Conditions: Crohn Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 215
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the efficacy and safety of a single intravenous (IV) re-induction dose of approximately 6 milligram per kilogram (mg/kg) ustekinumab in participants with secondary loss of response (LoR) to subcutaneous (SC) every 8 Weeks (q8w) 90 mg ustekinumab maintenance therapy.

Detailed description:
This study compares the efficacy and safety of a single weight-tiered based IV re-induction dose of approximately 6 mg/kg ustekinumab versus continuing with regular SC q8w 90 mg ustekinumab administration. It consists of screening (5 weeks); treatment period (Week 0 to 24); and safety follow up visit (20 weeks after last dose). The primary hypothesis is that a single IV re-induction dose of ustekinumab is superior to continuing with regular SC q8w maintenance treatment as measured by clinical response after 16 weeks of treatment. Study assessments will include Crohn's disease activity index (CDAI), video ileocolonoscopy, patient-reported outcomes (PROs), laboratory evaluations, biomarkers, review of concomitant medications and adverse events (AEs), and evaluation of serum concentrations of study agent as well as development of antibodies to study agent. All participants will be randomly assigned to receive either ustekinumab IV re-induction or regular SC q8w 90 mg ustekinumab injection at baseline in a double dummy design. No participants will be treated with placebo only.

Arms:
arm 1: Participants who experience a secondary loss of response (LoR) to 90 mg ustekinumab maintenance treatment, administered subcutaneously every 8 weeks (q8w) will receive a weight-tiered based ustekinumab IV re-induction dose of approximately 6 mg/kg and matching placebo subcutaneously at Week 0. At Weeks 8 and 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. Participants will resume their standard-of-care therapy at Week 24 at the discretion of the treating physician. arm 2: Participants who experience a secondary LoR to 90 mg ustekinumab maintenance treatment, administered subcutaneously q8w will receive ustekinumab 90 mg subcutaneously and matching placebo intravenously at Week 0. At Weeks 8 and 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. Participants will resume their standard-of-care therapy at Week 24 at the discretion of the treating physician.

Interventions: intervention 1: Ustekinumab approximately 6 mg/kg (IV) intervention 2: Placebo (SC) intervention 3: Placebo (IV) intervention 4: Ustekinumab 90 mg (SC) Group 1 intervention 5: Ustekinumab 90 mg (SC) Group 2
Intervention descriptions: intervention 1: Participants will receive ustekinumab approximately 6mg/kg intravenously at Week 0. intervention 2: Participants will receive SC injection of placebo at Week 0. intervention 3: Participants will receive IV infusion of placebo at Week 0. intervention 4: Participants will receive SC injection of ustekinumab 90 mg at Weeks 8 and 16. intervention 5: Participants will receive SC injection of ustekinumab 90 mg at Weeks 0, 8 and 16.

Protocol document:
Prot_000.pdf: 
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Status: Approved,  Date: 5 August 2020
Janssen Scientific and Medical Affairs*
Clinical Protocol
Protocol Title
A Phase 3b, Randomized, Double-blind, Multicenter Study to Evaluate the Safety and 
Efficacy of Intravenous Re-induction Therapy With Ustekinumab in Patients with 
Moderately to Severely Active Crohn’s Disease
Patient Optimization With ustEkinumab Re-induction (POWER)
Short Title
Efficacy and Safety of Ustekinumab Re-induction Therapy in Patients With
Moderately to Severely Active Crohn’s Disease With Secondary Loss of Response
Protocol CNTO1275CRD3008; Phase 3b
AMENDMENT 4
STELARA (ustekinumab)
* Janssen Scientific and Medical Affairs is an organization that operates through different legal entities in
various countries. The legal entity acting as the sponsor for Janssen Scientific and Medical Affairs studies
may vary, such as but not limited to: Janssen Scientific Affairs, LLC; Janssen Biologics BV; Janssen-Cilag
International NV; or Janssen Pharmaceutica NV. The term ‘sponsor’ is used throughout the protocol to
represent these various legal entities; the sponsor is identified on the Contact Information page that
accompanies the protocol.
EudraCT NUMBER:
2018-002629-51
Status:
Approved
Date:
5 August 2020
Prepared by:
Janssen-Cilag Ltd.
EDMS number:
EDMS-ERI-156184811, 10.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03782376


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4
5 August 2020
Amendment 3
19 May 2020
Amendment 2
8 April 2020 (COVID-19 amendment)
Amendment 1
19 July 2019
Original Protocol
17 August 2018
The changes in Amendment 4 are summarized in the table below. Changes in previous protocol 
amendments are presented in Section 10.9, Appendix 9.
Amendment 4, 5 August 2020
Overall Rationale for the Amendment: To increase enrollment into the study, through allowing patients 
who have previously received a dose interval shortening of 90mg SC ustekinumab less than every 8 weeks
and clarify ileocolonoscopy as an exploratory endpoint for participants who agree to this procedure.
Section Number
and Name
Description of Changes and Brief Rationale
5.1 Inclusion Criteria OR 5.2 
Exclusion Criteria; 
10.2 Definition of 
Ustekinumab Initial 
Response and Current 
Therapy.
Description of Change: Allowed for inclusion of patients who have previously 
received a dose interval shortening of 90 mg SC ustekinumab less than every 8 
weeks, provided they have since received specified per label doses.
Evidence of prior ustekinumab treatment and response/remission should be 
documented by medical records, if available. If such documentation is 
unavailable, the investigator can confirm the ustekinumab doses, and initial 
response/remission in the eCRF to their best knowledge and clinical judgement. 
Rationale: To enable recruitment of patients.
Synopsis; 9.5 Interim 
Analyses.
Description of Change: Included an overview of interim analysis to test for 
futility.
Rationale:
To test for futility and assess/confirm sample size.
Synopsis; 1.3 Schedule of 
Activities; 3 Objectives and 
Endpoints; 4.1 Overall 
Design; 8 Study Assessments 
and Procedures
Description of Change: Clarified that ileocolonoscopy should be performed 
only at the physician’s discretion and where participants agree for this 
procedure, for evaluation of this exploratory endpoint. Where this is not 
performed, this will not be considered a protocol deviation.
Rationale: To enable recruitment and patient retention.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
1.
PROTOCOL SUMMARY ..................................................................................................................... 6
1.1.
Synopsis........................................................................................................................................... 6
1.2.
Schema .......................................................................................................................................... 11
1.3.
Schedule of Activities..................................................................................................................... 12
2.
INTRODUCTION................................................................................................................................ 16
2.1.
Study Rationale.............................................................................................................................. 16
2.2.
Background .................................................................................................................................... 17
2.2.1.
Development of the Current Ustekinumab Dosing Regimen in Crohn’s Disease ...................... 17
2.2.2.
Loss of Response to Ustekinumab Maintenance Dosing........................................................... 18
2.2.3.
Dose Adjustment in Patients with Loss of Response to Ustekinumab....................................... 19
2.3.
Benefit/Risk Assessment ............................................................................................................... 20
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 22
4.
STUDY DESIGN ................................................................................................................................ 25
4.1.
Overall Design................................................................................................................................ 25
4.2.
Scientific Rationale for Study Design............................................................................................. 26
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 27
4.3.
Justification for Dose...................................................................................................................... 28
4.4.
End of Study Definition................................................................................................................... 29
5.
STUDY POPULATION ...................................................................................................................... 29
5.1.
Inclusion Criteria ............................................................................................................................ 29
5.2.
Exclusion Criteria ........................................................................................................................... 32
5.3.
Lifestyle Considerations................................................................................................................. 36
5.4.
Screen Failures .............................................................................................................................. 36
6.
STUDY INTERVENTION................................................................................................................... 37
6.1.
Study Interventions Administered .................................................................................................. 37
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 38
6.2.1.
Storage and Preparation............................................................................................................. 38
6.2.2.
Drug Accountability..................................................................................................................... 39
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 39
6.4.
Study Intervention Compliance...................................................................................................... 41
6.5.
Concomitant Therapy..................................................................................................................... 41
6.5.1.
Crohn’s Disease-specific Concomitant Medications .................................................................. 41
6.5.2.
Oral Corticosteroids.................................................................................................................... 42
6.5.3.
Prohibited Medications ............................................................................................................... 42
6.6.
Dose Modification........................................................................................................................... 43
6.7.
Intervention After the End of the Study.......................................................................................... 43
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION OR WITHDRAWAL......................................................................................... 43
7.1.
Discontinuation of Study Intervention ............................................................................................ 43
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 45
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 45
7.3.
Lost to Follow-up............................................................................................................................ 46
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 46
8.1.
Efficacy Assessments .................................................................................................................... 47


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8.1.1.
Overview..................................................................................................................................... 47
8.1.2.
Crohn’s Disease Activity Index ................................................................................................... 48
8.1.3.
C-reactive Protein....................................................................................................................... 48
8.1.4.
Calprotectin................................................................................................................................. 49
8.1.5.
Inflammatory Bowel Disease Questionnaire............................................................................... 49
8.1.6.
Fistula Assessment..................................................................................................................... 49
8.1.7.
Video Ileocolonoscopy................................................................................................................ 49
8.2.
Safety Assessments....................................................................................................................... 50
8.2.1.
Physical Examination.................................................................................................................. 50
8.2.2.
Vital Signs................................................................................................................................... 50
8.2.3.
Clinical Safety Laboratory Assessments .................................................................................... 51
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 51
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 52
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 52
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 52
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 52
8.3.5.
Pregnancy................................................................................................................................... 53
8.3.6.
Infusion/Injection Site Reactions and Allergic Reactions ........................................................... 53
8.3.7.
Infections .................................................................................................................................... 54
8.3.8.
Malignancies............................................................................................................................... 54
8.3.9.
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 54
8.4.
Treatment of Overdose .................................................................................................................. 54
8.5.
Pharmacokinetics and Immunogenicity ......................................................................................... 55
8.5.1.
Evaluations ................................................................................................................................. 55
8.5.2.
Analytical Procedures................................................................................................................. 55
8.5.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 55
8.6.
Genetics ......................................................................................................................................... 55
8.7.
Medical Resource Utilization and Health Economics .................................................................... 55
8.8.
Biomarkers ..................................................................................................................................... 56
8.8.1.
Serum-based Biomarkers........................................................................................................... 56
8.8.2.
Whole Blood-based Biomarkers ................................................................................................. 56
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 56
9.1.
Statistical Hypothesis..................................................................................................................... 56
9.2.
Sample Size Determination ........................................................................................................... 57
9.3.
Populations for Analysis................................................................................................................. 57
9.4.
Statistical Analysis ......................................................................................................................... 57
9.4.1.
Efficacy Analysis......................................................................................................................... 57
9.4.2.
Safety Analysis ........................................................................................................................... 58
9.4.3.
Other Analyses ........................................................................................................................... 59
9.5.
Interim Analysis.............................................................................................................................. 60
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 61
10.1.
Appendix 1: Abbreviations and Definition of Terms....................................................................... 61
10.2.
Appendix 2: Definition of Ustekinumab Initial Response and Current Therapy............................. 62
10.3.
Appendix 3: Tuberculin Skin Testing ............................................................................................. 64
10.4.
Appendix 4: Anticipated Events ..................................................................................................... 66
10.5.
Appendix 5: Clinical Laboratory Tests ........................................................................................... 67
10.6.
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations......................................... 68
10.7.
Appendix 7: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 79
10.8.
Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information........ 84
10.9.
Appendix 9: Protocol Amendment History ..................................................................................... 87
10.10.
Appendix 10: Sample Crohn’s Disease Activity Index ................................................................... 90
10.11.
Appendix 11: CDAI Standard Weight Table................................................................................... 91
10.12.
Appendix 12: Sample Inflammatory Bowel Disease Questionnaire .............................................. 93


