 


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to disease or response. Exploratory genetic analyses on DNA collection from subjects who signed 
the optional DNA consent will be presented in a separate technical report.
8.
HEALTH ECONOMICS
The medical resource utilization analysis will be based on the efficacy analysis set. The medical 
resource utilization data will be analyzed according to the treatment group to which they were 
assigned regardless of the treatment they actually received.
For Crohn’s disease-related hospitalizations and surgeries, comparison between the JNJ-64304500 
treatment group and the placebo treatment group will be performed for efficacy analysis set and 
by Bio-IR status (yes or no) (i.e., Bio-IR and Bio-NF) through Week 12. Only descriptive statistics 
will be provided to summarize the data beyond Week 12.
Crohn’s disease-related hospitalizations
The proportion of subjects with a Crohn’s disease-related hospitalization through Week 12 will be 
summarized and compared between each of the JNJ-64304500 treatment groups and the placebo 
group using a 2-sided Cochran Mantel-Haenszel Chi-square test, stratified by baseline CDAI score 
(<=300 or >300), Bio-IR status (yes or no), and SNP-positive status (yes or no), at a significance 
level of 0.05. In case of rare events, Fisher’s exact test will be used for treatment comparisons.
Crohn’s disease-related surgeries
The proportion of subjects with a Crohn’s disease-related surgery through Week 12 will be 
summarized and compared between each of the JNJ-64304500 treatment groups and the placebo 
group using a 2-sided Cochran Mantel-Haenszel Chi-square test, stratified by baseline CDAI score 
(<=300 or >300), Bio-IR status (yes or no), and SNP-positive status (Yes or no), at a significance 
level of 0.05. In case of rare events, Fisher’s exact test will be used for treatment comparisons.
Crohn’s disease-related hospitalizations or surgeries The proportion of subjects with a Crohn’s 
disease-related hospitalization or surgery through Week 12 will be summarized and compared 
between each of the JNJ-64304500 treatment groups and the placebo group using a 2-sided 
Cochran Mantel-Haenszel Chi-square test, stratified by baseline CDAI score (<=300 or >300), 
Bio-IR status (yes or no), and SNP-positive status (Yes or no), at a significance level of 0.05. In 
case of rare events, Fisher’s exact test will be used for treatment comparisons.


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2.
D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn's 
disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology. 1998;114(2):262-267.
3.
D'haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-
tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial. Gastroenterology. 
1999;116(5):1029-1034.
4.
Irvine EJ, Feagan B, Rochon J, et al.  Quality of life: a valid and reliable measure of therapeutic efficacy in the 
treatment of inflammatory bowel disease.  Canadian Crohn’s Relapse Prevention Trial Study Group. 
Gastroenterology. 1994; 106(2):287-296.
5.
Laharie D, Reffet A, Belleannée G, et al. Mucosal healing with methotrexate in Crohn's disease: a prospective 
comparative study with azathioprine and infliximab. Aliment Pharmacol Ther. 2011;33(6):714-721.
6.
Mantzaris GJ, Christidou A, Sfakianakis M, et al. Azathioprine is superior to budesonide in achieving and 
maintaining mucosal healing and histologic remission in steroid-dependent Crohn's disease. Inflamm Bowel 
Dis. 2009;15(3):375-382.
7.
Mojtahed A, Khanna R, Sandborn WJ, et al. Assessment of histologic disease activity in Crohn's disease: a 
systematic review. Inflamm Bowel Dis. 2014;20(11):2092-2103.
8.
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model uncertainty using general 
parametric models. Stat Med. 2014 May 10;33(10):1646-61. 
9.
Ware JE, Kosinski M, Keller SD. Interpretation: Norm-Based. In: SF-36 Physical and Mental Health Summary 
Scales: A User’s Manual. Boston, MA: The Health Institute; 1994; 8:1-8:42.
10.
Ware JE Jr, Sherbourne CD. The MOS 36 item short form health survey (SF 36), I. Conceptual framework and 
item selection. Med Care. 1992; 30(6):473 483.


JNJ-64304500  (TRIDENT)
Statistical Analysis Plan 64304500CRD2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
56
Status: Approved, Date: 26 August 2020
ATTACHMENTS
Attachment 1  Detailed prohibited changes in CD medication (category 2 of the Intercurrent 
events)

Initiation of prohibited medications:

Immunomodulatory agents other than 6-MP/AZA or MTX (including but not limited 
to 6-TG, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, tofacitinib, and 
other JAK inhibitors).

Immunomodulatory biologic agents (including but not limited to TNF antagonists, 
natalizumab, abatacept, vedolizumab).

Experimental Crohn’s disease medications (including but not limited to thalidomide, 
briakinumab, traficet, brodalumab [AMG 827]). 

Initiation of oral corticosteroids (including budesonide and beclomethasone dipropionate) 
due to worsening of Crohn’s disease.

Initiation of oral corticosteroids (including budesonide and beclomethasone dipropionate) 
for more than 7 days due to reasons other than worsening Crohn’s disease.

Increase in the dose of oral corticosteroids (excluding budesonide and beclomethasone 
dipropionate) > 5 mg/day (prednisone equivalent) above the baseline dose due to 
worsening of Crohn’s disease.

Increase in the dose of oral corticosteroids (excluding budesonide and beclomethasone 
dipropionate) > 5 mg/day (prednisone equivalent) above the baseline dose for more than 
7 days due to reasons other than worsening Crohn’s disease.