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10.13.
Appendix 13: Guidance on Study Conduct during the COVID-19 Pandemic.............................. 104
11.
REFERENCES................................................................................................................................. 109
INVESTIGATOR AGREEMENT ............................................................................................................... 111
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Recommended Tapering Schedule for Oral Corticosteroids.................................................... 42
Table 2:
Power to Detect a Treatment Effect Based on Different Proportions of Participants 
Achieving Clinical Response at Week 16 (Each Group) .......................................................... 57
Table 3:
Populations for Analysis............................................................................................................ 57
FIGURES
Figure 1:
Study Designs for the Ustekinumab Phase 3 Development Program in Crohn’s 
Disease ..................................................................................................................................... 18
Figure 2:
Minimum Required Time Windows Between Administration of Study Intervention (IV 
or SC) at Week 0 ...................................................................................................................... 37


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Phase 3b, Randomized, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of 
Intravenous Re-induction Therapy With Ustekinumab in Patients with Moderately to Severely 
Active Crohn’s Disease
Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal antibody to human 
IL-12/23p40 that binds with high affinity to human IL-12 and IL-23. Ustekinumab prevents IL-12 and 
IL-23 bioactivity by preventing their interaction with the cell surface IL-12Rβ1 receptor protein, thereby 
effectively neutralizing all IL-12 (Th1) and IL-23 (Th17) mediated cellular responses. Abnormal regulation 
of IL-12 and IL-23 has been associated with multiple immune-mediated diseases, including psoriasis, 
psoriatic arthritis, and inflammatory bowel disease. By binding the shared p40 subunit of IL-12 and IL-23, 
ustekinumab may exert its clinical effects through interruption of the Th1 and Th17 cytokine pathways, 
which are central to the pathology of these diseases.
OBJECTIVES AND ENDPOINTS
Objectives
The primary objective is to evaluate the achievement of clinical response at Week 16 following a single IV 
re-induction dose of 6 mg/kg ustekinumab, compared with continuing regular SC q8w 90 mg ustekinumab 
administration, in participants with secondary loss of response (LoR) to SC q8w 90 mg ustekinumab 
maintenance therapy.
The secondary objectives are to:

Evaluate the achievement of clinical response and clinical remission, as well as the reduction in 
inflammatory biomarkers (serum C-reactive protein [CRP] and fecal calprotectin [fCal] levels), after 
IV ustekinumab re-induction.

Assess the overall safety of IV ustekinumab re-induction.
Other objectives are to assess endoscopy and patient-reported assessment of bowel inflammation following
IV ustekinumab re-induction, and to assess the steroid-sparing effect and pharmacokinetics following a 
single IV re-induction dose of 6 mg/kg ustekinumab.
Endpoints
The primary endpoint is clinical response at Week 16, defined as a ≥100-point reduction from the baseline 
Crohn’s Disease Activity Index (CDAI) score or a CDAI score <150 points.
The major secondary endpoints, listed in order of testing, are as specified below:

Clinical remission at Week 16, defined as a CDAI score of <150 points.

Clinical response at Week 8, defined as a ≥100-point reduction from the baseline CDAI score or a 
CDAI score <150.

Clinical remission at Week 8, defined as a CDAI score of <150 points.

Normalization of CRP and/or fCal concentration(s) at Week 16, among participants with elevated CRP 
and/or fCal at baseline.


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Other secondary endpoints are:

Clinical remission at Week 24, defined as a CDAI score of <150 points.

Clinical response at Week 24, defined as a ≥100-point reduction from the baseline CDAI score or a 
CDAI score <150.

Normalization of CRP and/or fCal concentration(s) at Week 24, among participants with elevated CRP 
and/or fCal at baseline.

Safety endpoints, including the proportion of participants with at least one adverse event and 
subcategories of adverse events (all infections, all serious adverse events and serious infections), as 
well as changes in clinical laboratory test results.
Other endpoints are described in Section 3 of the protocol.
Hypothesis
The study hypothesis is that in patients with secondary LoR to SC q8w 90 mg ustekinumab maintenance 
treatment, a single weight-tiered based IV ustekinumab re-induction dose of 6 mg/kg 
(ie, IV ustekinumab/SC placebo at Week 0) followed by q8w 90 mg ustekinumab maintenance will result 
in a higher clinical response rate (defined as a ≥100-point reduction from the baseline CDAI score, or a 
CDAI score <150) compared with continuous SC q8w 90 mg ustekinumab maintenance treatment
(ie, IV placebo/SC ustekinumab at Week 0) after 16 weeks.
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter, 24-week, Phase 3b study in adult 
patients with moderately to severely active Crohn’s disease who initially responded (as defined in 
Section 10.2, Appendix 2 of the protocol) to ustekinumab induction therapy per label followed, at any time, 
by secondary LoR to SC q8w ustekinumab maintenance therapy. The benefit of a single weight-tiered based 
IV re-induction dose of 6 mg/kg body weight ustekinumab versus continuous SC q8w maintenance 
treatment will be evaluated.
Secondary LoR is defined as a CDAI score of 220 and ≤450 plus at least one of the following:

Elevated CRP (>3.0 mg/L); and/or

Elevated fCal (>250 mg/kg); and/or

Endoscopy (ileocolonoscopy) performed ≤3 months before baseline with evidence of active Crohn’s 
disease (defined as one or more ulcerations in the ileum and/or colon).
Eligible participants will be randomly assigned to 1 of the following 2 intervention groups in a 1:1 ratio,
using permuted block randomization stratified at the study level by participant’s baseline CDAI score 
(≤300 or >300) and prior biologic failure (yes or no) at baseline:

Ustekinumab re-induction: IV ustekinumab and SC placebo at Week 0.

Continuous maintenance:
IV placebo and SC ustekinumab at Week 0.
At baseline (Week 0), approximately 8 weeks (±2 weeks) after the previous per label dose of SC 90 mg 
ustekinumab maintenance, participants will undergo clinical assessments. Following randomization, 
participants will receive either IV ustekinumab 6 mg/kg and SC placebo or IV placebo and SC 
ustekinumab 90 mg in a double-blind manner (IV administration will be as an infusion and SC 
administration will be as an injection). Either the IV infusion or the SC injection may be administered first 
at Week 0, based on the standard-of-care practices at the study site; there must be no concurrent 
administration of IV and SC study intervention.


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At Week 8 and Week 16, all participants will receive SC ustekinumab 90 mg and undergo clinical 
assessments. The SC injections at Week 8 and Week 16 should be administered by qualified study site staff 
during the study visit. In exceptional cases, where a site visit is not possible, participants who have 
appropriate experience or have received required training may self-administer SC study intervention at the 
times instructed by the investigator.
At Week 24, all participants will undergo study assessments before resuming their standard-of-care therapy 
at the discretion of the treating physician. All participants will have a follow-up for evaluation of safety 
approximately 20 weeks after their last study intervention administration (ie, Week 36 for participants who 
complete the final study intervention visit at Week 16); this may be conducted at a site visit or by telephone.
A participant will be considered to have completed the study if he/she has completed assessments through 
the 24-week treatment period and the Week 36 safety follow up. Participants will be considered to have 
completed the primary efficacy period of the study if they have completed the study assessments through 
Week 16 (or at an early termination visit). The end of study is considered the last scheduled study 
assessment for the last participant in the study.
Key efficacy assessments will include clinical response (CDAI reduction ≥100), clinical remission (CDAI 
value <150) and biomarker normalization. Safety assessments will include the monitoring of adverse 
events, vital signs, and clinical laboratory tests.
NUMBER OF PARTICIPANTS
The study will include approximately 200 participants, with approximately 100 participants in each of the 
2 intervention groups.
INTERVENTION GROUPS AND DURATION
Administration of Interventions
Study intervention will start at baseline (Week 0), approximately 8 weeks (±2 weeks) after the previous 
dose of per label SC 90 mg ustekinumab maintenance treatment. The date of the previous dose of 
ustekinumab will be recorded in the case report form (CRF).
To maintain the double-blind, at Week 0 all participants will receive one IV infusion of study intervention 
(ustekinumab 6 mg/kg or placebo) plus one SC administration of study intervention (ustekinumab 90 mg 
or placebo).
At Week 8 and Week 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. 
Following study assessments at Week 24, all participants will resume their standard-of-care therapy with 
either ustekinumab maintenance therapy per label or another treatment modality at the discretion of their 
physician.
Description of Interventions
Study intervention should be dispensed under the supervision of the investigator, a qualified member of the 
study-site personnel, or by a hospital/clinic pharmacist. Study intervention in glass vials and PFS will be 
ready to use. The required volume of study intervention will be prepared using the appropriate vials or PFS.
Aseptic procedures must be used during the preparation and administration of the ustekinumab solution for 
IV infusion.
For IV administration, the study intervention will be administered to each participant as an infusion over a 
period of not less than 1 hour by qualified staff. The infusion should be completed within 8 hours of 
preparation. Details of each infusion will be recorded in the CRF (including date, start and stop times of the 
IV infusion, and volume infused).


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Subcutaneous injections at Week 0 will be administered by qualified staff at the study site. At Week 8 and 
Week 16, SC injections should be administered by qualified study site staff during the study visit. In 
exceptional cases, where a site visit is not possible, participants who have appropriate experience or have 
received required training may self-administer SC study intervention at the times instructed by the 
investigator. The study site staff must ensure that those participants have the appropriate experience or have 
received the required training to perform self-administration of SC injections. Details of each administration 
will be recorded in the CRF (including date and time of administration).
EFFICACY EVALUATIONS
Efficacy evaluations will include the following:

CDAI (the primary tool for assessing disease activity response to ustekinumab).

PRO-2 (the CDAI components of the total number of liquid or very soft stools and the abdominal pain 
score).

Inflammatory Bowel Disease Questionnaire (IBDQ).

Inflammatory markers including serum CRP and fCal.

Fistula assessment.

Endoscopic assessments of the intestinal mucosa based on the presence and absence of mucosal 
ulcerations and the SES-CD in the subset of patients with endoscopies performed.
Other endpoints are described in Section 3 of the protocol.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Serum samples will be used to evaluate the PK of ustekinumab and to detect and characterize
anti-ustekinumab antibodies. Serum collected for PK and immunogenicity evaluations may additionally be 
used to explore safety or efficacy aspects arising during or after the study period.
The blood sample for trough serum PK must be collected at all study visits prior to the administration of 
ANY study intervention (ie, IV or SC ustekinumab) as well as prior to the administration of standard-of-
care therapy at Week 24. The post-IV infusion PK blood sample at Week 0 should be drawn approximately 
60 minutes after completion of the IV infusion.
BIOMARKERS
Biomarker assessments will be conducted to examine the biologic response to treatment and to identify 
biomarkers that are relevant to ustekinumab treatment and/or Crohn’s disease. Assessments may include 
the evaluation of relevant biomarkers in serum, blood, and/or stool samples collected as specified in the 
Schedule of Activities. Data collected from these samples will be used for exploratory research purposes.
SAFETY EVALUATIONS
Safety will be assessed through Week 24 by evaluating adverse events, clinical laboratory changes, physical 
examination, and vital signs. Adverse events will also be evaluated at a safety follow up performed at a site 
visit or by telephone approximately 20 weeks after the last study intervention administration (ie, Week 36 
for participants who complete the final study intervention visit at Week 16).


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STATISTICAL METHODS
The assumptions that form the basis for sample size and power calculations incorporated into this protocol 
to support the primary endpoint are based on the dose adjustment data from the IMUNITI Phase 3 study. 
In IMUNITI, 17 of 29 (59%) participants attained clinical response 16 weeks after LoR in the q12w adjusted 
to q8w group, while 11 of 28 (39%) participants attained clinical response 16 weeks after LoR in the sham 
dose adjustment group (ie. continually remaining on SC q8w dosing). The hypothesis for the sample size 
determination is that the IV ustekinumab group in this study will perform similarly to, if not better than, the 
q12w adjusted to q8w group in the IMUNITI study, given that the participants in this group will receive a 
higher dose of ustekinumab than those in the IMUNITI study, who received an adjustment from q12w to 
q8w.
Assuming a 60% clinical response rate at Week 16 in the IV ustekinumab group and 40% in the continuous 
SC q8w 90mg group, 100 participants per intervention group will yield an overall power above 80%, at a
significance level of 0.05 (2-sided, Mantel-Haenszel test).
Efficacy analyses will be based on an intent-to-treat principle; the efficacy data for each participant will be 
analyzed according to the assigned treatment regardless of the actual treatment received.
For the primary endpoint, the proportion of participants in clinical response at Week 16 will be compared 
between the IV ustekinumab group and the continuous SC q8w group using a 2-sided Cochran-Mantel-
Haenszel-chi-square test, stratified by baseline CDAI score (≤300 or >300) and prior biologic failure status 
at baseline (yes or no) at a significance level of 0.05.
Participants with missing data, defined as those participants who terminate the study before the designated 
visit or participants who have (a) missing value(s) at the designated visit, will be considered to not have 
achieved their dichotomous efficacy endpoints. For continuous endpoints, the last available value will be 
carried forward for participants with missing data.
Treatment failure rules will override the response status (eg, clinical response, clinical remission, and 
mucosal healing). Participants who meet any of the following criteria for treatment failure will be 
considered to not have achieved their dichotomous efficacy endpoints from the time the treatment failure 
occurs onwards:

Had a Crohn’s disease-related surgery due to lack of efficacy; OR

Discontinued study intervention due to an adverse event of worsening Crohn’s disease or due to lack 
of efficacy; OR

Had a prohibited change in concomitant medications (to be detailed in the statistical analysis plan).
For continuous efficacy endpoints, the baseline value will be carried forward from the time the treatment 
failure occurs onwards.
An interim analysis will be performed in the study to test for futility after 40 randomized participants have 
completed the efficacy assessment at Week 16, and to assess sample size.


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1.2.
Schema
C=clinical assessment; E=endoscopy (where applicable); IV=intravenous (infusion); LoR=Loss of response; PBO=Placebo; PE=primary endpoint; 
PK=pharmacokinetic sampling (for immunogenicity + ustekinumab concentration); q8w=dosing every 8 weeks; R=randomization; SC=subcutaneous (injection); 
SOC=Standard of care (participants will resume their standard-of-care therapy after study assessments at Week 24); UST=ustekinumab; BW=body weight.
Follow-up for evaluation of safety approximately 20 weeks after the last study intervention administration (ie, Week 36 for participants who complete the final study 
intervention visit at Week 16) may be conducted at a site visit or by telephone.








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Footnotes:
a.
Visit window should be ±4 days for each visit up to and including Week 16 and ±7 days for Week 24 and Week 36.
b.
Participants should complete the safety follow up approximately 20 weeks after their last study intervention administration; for participants who complete the final 
study intervention visit at Week 16, this will occur at Week 36. The safety follow up may be conducted at a site visit or by telephone and applies to all participants,
including those who discontinued study intervention before Week 24 or otherwise terminated study participation (eg, through withdrawal of consent), unless they 
do not consent to this follow up by study-site staff.
c.
Stool test for enteric pathogens must include a stool culture and C. difficile toxin assay performed within 4 months before Week 0. Additional testing may be 
performed at the investigator’s discretion.
d.
Screening for HBV to include HBsAg, anti-HBs, and anti-HBc. Participants are eligible if they are: 1) negative for these tests OR 2) negative for HBsAg; positive 
only for anti-HBs; or positive for anti-HBc and surface antibody OR 3) positive only for anti-HBc, but with a negative HBV DNA test.
HIV antibody test need not be performed if a negative result in last 6 months is available.
e.
In exceptional cases, where a site visit is not possible, participants who have appropriate experience or have received required training may self-administer SC 
study intervention at Week 8 and/or Week 16.
f.
Clinical laboratory tests for assessment of screening criteria and for study evaluations are further described in Section 10.5, Appendix 5 of the protocol.
g.
The IBDQ at the early termination visit is required only for participants who did not remain in the study at Week 16 (due to early discontinuation of study 
intervention and/or early termination of study participation) or did not perform the IBDQ at Week 16.
h.
All reasonable attempts should be made to collect samples at the scheduled timepoints and record the actual times of PK sample collections.
At each time point, one venous blood sample of sufficient volume should be collected. Each serum sample will be divided into 3 aliquots (for ustekinumab serum 
concentration, antibody assessment, and a back-up), except for the post-infusion blood sample at Week 0 which will be for PK evaluation only.
Determination of ustekinumab serum concentrations and antibody assessments will be performed by a central laboratory.
CDAI=Crohn’s Disease Activity Index; CRP=C-reactive protein; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
IV=intravenous; PK=pharmacokinetic.


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2.
INTRODUCTION
Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal antibody to human 
IL-12/23p40 that binds with high affinity to human IL-12 and IL-23. Ustekinumab prevents IL-12 
and IL-23 bioactivity by preventing their interaction with the cell surface IL-12Rβ1 receptor 
protein, thereby effectively neutralizing all IL-12 (Th1) and IL-23 (Th17) mediated cellular 
responses. Abnormal regulation of IL-12 and IL-23 has been associated with multiple immune-
mediated diseases, including psoriasis, psoriatic arthritis, and inflammatory bowel disease. By 
binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects 
through interruption of the Th1 and Th17 cytokine pathways, which are central to the pathology 
of these diseases.
STELARA® (ustekinumab)27 was initially approved for the treatment of adults with moderate to 
severe chronic plaque psoriasis in the European Union (EU) in January 2009 and in the United 
States (US) in September 2009, and gained subsequent approvals for psoriatic arthritis and
adolescent psoriasis, followed by approval for the treatment of adult patients with moderately to 
severely active Crohn’s disease on 23 September 2016 in the US and 11 November 2016 in the 
EU.
For the most comprehensive nonclinical and clinical information regarding ustekinumab, refer to 
the latest version of the Investigator’s Brochure for STELARA (ustekinumab).
The term ‘study intervention’ used throughout this document refers to ustekinumab administered 
as a 6 mg/kg intravenous (IV) infusion or as a 90 mg subcutaneous (SC) injection.
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.
2.1.
Study Rationale
Crohn’s disease is a chronic debilitating inflammatory disease of the digestive tract with a 
remitting and relapsing course. For the last decade, Crohn’s disease has been most effectively 
treated with monoclonal antibodies to tumor necrosis factor (TNF); however, approximately 
one-third of patients do not respond to anti-TNFs initially, and a further third lose response during 
their course of treatment, requiring dose adjustment or switch to another medication.16 There is a 
significant medical need for new safe and effective therapies for moderate to severe, active Crohn’s 
disease as well as to optimize the limited treatment options currently available.
The approved dosing regimen for ustekinumab in the treatment of Crohn’s disease comprises an 
initial weight-tiered based induction dose of approximately 6 mg ustekinumab per kg body weight 
(6 mg/kg) administered intravenously followed by maintenance doses of 90 mg administered 
subcutaneously from Week 8. In the EU, the approved maintenance dosing regimen is 90 mg SC 
every 12 weeks (q12w) after Week 8, although patients who have not demonstrated an adequate 
response at Week 16 or who subsequently lose response may be dosed every 8 weeks (q8w). In 
the US, patients receive maintenance doses of 90 mg SC q8w from Week 8 per label.