Increase in the dose of oral budesonide > 3 mg/day above the baseline dose due to 
worsening of Crohn’s disease.

Increase in the dose of oral beclomethasone dipropionate > 5 mg/day above the baseline 
dose due to worsening of Crohn’s disease.

Initiation of parenteral or rectal corticosteroids due to worsening Crohn’s disease.

Any switch among oral budesonide, oral beclomethasone dipropionate or other oral 
corticosteroids (excluding prednisone equivalent changes) due to worsening of Crohn’s 
disease.

Initiation of oral or rectal 5-ASA compounds due to worsening of Crohn’s disease

Increase above baseline in the dosage of oral 5-ASA compounds due to worsening of 
Crohn’s disease

Change from one oral 5-ASA compound to another 5-ASA compound due to worsening 
of Crohn’s disease

Initiation of 6-MP/AZA/MTX due to worsening of Crohn’s disease


JNJ-64304500  (TRIDENT)
Statistical Analysis Plan 64304500CRD2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
57
Status: Approved, Date: 26 August 2020

Increase above baseline in the dosage of 6-MP/AZA/MTX due to worsening of Crohn’s 
disease

Any switch between 6-MP/AZA and MTX due to worsening of Crohn’s disease.

Initiation of antibiotics due to worsening Crohn’s disease.


JNJ-64304500  (TRIDENT)
Statistical Analysis Plan 64304500CRD2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
58
Status: Approved, Date: 26 August 2020
Attachment 2:  Grading Criteria for Clinical Laboratory Tests [CTCAE Version 4.03]
Hematology Tests
Criteria
Test
Direction
1
2
3
4
Hemoglobin (g/L)
Decrease
≥100 - <LLN
≥80 - <100.0
≥65 - <80
<65
Neutrophils (109/L)
Decrease
≥1.5 - <LLN
≥1.0 - <1.5
≥0.5 - <1.0
<0.5
Platelets (109/L)
Decrease
≥75.0 - <LLN
≥50.0 - <75.0
≥25.0 - <50.0
<25.0
Total WBC count 
(Leukocytes 109/L)
Decrease
≥3.0 - <LLN
≥2.0 - <3.0
≥1.0 - <2.0
<1.0
Lymphocytes (109/L)
Decrease
≥0.8 - <LLN
≥0.5 - <0.8
≥0.2 - <0.5
<0.2
Chemistry Tests
Criteria
Test
Direction
1
2
3
4
ALT
Increase
>ULN - ≤3.0 
xULN
>3.0 xULN -
≤5.0 xULN
>5.0 xULN -
≤20.0 xULN
>20.0 xULN
AST
Increase
>ULN - ≤3.0 
xULN
>3.0 xULN -
≤5.0 xULN
>5.0 xULN -
≤20.0 xULN
>20.0 xULN
Albumin (g/L)
Decrease
≥30 - <LLN
≥20 - <30
<20
Alkaline Phosphatase
Increase
>ULN - ≤2.5 
xULN
>2.5 xULN -
≤5.0 xULN
>5.0 xULN -
≤20.0 xULN
>20.0 xULN
Bilirubin (total)
Increase
>ULN - ≤1.5 
xULN
>1.5 xULN -
≤3.0 xULN
>3.0 xULN -
≤10.0 xULN
>10.0 xULN
Calcium (mmol/L)
Increase
>ULN - ≤2.9
>2.9 - ≤3.1
>3.1 - ≤3.4
>3.4
Calcium (mmol/L)
Decrease
[Albumin 
≥40 g/L or 
missing and 
calcium ≥2.0 -
<LLN]; or
[Albumin < 
40 g/L and 
(calcium – 0.8 
x (albumin –
40)) ≥2.0 -
<LLN]
[Albumin 
≥40 g/L or 
missing and 
calcium ≥1.75 
- <2.0]; or
[Albumin < 
40 g/L and 
(calcium – 0.8 
x (albumin –
40)) ≥1.75 -
<2.0]
[Albumin ≥40 
g/L or missing 
and calcium 
≥1.5 - <1.75]; 
or
[Albumin < 40 
g/L and 
(calcium – 0.8 
x (albumin –
40)) ≥1.5 -
<1.75]
[Albumin 
≥40 g/L or 
missing and 
calcium <1.5]; 
or
[Albumin < 
40 g/L and 
(calcium – 0.8 
x (albumin –
40)) <1.5]
Creatinine
Increase
>ULN - ≤1.5 
xULN
>1.5 xULN -
≤3.0 xULN
>3.0 xULN -
≤6.0 xULN
>6.0 xULN
Phosphate (mmol/L)
Increase
>ULN - ≤5.5
>5.5 - ≤6.0
>6.0 - ≤7.0
>7.0
Phosphate (mmol/L)
Decrease
≥0.8 - <LLN
≥0.6 - <0.8
≥0.3 - <0.6
<0.3
Potassium (mmol/L)
Increase
>ULN - ≤5.5
>5.5 - ≤6.0
>6.0 - ≤7.0
>7.0
Potassium (mmol/L)
Decrease
≥3.0 - <LLN
≥2.5 - <3.0
<2.5
Sodium (mmol/L)
Increase
>ULN - ≤150
>150 - ≤155
>155 - ≤160
>160
Sodium (mmol/L)
Decrease
≥130 - <LLN
≥120 - <130
<120