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While the clinical development program for ustekinumab established that both of the approved 
maintenance doses maintained clinical response through Week 44 (Section 2.2.1), it was 
demonstrated that a proportion of patients on maintenance dosing with ustekinumab will lose their 
response over time (Section 2.2.2). In a proportion of patients, the loss of response (LoR) to 
ustekinumab maintenance treatment is associated with low serum levels of ustekinumab 
(Section 2.2.3). Patients commonly lose response to biologics for the treatment of Crohn’s disease, 
requiring dose intensification to regain response.20 Similarly, patients in the EU with LoR to q12w 
maintenance dosing with ustekinumab may regain the response following dose adjustment to q8w 
maintenance dosing. However, there is no option for dose adjustment for patients in the US or EU 
who have lost response to q8w maintenance dosing. It is expected that a proportion of patients
with LoR to q8w maintenance dosing will regain response employing a strategy of increasing 
serum concentrations. The approved IV dose provides a logical option to rapidly increase the 
serum concentrations of ustekinumab.
The aim of this study is to demonstrate the efficacy of a single weight-tiered based ustekinumab 
IV re-induction dose of 6 mg/kg versus continuous ustekinumab SC maintenance treatment in 
adult patients with moderately to severely active Crohn’s disease demonstrating a secondary LoR
to ustekinumab q8w maintenance treatment.
2.2.
Background
2.2.1.
Development of the Current Ustekinumab Dosing Regimen in Crohn’s 
Disease
The Phase 3 development program for ustekinumab in Crohn’s disease consisted of three Phase 3 
trials: two 8-week induction studies (CNTO1275CRD3001 [UNITI-1] and CNTO1275CRD3002 
[UNITI-2]) that fed into one 44-week maintenance study (CNTO1275CRD3003 [IMUNITI]) 
(Figure 1).
Participants in the UNITI-1 and UNITI-2 studies who met the criteria for clinical response to IV 
induction with ustekinumab at Week 8 (defined as a reduction from baseline in CDAI score 
100 points or total CDAI score <150 points) were randomized to receive either placebo 
maintenance or ustekinumab maintenance of q8w or q12w through Week 40 in the IMUNITI 
study, in which the primary endpoint was clinical remission at Week 44 (CDAI<150). The 
IMUNITI protocol allowed for blinded crossover to dose escalation for participants who qualified 
due to LoR; participants with LoR on placebo maintenance or q12w ustekinumab maintenance 
were switched to q8w ustekinumab maintenance, while participants with LoR on q8w maintenance 
received a sham dose escalation of continued q8w maintenance.
Based on the results of these studies, a weight-tiered based IV dose of 6 mg/kg body weight was 
selected as the approved induction dose and 90 mg SC was selected as the approved maintenance 
doses, starting at Week 8. Patients in the US are to be maintained on q8w maintenance dosing from 
Week 8 per label. While q12w maintenance injections are recommended in the EU from Week 8, 
patients who have not shown adequate response at Week 16 or who subsequently lose response 
may be switched to q8w maintenance dosing. Indeed, the flexibility to optimize results is 
recognized as an important option in the treatment of Crohn’s disease.


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Figure 1:
Study Designs for the Ustekinumab Phase 3 Development Program in Crohn’s Disease
*
Conventional therapy is defined as corticosteroids and/or immunomodulator. IV=intravenous; LTE=long-term 
extension, q8w=every 8 weeks; q12w=every 12 weeks; SC=subcutaneous; TNF=Tumor necrosis factor; 
PE=primary endpoint; SE=secondary endpoint; UST=ustekinumab
2.2.2.
Loss of Response to Ustekinumab Maintenance Dosing
While the results of the IMUNITI study established that both the q12w and q8w doses of 
ustekinumab maintenance therapy were superior to placebo and maintained clinical response 
through Week 44, by Week 32 approximately 20% of participants in each ustekinumab 
maintenance arm met the criteria for dose escalation due to LoR (defined as CDAI ≥220 points 
and an increase in CDAI score from baseline of maintenance of ≥100 points).9 Of those who 
entered the long-term extension, an additional approximately 10% were no longer in response by 
Week 92.21 The results were similar between the 2 maintenance dosing regimens at both 
timepoints.
The observation of patients losing response over time has been observed with all biologics in the 
treatment of Crohn’s disease, including 3 TNF inhibitors1,5,13 and an integrin receptor antagonist29. 
A recent systematic review and meta-analysis of 86 studies of patients with Crohn’s disease found 
that approximately 30% of primary anti-TNF responders experienced a LoR and required dose 
adjustment to regain and maintain response.20 Rates of LoR after up to 1 year of treatment with 
vedolizumab have been reported to be around 50% in normal clinical practice.3,26
Considerable research has been conducted on the reasons for patients losing their initial response 
to biologic therapy. The causes for LoR, known as secondary nonresponse, fall into 2 general 
categories8: causes linked to the disease (eg, changes in disease pathology or progression) and 
causes linked to the drug’s ability to treat the disease (eg, an increase in the level of inflammation 
and/or an increase in drug clearance, leading to inadequate levels of drug to maintain activity).


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2.2.3.
Dose Adjustment in Patients with Loss of Response to Ustekinumab
Pharmacokinetic (PK) analysis from the IMUNITI study showed that participants who lost 
response to q12w dosing had lower serum ustekinumab concentrations than those who did not lose 
response, suggesting that lower drug levels may be associated with LoR.2 Similarly, participants 
with LoR to q8w dosing were also observed to have lower serum levels of drug compared with 
q8w participants who did not lose response. Median serum ustekinumab concentrations at Weeks 8 
and 16 of q8w maintenance were 1.63 µg/mL and 1.19 µg/mL, respectively, for participants who 
met the criteria for dose adjustment, and 2.21 µg/mL and 2.04 µg/mL, respectively, for participants 
who did not need dose adjustment.28
Consistent with the hypothesis that patients with LoR have lower levels of drug than those with 
sustained response and considering the PK characteristics and exposure-response (E-R)
relationship of ustekinumab, a potential strategy to address LoR is a dose escalation to raise serum 
drug levels, either in the form of an increase in dose or a shortening of the interval of ustekinumab 
administration. In IMUNITI, use of dose escalation to address LoR was studied only in the q12w 
group; participants with LoR to q8w dosing received blinded sham dose escalation of continued 
q8w maintenance. Upon dose escalation from q12w to q8w, 55% regained their response and 42% 
achieved remission by Week 16. Regaining of response was accompanied by a 4-fold increase in 
serum drug levels.28 Thus, the concept of dose escalation for LoR is established for the q12w dose
and was accordingly included in the approved European posology; however, for patients losing 
response to the q8w dose there is currently no established or approved strategy to address the LoR.
During induction and maintenance, ustekinumab concentration was inversely related to 
concentrations of C-reactive protein (CRP). At Week 8 in both induction studies, serum 
ustekinumab concentration was positively correlated with normalization of CRP. This suggests 
that ustekinumab clearance, and therefore ustekinumab concentration, is associated with baseline 
CRP, presumably as a function of the higher underlying inflammatory activity for which CRP is a 
marker.2 These data suggest that ustekinumab clearance could slow as inflammation is suppressed 
and response is regained in these patients. Consequently, a permanent increase in dose might not 
be necessary to sustain adequate drug levels once response has been regained. Indeed, studies with 
other biologics have demonstrated that patients can return to standard doses after regaining 
response. Schnitzler et al23 reported that more than 70% of patients who underwent infliximab dose 
optimization could return to their original treatment regimen during follow-up. Furthermore, as 
Crohn’s disease is characterized by periodic flares, permanently high doses might not be needed 
to sustain response once regained, rather increased doses of drug would be required only until the 
flare quiesces or subsides.
There is evidence demonstrating that a strategy of re-induction can be as effective as long-term 
dose increase or interval shortening. Srinivasan et al25 compared re-induction with shortened 
dosing intervals in patients who had lost response to standard maintenance dosing with either 
infliximab or adalimumab and found no significant difference in the incidence of treatment failure 
at 12 months follow-up (24% vs 15%, p=0.27). Although there were few patients and the dosing 
regimens varied, Heron12 reported on 11 patients with Crohn’s disease on SC 90 mg q4w 
ustekinumab with either clinical or endoscopic LoR who were dose adjusted with either SC (n=3) 


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or IV re-induction (n=8). The IV re-induction dose used was 260 mg IV in 2 patients and 390 mg
IV in 6 patients. Five of the 8 (62.5%) participants receiving IV re-induction were in clinical 
remission or endoscopic response at follow-up (2 months and 7 months, respectively). Additional 
evidence supporting the efficacy of re-induction has been demonstrated in a small number of 
patients (n=3) who had been initially treated with non-weight-based SC induction and had not 
demonstrated an adequate clinical response to ustekinumab.19
Pharmacokinetic modeling of ustekinumab shows that IV re-induction with the approved 
6 mg/kg dose would achieve an approximately 10-fold higher peak concentration than would be 
achieved with even more frequent SC doses of 90 mg, such as q4w, the attained serum ustekinumab 
exposure being similar to the exposure following the initial induction. Based on the PK analysis, 
re-induction would not result in a meaningfully higher ustekinumab exposure than with the initial 
induction dose, since at the time of the re-induction serum concentrations would be at relatively 
low levels (1.19 µg/mL to 1.63 µg/mL). The Cmax after re-induction would be expected to be only 
marginally higher than the Cmax observed in the UNITI-1 and UNITI-2 induction studies 
(126.1 µg/mL and 124.4 µg/mL, respectively). Thereafter, serum concentrations would likely 
return to levels typically expected with ustekinumab maintenance dosing within 16 weeks, since 
median serum concentrations of ustekinumab are undetectable 16 weeks after infusion of the 
induction dose.
2.3.
Benefit/Risk Assessment
The safety profile of ustekinumab is well documented, based on information from clinical trials 
and postmarketing experience. As of 31 December 2017, an estimated 11,557 participants have 
been exposed to ustekinumab in the clinical development program, including 2,742 patients with 
Crohn’s disease. The estimated cumulative exposure to ustekinumab from launch through 
31 December 2017 is 1,036,701 person-years across all disease indications.
The benefits of ustekinumab in patients with moderate to severe Crohn’s disease have been well 
characterized, with a significant improvement in control of disease and a potential for decreased 
colectomy, lower frequency of hospitalization, and improved quality of life.
Re-induction dosing for LoR employs the currently approved initial IV induction dose that was
demonstrated to be safe and effective in clinical trials. This incremental, short-term increase in 
serum levels of ustekinumab is unlikely to have safety consequences compared with the initial 
induction; indeed, no dose response was observed for safety between the different induction doses 
tested in clinical trials with ustekinumab. In Crohn’s disease induction studies, no events of 
anaphylaxis or other serious infusion reactions were reported following the single IV dose; 2.4% 
of 466 participants who received placebo and 2.6% of 470 participants who received the 
recommended dose of ustekinumab reported adverse events occurring during or within an hour of 
the infusion.
As described in Section 2.2.3, it is likely that serum concentrations after re-administration of the 
IV induction dose in patients on q8w maintenance would be similar to those after the initial IV
induction dose administration. Use of the approved maintenance dose and dosing interval after IV 


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re-induction would avoid increased long-term exposure to ustekinumab and present a lower 
treatment administration burden on patients than more frequent injections.
There is evidence in the literature demonstrating that a strategy of re-inducing therapy can be as 
effective as long-term dose increases
or interval shortening
with reduced safety 
considerations.6,11,12,15,16,18,32 Of particular interest is the most recent of these reports
(Heron 201812), in which 8 patients with Crohn’s disease who were on SC 90 mg q4w
ustekinumab, with either clinical or endoscopic LoR, were dose adjusted with IV re-induction. Of 
the 8 patients who received IV re-induction, 5 (62.5%) were in clinical remission or endoscopic 
response at follow-up.
In this study, the potential risks of treatment with ustekinumab (eg, serious infections, including 
tuberculosis [TB] and hypersensitivity reactions) are addressed in multiple ways:

The inclusion/exclusion criteria set appropriate limits regarding, for example, infections or 
predisposition to infections, history of reactions to biologic agents, and baseline laboratory 
abnormalities (see Sections 5.1 and 5.2, respectively).

Comprehensive medical monitoring of data by the sponsor during the conduct of this study 
includes regular assessment of adverse events and serious adverse events, vital signs, physical 
examination, and laboratory test results to evaluate individual cases as well as potential 
emerging safety trends (see Schedule of Activities and Section 8.2).

Certain concomitant medications have been prohibited and limitations set on dose levels of 
permitted concomitant medications in this study, such as high dose glucocorticoids and use of 
multiple biologics simultaneously, which could introduce safety risks due to over-suppression 
of the immune system (see Section 6.5).

Finally, the steroid-sparing effects of ustekinumab are evaluated by implementation of a 
glucocorticoid taper from Week 8 (see Section 6.5.2). This may benefit participants by 
reducing risk of infection and other glucocorticoid-related complications; however, if a 
participant experiences a worsening in their disease activity while tapering corticosteroids, 
further dose decreases can be suspended, and/or the participant’s oral corticosteroid dose may 
be temporarily increased if deemed necessary by the investigator.
The benefit risk ratio is considered favorable, given the potential benefit of a re-induction strategy 
to regain response to ustekinumab with a single intervention, and considering the current 
understanding of the safety profile of ustekinumab and the cumulative ongoing safety evaluations.


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3.
OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objective
The primary objective is to evaluate the achievement of clinical response at Week 16 following a 
single IV re-induction dose of 6 mg/kg ustekinumab, compared with continuing regular SC q8w 
90 mg ustekinumab administration, in participants with secondary LoR to SC q8w 90 mg 
ustekinumab maintenance therapy.
Secondary Objectives
The secondary objectives are to:

Evaluate the achievement of clinical response and clinical remission, as well as the reduction 
in inflammatory biomarkers (serum CRP and fecal calprotectin [fCal] levels), after IV 
ustekinumab re-induction.

Assess the overall safety of IV ustekinumab re-induction.
Other Objectives
Other objectives are to assess endoscopy and patient-reported assessment of bowel inflammation
following IV ustekinumab re-induction, and to assess the steroid-sparing effect and 
pharmacokinetics following a single IV re-induction dose of 6 mg/kg ustekinumab.
ENDPOINTS
Primary Endpoint
The primary endpoint is clinical response at Week 16, defined as a ≥100-point reduction from the 
baseline CDAI score or a CDAI score <150 points.
Secondary Endpoints
The major secondary endpoints, listed in order of testing, are as specified below:

Clinical remission at Week 16, defined as a CDAI score of <150 points.

Clinical response at Week 8, defined as a ≥100-point reduction from the baseline CDAI score 
or a CDAI score <150.

Clinical remission at Week 8, defined as a CDAI score of <150 points.

Normalization of CRP and/or fCal concentration(s) at Week 16, among participants with an 
elevated CRP and/or fCal at baseline.
Other secondary endpoints are:

Clinical remission at Week 24, defined as a CDAI score of <150 points.

Clinical response at Week 24, defined as a ≥100-point reduction from the baseline CDAI score 
or a CDAI score <150.


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
Normalization of CRP and/or fCal concentration(s) at Week 24, among participants with an 
elevated CRP and/or fCal at baseline.

Safety endpoints, including the proportion of participants with at least one adverse event and 
subcategories of adverse events (all infections, all serious adverse events and serious 
infections), as well as changes in clinical laboratory test results.
Other Endpoints
The following other endpoints will be assessed:

Endoscopy

Reduction of ≥50% from baseline in simple endoscopic score for Crohn’s disease 
(SES-CD) at Week 16.

Reduction of ≥3 points from baseline in SES-CD at Week 16.

SES-CD score ≤3 at Week 16.

Complete absence of mucosal ulcerations in any ileocolonic segment at Week 16

Change from baseline in simple endoscopic score for SES-CD score at Week 16.

Proportion of participants with a minimum of 25% improvement from baseline in 
SES-CD score at Week 16.

Patient-reported outcomes

Change from baseline in the sum of the number of stools and the abdominal pain scores 
in the prior 7 days, without weighting (PRO-2), at Week 16.

Change from baseline in the weighted sum of the abdominal pain and stool frequency 
subscores of the CDAI (PRO-2 weighted) at Week 16.

Change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score 
(including IBDQ domains) at Week 16.

Proportion of participants with IBDQ remission (IBDQ score >170) at Week 16.

Steroids

Proportion of participants with corticosteroid-free response at Week 24, defined as a 
CDAI score decrease ≥100 from baseline.

Proportion of participants with corticosteroid-free response at Week 24, defined as a 
CDAI score decrease ≥100 from baseline, among participants who were on 
corticosteroids at baseline.

Proportion of participants with corticosteroid-free remission at Week 24, defined as a 
CDAI score <150, among participants who were on corticosteroids at baseline.

Pharmacokinetics

Serum ustekinumab concentrations and PK parameters.

Proportion of participants with anti-ustekinumab antibodies.


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Additionally, the following other combined endpoints will be assessed at Week 16:

Proportion of participants with clinical remission and ≥50% reduction from baseline in CRP 
or fCal.

Proportion of participants with clinical remission and ≥50% reduction from baseline in CRP 
or fCal, among participants with elevated CRP (>3 mg/L) or elevated fCal (>250 mg/kg) at 
baseline.

Proportion of participants with clinical remission and CRP <3 mg/L and fCal ≤250 mg/kg.

Proportion of participants with clinical remission and CRP <3 mg/L and fCal ≤250 mg/kg, 
among participants with elevated CRP (>3 mg/L) or elevated fCal (>250 mg/kg) at baseline.

Proportion of participants with clinical biomarker response (clinical response and 
≥50% reduction from baseline in CRP or fCal).

Proportion of participants with clinical biomarker response (clinical response and 
≥50% reduction from baseline in CRP or fCal), among participants with elevated CRP 
(>3 mg/L) or elevated fCal (>250 mg/kg) at baseline.

Proportion of participants with clinical response and CRP <3 mg/L and fCal ≤250 mg/kg.

Proportion of participants with clinical response and CRP <3 mg/L and fCal ≤250 mg/kg, 
among participants with elevated CRP (>3 mg/L) or elevated fCal (>250 mg/kg) at baseline.
Refer to Section 8, Study Assessments and Procedures, for evaluations related to endpoints.
HYPOTHESIS
The study hypothesis is that in patients with secondary LoR to SC q8w 90 mg ustekinumab 
maintenance treatment, a single weight-tiered based IV ustekinumab re-induction dose of 
6 mg/kg (ie, IV ustekinumab/SC placebo at Week 0) followed by q8w 90 mg ustekinumab 
maintenance will result in a higher clinical response rate (defined as a ≥100-point reduction from 
the baseline CDAI score, or a CDAI score <150) compared with continuous SC q8w 90 mg 
ustekinumab maintenance treatment (ie, IV placebo/SC ustekinumab at Week 0) after 16 weeks.


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4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, double-blind, placebo-controlled, multicenter, 24-week, Phase 3b study in 
adult patients with moderately to severely active Crohn’s disease who initially responded to 
ustekinumab induction therapy per label followed, at any time, by secondary LoR to SC q8w 
ustekinumab maintenance therapy. The benefit of a single weight-tiered based IV re-induction 
dose of 6 mg/kg body weight ustekinumab versus continuous SC q8w maintenance treatment will 
be evaluated.
Initial response criteria are described in Section 10.2, Appendix 2.
Secondary LoR is defined as a CDAI score of 220 and ≤450 plus at least one of the following:

Elevated CRP (>3.0 mg/L); and/or

Elevated fCal (>250 mg/kg); and/or

Endoscopy (ileocolonoscopy) performed ≤3 months before baseline with evidence of active 
Crohn’s disease (defined as one or more ulcerations in the ileum and/or colon).
The study will include approximately 200 participants. Eligible participants will be randomly 
assigned to one of the following 2 intervention groups, in a 1:1 ratio, using permuted block 
randomization stratified at the study level by participant’s baseline CDAI score (≤300 or >300) 
and prior biologic failure (yes or no) at baseline.

Ustekinumab re-induction:
IV ustekinumab and SC placebo at Week 0.

Continuous maintenance:
IV placebo and SC ustekinumab at Week 0.
At baseline (Week 0), approximately 8 weeks (±2 weeks) after the previous per label dose of SC
90 mg ustekinumab maintenance, participants will undergo clinical assessments. Following 
randomization, participants will receive IV ustekinumab 6 mg/kg and SC placebo or IV placebo 
and SC ustekinumab 90 mg in a double-blind manner. Either the IV infusion or the SC injection 
may be administered first at Week 0, based on the standard-of-care practices at the study site; there 
must be no concurrent administration of IV and SC study intervention (see Section 6.1).
At Week 8 and Week 16, all participants will receive SC ustekinumab 90 mg and undergo clinical 
assessments.
At Week 24, all participants will undergo study assessments before resuming their standard-of-
care therapy at the discretion of the treating physician. All participants will have a follow-up for 
evaluation of safety approximately 20 weeks after their last study intervention administration 
(ie, Week 36 for participants who complete the final study intervention visit at Week 16); this may 
be conducted at a site visit or by telephone.


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Key efficacy assessments will include clinical response (CDAI reduction ≥100), clinical remission 
(CDAI value <150) and biomarker normalization. Safety assessments will include the monitoring 
of adverse events, vital signs, and clinical laboratory tests.
A diagram of the study design is provided in Section 1.2, Schema. The timing of study 
interventions and clinical assessments is summarized in Section 1.3, Schedule of Activities.
4.2.
Scientific Rationale for Study Design
Study Population
The population for this study includes only adult patients with moderately to severely active
Crohn’s disease who experience a secondary LoR to SC q8w ustekinumab maintenance treatment, 
representative of the population of patients with Crohn’s disease in which ustekinumab is 
approved. Since anti-TNF agents are often the first-line biologics used in the treatment of patients 
with Crohn’s disease, based on recommended treatment algorithms11,17, and the relatively recent 
approval of ustekinumab for the treatment of Crohn’s disease, these patients likely have few 
remaining therapeutic options; hence regaining and preserving the response to ustekinumab is 
essential for the long-term management of their disease. While the current EU labeling for 
ustekinumab provides the option for dose adjustment in patients with LoR to q12w maintenance, 
there is no option for patients with LoR to q8w maintenance. Since dose adjustment using IV 
re-induction has not yet been studied in a controlled manner in these patients, this represents an 
important gap in the scientific literature that is important for evidence-based practice. This study 
will fill this gap by providing a prospective, randomized direct comparison of IV re-induction with
continuous q8w maintenance therapy.
To mimic normal clinical practice and consistent with other studies, enrolled participants will be 
permitted to receive concomitant immunosuppressants or oral corticosteroids for the treatment of 
Crohn’s disease during the study, provided they were on a stable dose for a specified period prior 
to baseline and will maintain a stable dose throughout the trial, with the exception of oral 
corticosteroids which will be tapered in Week 8 CDAI-70 responders.
Blinding, Control
This study is double-blind and utilizes a double-dummy design to maintain blinding and prevent 
bias. Placebo is included in each intervention group for blinding purposes, rather than for 
determination of the effect of the study intervention (IV re-induction with ustekinumab versus 
continuous SC ustekinumab maintenance therapy). All participants will receive ustekinumab 
treatment until Week 24, at which time they will receive standard-of-care therapy.
Dosing, Study Duration
The dosage and dosing interval are designed to align with the currently approved label for 
ustekinumab for Crohn’s disease in both the EU and the US.
The relatively short duration of the study (24 weeks, with a safety follow up at Week 36) is
intended to provide evidence for the effectiveness of re-induction without requiring prolonged 
treatment, should a patient not respond to the therapeutic intervention. Based on PK modeling, it 


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is expected that serum concentrations of ustekinumab will have nearly normalized by Week 16 
with complete normalization by Week 24.
Study Endpoints
The primary endpoint at Week 16 aligns with the current recommendations to evaluate the 
response to initial induction or dose escalation after 16 weeks of therapy. The primary endpoint of 
clinical response is designed to mimic the real-world treatment of patients with Crohn’s disease.
The population of patients enrolled in this trial (ie, with LoR despite high dose ustekinumab 
maintenance therapy and a likely history of previous, inadequate response to biologic agents) is 
expected to be difficult to treat. In this refractory setting the primary goal is to achieve a clinical 
response, rather than clinical remission or endoscopic response. In addition, it is not clear if
patients who experience LoR necessarily have associated endoscopic recurrence, nor has it been 
established for any biologic that endoscopic response can be regained with dose adjustment for 
LoR in patients with Crohn’s disease. The use of the CDAI to assess response to treatment has 
been demonstrated in clinical trials for recently approved therapeutics for Crohn’s disease.9,21
This study will also evaluate patient-reported outcomes (PROs), recognizing the important 
information these tools can provide to help clinicians evaluate response to therapies. The 
evaluation of endoscopic outcome measures at Week 16 will seek to provide additional 
information on the efficacy of IV re-induction and of mucosal inflammation in the setting of LoR. 
Additional evaluations will examine the pharmacodynamics of IV re-induction, correlating the PK 
with clinical outcomes (eg, CDAI, changes in CRP and fCal, and endoscopic measures where 
applicable); these evaluations may provide further information to enable clinicians to make 
informed treatment decisions for patients with a secondary LoR to ustekinumab.
Database Locks
Two database locks are planned for this study. The first (the primary endpoint database lock) will 
occur when all participants have completed Week 16 or have terminated study participation prior 
to Week 16. The second (the final database lock) will occur when all participants have completed 
Week 36 or have terminated study participation prior to Week 36.
At the time of the Week 16 database lock, 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, participants, and sponsor site monitors 
until the final assessments have been completed for all study participants at Week 36. This measure 
will mitigate the potential bias in the remaining investigator and participant assessments.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study. During the 
study, participants 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 participants who are fully able to understand the risks, benefits, 
and potential adverse events of the study, and who provide their consent voluntarily will be enrolled.


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The efficacy and safety profile for ustekinumab in the treatment of moderately to severely active 
Crohn’s disease is well-established. All participants will receive active treatment for their disease 
throughout the study, including those patients who receive IV placebo. Additionally, the dosage and 
dosing interval used in this study are designed to align with the currently approved label for 
ustekinumab for Crohn’s disease in both the EU and the US.
The total blood volume to be collected in this study (see Section 8) is considered an acceptable 
amount for the study duration and study population based upon the standard of the World Health 
Organization (450 mL once every 2 months, up to a maximum of 3 L over 12 consecutive months 
for blood donation).
4.3.
Justification for Dose
The IV ustekinumab re-induction dose (6 mg/kg) is the approved dose for the initial induction 
with ustekinumab in patients with Crohn’s disease, which is being investigated in this study for 
re-induction in patients with secondary LoR to ustekinumab.
The maintenance dose of ustekinumab (90 mg) SC q8w is the approved dose for maintenance 
treatment in patients with Crohn’s disease in the US and for EU patients who have not responded 
adequately to ustekinumab induction treatment or q12w treatment. All participants must have 
demonstrated secondary LoR to current SC q8w ustekinumab maintenance therapy to qualify for
this study (see Section 4.1); any patients who initially did not respond adequately to ustekinumab 
q12w treatment must also have not responded to q8w treatment before being considered eligible 
for this study.
The rationale for re-induction rather than dose interval shortening to address LoR in patients on 
q8w maintenance is supported by 2 key arguments:

Ustekinumab PK analysis shows that ustekinumab clearance is increased with increased levels 
of underlying inflammation, as measured by CRP. This raises the possibility that ustekinumab 
clearance could slow as inflammation is suppressed and response is regained and, if so, that a 
longer-term increase in dose might not be necessary to sustain adequate ustekinumab levels 
once response has been regained.

Crohn’s disease is characterized by periodic flares, which suggests that increased doses of 
drug would be required only until the flare is quiesced or has subsided, after which 
maintenance dosing can be continued.
The therapeutic intervention takes advantage of an approved induction dose and route of 
administration with known PK characteristics and safety, minimizing risk to the study participants, 
particularly over an extended time since no safety data exist for long-term use of 90-mg SC q6w 
or q4w dosing.


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4.4.
End of Study Definition
A participant will be considered to have completed the study if he/she has completed assessments 
through the 24-week treatment period and the Week 36 safety follow up. Participants will be 
considered to have completed the primary efficacy period of the study if they have completed the 
study assessments through Week 16 (or at an early termination visit).
The end of study is considered the last scheduled study assessment for the last participant in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final participant assessment at that study site, in the time frame specified in the Clinical Trial 
Agreement.
5.
STUDY POPULATION
Screening for eligible participants will be performed within 5 weeks before the first administration 
of study intervention at Week 0. Refer to Section 5.4 for information on repeat of any screening 
procedures.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about any of these criteria, the investigator must consult with the appropriate 
sponsor representative and resolve any issues before enrolling a participant in the study. Waivers 
are not allowed. For a discussion of the statistical considerations of participant selection, refer to 
Section 9.2.
5.1.
Inclusion Criteria
Each potential participant must satisfy all the following criteria to be enrolled in the study:
1.
Male or female aged 18 years (or the legal age of consent in the jurisdiction in which 
the study is taking place if older than 18 years).
2.
A history of 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.
Criterion changed per Amendment 4.
3.1
Initially responded to ustekinumab induction therapya, administered according to the local 
label, followed by secondary LoR to ustekinumabb.
a
Initial response to ustekinumab as defined in Section 10.2, Appendix 2.
b
Secondary LoR to ustekinumab is defined as active disease at study baseline, proven 
by a CDAI score of 220 and ≤450 with at least one of the following:

Elevated CRP (>3.0 mg/L); and/or

Elevated fCal (>250 mg/kg); and/or

Endoscopy (performed ≤3 months before baseline) with evidence of active 
Crohn’s disease (defined as one or more ulcerations in the ileum and/or colon).


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Participants must currently be on a SC 90 mg ustekinumab q8w maintenance dose 
regimen and have received at least 2 doses of SC 90 mg ustekinumab treatment 8 weeks 
apart prior to enrollment.
4.
The following medications for the treatment of Crohn’s disease are permitted providing 
the doses indicated are stable for at least 3 weeks before baseline or have been 
discontinued at least 3 weeks before baseline:

Oral 5-aminosalicylic acid (5-ASA) compounds.

Oral corticosteroids (eg, prednisone, budesonide) at a prednisone-equivalent dose of 
≤40 mg/day or ≤9 mg/day of budesonide.

Antibiotics used as the primary treatment of Crohn’s disease.
Any participants receiving conventional immunomodulators (ie, azathioprine [AZA], 
6-mercaptopurine [6-MP], or methotrexate [MTX]) must have been taking them for 
≥12 weeks and must have been on a stable dose for a least 4 weeks before baseline.
5.
The following laboratory test results are within the specified limits at screening:

Hemoglobin 8.5 g/dL (85 g/L).

White blood cell (WBC) count 3.5 x 103/L (3.5 GI/L).

Neutrophils 1.5 x 103/L (1.5 GI/L).

Platelets 100 x 103/L (100 GI/L).

Serum creatinine <1.7 mg/dL (≤150 µmol/L).

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase levels ≤2 times the upper limit of normal for the laboratory conducting 
the test.

Direct (conjugated) bilirubin <1.0 mg/dL (<0.01 g/L).
NOTE: A repeat of these screening laboratory tests is allowed during the screening phase. 
The investigator may consider the participant eligible if the previously abnormal 
laboratory test result is within the acceptable range on repeat testing in the laboratory.
6.
Criterion changed per Amendment 1.
6.1
Meet the following TB screening criteria:

No history of latent or active TB before screening. An exception is made for 
participants who have a history of latent TB and are currently receiving treatment for 
latent TB, will initiate treatment for latent TB prior to first administration of study 
intervention, or have documentation of having completed appropriate treatment for 
latent TB within 5 years prior to the first administration of study intervention. It is 
the responsibility of the investigator to verify the adequacy of previous TB treatment 
and provide appropriate documentation.

No signs or symptoms suggestive of active TB upon medical history and/or physical 
examination.


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
No recent close contact with a person with active TB. If there has been such contact,
the participant will be referred to a physician specializing in TB to undergo additional 
evaluation and, if warranted, will receive appropriate treatment for latent TB prior to
or simultaneously with the first administration of study intervention.

Within 5 weeks before the first administration of study intervention, has a negative 
QuantiFERON®-TB test result, or 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 prior to the first administration of study intervention. If the 
QuantiFERON-TB test is not approved or is not registered in a country or if the 
tuberculin skin test is mandated by local health authorities, a negative tuberculin skin 
test (see Section 10.3, Appendix 3), or a newly identified positive tuberculin skin test 
in which active TB has been ruled out and for which appropriate treatment for latent 
TB has been initiated prior to the first administration of study intervention, is 
additionally required within 5 weeks prior to the first administration of study 
intervention.

Participants who have an indeterminate result should have the test repeated. 
Participants with persistently indeterminate QuantiFERON-TB test results may be 
enrolled without treatment for latent TB if active TB is ruled out, their chest 
radiograph shows no abnormality suggestive of TB (active or old, inactive TB), and 
the participant has no additional risk factors for TB as determined by the investigator. 
This determination must be promptly reported to the sponsor’s medical monitor,
recorded in the participant's source documents, and initialed by the investigator.
NOTE: The QuantiFERON-TB test and/or the tuberculin skin test is/are not required 
to be performed at screening for participants with a history of latent TB and ongoing 
treatment for latent TB or documentation of having completed adequate treatment as 
described above. Participants with documentation of having completed adequate 
treatment as described above are not required to initiate additional treatment for latent 
TB.

Has a chest radiograph (at least a posterior-anterior view) or computed tomography 
of the chest, taken within 6 months before the first administration of study 
intervention and read by a qualified radiologist, with no evidence of current, active 
TB or old, inactive TB.
7.
A female participant must be:

Not of childbearing potential (as defined in Section 10.8, Appendix 8)
OR

If heterosexually active, must be practicing a highly effective method of birth control,
consistent with local regulations regarding the acceptable methods of contraception 
for those participating in clinical studies, for the duration of their participation in the 
study and for 15 weeks after the last dose of study intervention, the end of relevant 
systemic exposure.
NOTE: If the participant’s childbearing potential changes after the start of the study, 
that participant must begin practicing a highly effective method of birth control as 
described above.


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OR

Not be heterosexually active and agrees to utilize a highly effective method of birth 
control if they become heterosexually active during their participation in the study.
Examples of highly effective methods of contraception are presented in Section 10.8, 
Appendix 8.
8.
All female participants of childbearing potential must have a negative highly sensitive 
serum (-human chorionic gonadotropin [-hCG]) pregnancy test at screening and a 
negative urine pregnancy test at baseline and prior to each administration of study 
intervention.
9.
A male participant who is heterosexually active with a woman of childbearing potential 
and is not surgically sterile must agree to use a double-barrier method of birth control and 
not donate sperm during the study and for 15 weeks after receiving study intervention.
10.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
11.
Sign an informed consent document indicating that he/she understands the purpose of and 
procedures required for the study and is willing to participate in the study.
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
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 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 there is no anticipated
need for any further surgery. Participants with active fistulas may be included if there is 
no anticipation of a need for surgery and there are currently no abscesses identified.
3.
Any kind of bowel resection within 6 months or any other intra-abdominal surgery within 
3 months before baseline.
4.
A draining (ie, functioning) stoma or ostomy.


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5.
Criterion changed per Amendment 4:
5.1
Received any of the following prescribed medications or therapies within the specified 
period:

Use of IV ustekinumab re-induction after the initial weight-tiered-based IV induction 
dose of ustekinumab.

Any known history of shortened frequency of SC dose administration (<q8w) for a 
secondary loss of response where the participant did not, in the opinion of the treating 
physician, benefit from the dose interval shortening.

Intravenous corticosteroids as a treatment for Crohn’s disease within 3 weeks before 
baseline.

Oral immunomodulatory agents other than AZA, 6-MP, or MTX (eg, Janus kinase 
[JAK] inhibitors, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, 
tofacitinib, or mycophenolate mofetil) within 4 weeks before baseline.
NOTE: See Inclusion Criterion 4 for restrictions on typical immunomodulator 
agents (AZA, 6-MP or MTX).

Any other investigational agent for Crohn’s disease (eg other biologics, small 
molecules or anti-sense RNA such as mongersen), unless at least 3 months or 5 half-
lives (whichever is longer) have elapsed since the last dose.

Treatment with apheresis (eg, Adacolumn apheresis) or total parenteral nutrition as 
a treatment for Crohn’s disease within 3 weeks before baseline.
6.
A stool culture or other examination in the last 4 months that is positive for an enteric 
pathogen, including Clostridium difficile toxin, unless a repeat examination is negative 
and there are no signs of ongoing infection with that pathogen.
7.
Received a Bacille Calmette-Guérin (BCG) vaccination within 12 months before baseline 
or any other live bacterial or live viral vaccination within 2 weeks before baseline.
8.
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.
9.
Any current signs or symptoms of infection. Established non-serious infections (eg, acute 
upper respiratory tract infection, simple urinary tract infection) need not be considered 
exclusionary at the discretion of the investigator.
10.
A history of serious infection (eg, sepsis, pneumonia, or pyelonephritis), including any 
infection requiring hospitalization or IV antibiotics, for 8 weeks before baseline.
11.
Evidence of a herpes zoster infection 8 weeks before baseline.


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12.
A history of latent or active granulomatous infection, including histoplasmosis or 
coccidioidomycosis, before screening; refer to Inclusion Criterion 6 for information 
regarding eligibility with a history of latent TB.
13.
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.
14.
A current or (lifetime) history of a nontuberculous mycobacterial infection or serious 
opportunistic infection (eg, Cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
15.
Known to be infected with human immunodeficiency virus, hepatitis B, or hepatitis C.
16.
Severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, 
cardiac, neurologic, cerebral, or psychiatric disease, or any signs or symptoms thereof.
17.
A transplanted organ, with the exception of a corneal transplant performed >12 weeks 
before screening.
18.
A known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy 
and/or splenomegaly.
19.
Any known malignancy or a history of malignancy, with the exception of: basal cell 
carcinoma; squamous cell carcinoma in situ of the skin; cervical carcinoma in situ that 
has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin 
that was treated with no evidence of recurrence within 5 years before screening.
20.
Previous allergy immunotherapy for prevention of anaphylactic reactions.
21.
Unable or unwilling to undergo multiple venipunctures because of poor tolerability or 
lack of easy access to veins.
22.
Known to have had a substance abuse (drug or alcohol) problem within the 12 months 
before baseline.
23.
Known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients (refer 
to the Investigator's Brochure for further details).
24.
Currently is participating in or is intending to participate in any other study using an 
investigational agent or procedure during participation in this study.
25.
A woman who is pregnant, or breastfeeding, or planning to become pregnant, or is a man 
who plans to father a child while enrolled in this study or within 15 weeks after the last 
dose of study intervention.


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26.
Any condition that, in the opinion of the investigator, would make study participation not 
in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
27.
Criterion added per Amendment 3:
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

obtained at least 2 weeks after conditions (a), (b), or (c) above (timed from 
resolution of key clinical features if present, eg, fever, cough, dyspnea)
AND

with absence of ALL conditions (a), (b) and (c) above during the period between 
the negative test result and the baseline study visit.
Notes on COVID-19-related Exclusion:

If a patient is excluded due to recent COVID-19-related features, the reason for 
screen failure should be documented in the case report form (CRF) under the 
exclusion criterion of having a condition for which study participation would not 
be in the patient’s interest or could confound study assessments.

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, or standards 
of care.
Precautions:
For those patients who may carry a higher risk for severe COVID-19 illness (eg, patients 
aged over 65 years), follow the guidance from local health authorities when considering 
the potential benefits and risks of enrolling patients into the study and during study 
participation.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he/she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. The required source documentation to support meeting the 
enrollment criteria are indicated in Section 10.6, Appendix 6.


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5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the study to be eligible for participation:
1.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
2.
Must not receive ustekinumab outside of the study or participate in any other clinical 
study with an investigational agent while in this study. If a participant intends to receive 
ustekinumab or participate in any other clinical study with an investigational agent, they 
must terminate study participation and an early termination visit should occur.
3.
Must agree to adhere to the restrictions/prohibitions regarding concomitant therapies 
during the study (see Section 6.5).
4.
Must agree not to receive a live virus or live bacterial vaccination, including a BCG 
vaccination, during the study or for 12 months after receiving study intervention for BCG 
vaccination and for at least 15 weeks for other live vaccines.
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent (as allowed by local regulations). In cases where 
the participant is not randomized into the study, the date seen and age at initial informed consent
(as allowed by local regulations) will be used.
If a participant does not meet all inclusion and exclusion criteria as listed in Sections 5.1 and 5.2
(ie, is a screen failure), but at some point is expected to meet the study eligibility criteria, the 
participant may be rescreened. Participants who are rescreened will be assigned a new participant 
number, undergo the informed consent process, and then restart a new screening phase.


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6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
Study intervention will start at baseline (Week 0), approximately 8 weeks (±2 weeks) after the 
previous dose of per label SC 90 mg ustekinumab maintenance treatment. The date of the previous 
dose of ustekinumab will be recorded in the case report form (CRF).
To maintain the double-blind, at Week 0 all participants will receive one IV infusion of 
ustekinumab 6 mg/kg or placebo plus one SC injection of ustekinumab 90 mg or placebo. Either 
the IV infusion or the SC injection may be administered first at Week 0, based on the standard-of-
care practices at the study site, but there must be no concurrent administration of study intervention 
(ie, IV and SC). The minimum required time windows between administration of IV infusion and 
SC injection at Week 0 are indicated below and in Figure 2:

If the SC injection is administered first, the IV infusion must not begin until at least 30 minutes 
after completion of the SC injection.

If the IV infusion is administered first, the SC injection must not begin until at least 
120 minutes after the start of the IV infusion, or at least 60 minutes after completion of the 
IV infusion.
The blood sample for trough serum PK must be collected at all study visits prior to the 
administration of ANY study intervention (ie, IV or SC) as well as prior to the administration of 
standard-of-care therapy at Week 24. The post-IV infusion PK blood sample at Week 0 should be 
drawn approximately 60 minutes after completion of the IV infusion.
Figure 2:
Minimum Required Time Windows Between Administration of Study Intervention (IV or SC) 
at Week 0


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At Week 8 and Week 16, all participants will receive SC maintenance injections of 90 mg 
ustekinumab. Following study assessments at Week 24, all participants will resume their standard-
of-care therapy with either ustekinumab maintenance therapy per label or another treatment 
modality at the discretion of their physician.
For IV administration, the study intervention will be administered to each participant as an infusion 
over a period of not less than 1 hour by qualified staff. The infusion should be completed within 
8 hours of preparation. Details of each infusion will be recorded in the CRF (including date, start 
and stop times of the IV infusion, and volume infused).
Subcutaneous injections at Week 0 will be administered by qualified staff at the study site. At 
Week 8 and Week 16, SC injections should be administered by qualified study site staff during the 
study visit, if possible. However, in cases where a site visit is not possible, participants who have 
appropriate experience or have received required training may self-administer SC study 
intervention at the times instructed by the investigator. The study site staff must ensure that those 
participants have the appropriate experience or have received the required training to perform self-
administration of SC injections. Details of each administration will be recorded in the CRF 
(including date and time of administration).
Study-site personnel will instruct participants on how to store study intervention for at-home use
during Weeks 8 and 16. For each administration of study intervention, the time and date of 
injection, whether study intervention was self-administered, and if so, whether SC administration 
was complete (based on the returned syringe[s]) will be recorded in the CRF.
Detailed instructions on the administration of study interventions are provided in the site 
investigational product procedures manual.
Ustekinumab will be manufactured and provided under the responsibility of the sponsor. Refer to 
the Investigator's Brochure for a list of excipients.
6.2.
Preparation/Handling/Storage/Accountability
6.2.1.
Storage and Preparation
All study intervention must be stored at controlled temperatures ranging from 2°C to 8°C, must 
not be frozen, and must be protected from light. The solution in the vial or prefilled syringe (PFS)
should not be shaken. Prior to administration, the solution should be visually inspected for 
particulate matter and discoloration, and should not be used if it is discolored, cloudy, or if foreign 
particulate matter is present.
Study intervention should be dispensed under the supervision of the investigator, a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention in glass 
vials and PFS will be ready to use. The required volume of study intervention will be prepared 
using the appropriate vials or PFS. Aseptic procedures must be used during the preparation and 
administration of the ustekinumab solution for IV infusion.


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Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study intervention preparation, handling, and storage.
6.2.2.
Drug Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for. The study intervention administered to the participant must be 
documented on the intervention accountability form. All study intervention will be stored and 
disposed of according to the sponsor's instructions. Study-site personnel must not combine 
contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and container label and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Any study participant who will be self-administering study intervention
at home during Week 8 and Week 16 will receive detailed instructions for study intervention
storage, disposal of used syringes, and handling of unused study material. Participants will receive 
a sharps container to dispose of used syringes and will be instructed to return the sharps container 
and cartons to the study site. Participants will record SC administrations with time and date 
information in the participant’s diary. Unused study intervention must be available for verification 
by the sponsor's study site monitor during on-site monitoring visits. The return to the sponsor of 
unused study intervention, or used returned study intervention for destruction, will be documented 
on the intervention return form. When the study site is an authorized destruction unit and study 
intervention supplies are destroyed on-site, this must also be documented on the intervention return 
form.
Potentially hazardous materials, such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for intervention accountability purposes.
Study intervention should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be 
supplied only to participants participating in the study. Study intervention may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Following clinical assessments at baseline, all enrolled participants will be randomized in a 1:1 
ratio to 1 of 2 intervention groups to receive either IV ustekinumab 6 mg/kg and SC placebo or 
IV placebo and SC ustekinumab 90 mg in a blinded manner.


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Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of the 2 intervention groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. Permuted block randomization with 
stratification variables, including the participant’s baseline CDAI score (≤300 or >300) and 
whether the participant had failed a prior biologic at baseline (yes or no), will be used. The
interactive web response system (IWRS) will assign a unique intervention code, which will dictate 
the intervention assignment and matching study intervention kit for the participant. The requestor 
must use his or her own user identification and personal identification number when contacting 
the IWRS, together with the relevant unique participant details to identify the participant.
Blinding
At Week 0 participants will receive a single IV infusion of study intervention (ustekinumab 
6 mg/kg or placebo) plus a single SC injection of study intervention (ustekinumab 90 mg or 
placebo) in a double-blind, double-dummy manner. During study visits at Week 8 and Week 16, 
all participants will receive SC maintenance injections of 90 mg ustekinumab.
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 participant. Appropriate sponsor representatives will also have access to the IWRS to 
break the blind for an individual participant, if needed.
Data that may potentially unblind the intervention assignment (ie, treatment allocation, study 
intervention preparation/accountability, and administration of study intervention; see details in 
Sections 6.1, 6.2 and 6.3) will be handled with special care to ensure that the integrity of the blind 
is maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others as 
appropriate until the time of database lock and unblinding (at Weeks 16 and 36, see Section 4.2).
Under normal circumstances, the blind should not be broken until the database is finalized. The 
investigator may in an emergency determine the identity of the intervention by contacting the 
IWRS. While the responsibility to break the intervention code in emergency situations resides 
solely with the investigator, it is recommended that the investigator contact the sponsor or its 
designee if possible to discuss the 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 and reason for the unblinding 
must be documented by the IWRS in the appropriate section of the CRF. The documentation 
received from the IWRS, indicating the code break, must be retained with the participant's source 
documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for 
scheduled evaluations.


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6.4.
Study Intervention Compliance
Study intervention will be administered at the study site throughout the study, whenever possible, 
and study personnel will maintain a log of all study intervention administrations. Study 
intervention supplies for each participant will be inventoried and accounted for. All ongoing 
therapies administered at the time of screening must be recorded.
Each administration of study intervention performed will be recorded in the participant’s source 
documents or diary. Study intervention at Week 0 will be administered with the assistance of a 
staff member at the study site who will be supervising study intervention administration at this
visit. Study intervention at Week 8 and Week 16 will be administered at the study visit, whenever 
possible, with the assistance of a staff member. For any study intervention administration 
performed by the participant outside of a study site, participants will keep the syringe carton and 
return the empty carton to the study site with the diary at their next visit. The participant will record 
the corresponding date and time of the administration in the diary. Study site personnel will utilize 
participant’s diaries to ensure compliance and record at-home study intervention administrations 
in the eCRF. Additionally, a sharps container to dispose of used syringes will be provided to 
participants who will administer any study intervention outside of the study site. Participants will 
be instructed to return the sharps container, the syringe cartons and diaries to the study site at their 
next visit.
Additional details will be provided in the pharmacy manual/study site investigational product 
manual provided separately.
6.5.
Concomitant Therapy
Concomitant medications will be reviewed at each visit. All concomitant therapies (including 
vaccines) must be recorded throughout the study, from signing of the informed consent form (ICF)
to the last study visit. Recorded information will include a description of the type of the therapy, 
treatment period, dosing regimen, route of administration, and its indication.
6.5.1.
Crohn’s Disease-specific Concomitant Medications
During the study, participants are permitted to receive oral 5-ASA compounds, the 
immunomodulators AZA, 6-MP and MTX, oral corticosteroids, and/or antibiotics for the treatment 
of Crohn’s disease, provided the participant was on a stable dose for a specified period before
baseline (as defined in the inclusion criteria, Section 5.1). Participants receiving these medications 
at baseline should maintain a stable dose throughout the study, except for oral corticosteroids 
which must be tapered in participants with a CDAI-70 response at Week 8 (see Section 6.5.2).
Enrolled participants should not initiate any of the following concomitant Crohn’s disease-specific 
medical therapies during the study:

Oral or rectal 5-ASA compounds.

Immunomodulators (AZA, 6-MP, or MTX).

Oral, parenteral, or rectal corticosteroids.




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
Immunomodulatory biologic agents (including but not limited to TNF antagonists, 
vedolizumab, natalizumab, abatacept).

Experimental or investigational Crohn’s disease medications (including but not limited to 
thalidomide, briakinumab, traficet, AMG 827).
NOTE: Participants must not receive ustekinumab outside of the study or participate in any other 
clinical study with an investigational agent while in this study. If they intend to receive 
ustekinumab or participate in any other clinical study with an investigational agent, an early 
termination visit should occur beforehand. The sponsor must be notified in advance (or as soon as 
possible thereafter) of any instances in which prohibited therapies are administered.
6.6.
Dose Modification
Dose/dosage adjustment of study intervention is not permitted within this study.
6.7.
Intervention After the End of the Study
Participants will be instructed that study intervention will not be made available to them after they 
have completed or discontinued the study and that they should return to their primary physician to 
determine the standard of care at the end of the study period.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION OR WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study intervention (ie, ustekinumab IV infusion and/or SC injection) must be
discontinued if:

The investigator believes that for safety or tolerability reasons (eg, an adverse event) it is in 
the best interest of the participant to stop study intervention.

The participant becomes pregnant, plans a pregnancy within the study period, or plans a 
pregnancy within 15 weeks after the last study intervention administration; refer to 
Section 10.8, Appendix 8 for further information.

The participant is deemed ineligible according to the following TB screening criteria:

A diagnosis of active TB is made.

A participant 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 participant undergoing continued evaluation has a chest radiograph with evidence of 
current active TB and/or a positive QuantiFERON-TB test result (or a positive tuberculin 
skin test result in countries in which the QuantiFERON-TB test is not approved/registered 
or the tuberculin skin test is mandated by local health authorities), unless active TB can 
be ruled out and appropriate treatment for latent TB can be initiated before the next 
administration of study intervention and continued to completion. Participants who have 
an indeterminate result should have the test repeated. Participants with persistently 
indeterminate QuantiFERON-TB test results may continue without treatment for latent 


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TB if active TB is ruled out, their chest radiograph shows no abnormality suggestive of 
TB (active or old, inactive TB) and the participant has no additional risk factors for TB 
as determined by the investigator. This determination must be promptly reported to the 
Sponsor’s medical monitor, recorded in the participant's source documents, and initialed 
by the investigator.

A participant receiving treatment for latent TB discontinues this treatment prematurely 
or is noncompliant with the therapy.

The participant experiences a serious adverse event related to either an injection or infusion. 
Discontinuation of ustekinumab administration must also be considered for participants who 
develop a non-serious but severe infusion or injection site reaction (as defined in Section 10.7, 
Appendix 7).

The participant is diagnosed with a malignancy, including squamous cell skin cancer. 
Consideration may be given to allow participants to continue to receive study intervention if 
they develop 1 to 2 basal cell skin cancers that are adequately treated with no evidence of 
recurrence or residual disease.

The participant initiates the following prohibited medications before Week 24:

Immunomodulatory agents other than 6-MP, AZA or MTX.

Immunomodulatory biologic agents.

Experimental or investigational Crohn’s disease medications.

The participant receives ustekinumab outside of the protocol.

A serious opportunistic infection occurs.

The participant withdraws consent for administration of study intervention.

The participant is unable to adhere to the study visit schedule or comply with protocol 
requirements.

The participant has Crohn’s disease-related surgeries that precludes the ability to further 
assess efficacy through the CDAI. Surgeries that are thought to represent a lack of efficacy of 
study intervention should be considered for discontinuation at the discretion of the investigator 
other than minor procedures (eg, placement of a seton or cutaneous drainage of an abscess).
Consideration should also be given to discontinuing treatment in participants who show no 
evidence of therapeutic benefit 16 weeks after the IV re-induction.


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7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal of consent.

Death.

Sponsor decision (eg, receiving ustekinumab outside of the protocol or participating in any 
other clinical study with an investigational agent).

Investigator decision (eg, because of an adverse event or lack of efficacy).
Participants who terminate study participation will not be required to return for any follow-up 
assessments but should complete the safety and efficacy evaluations specified for early withdrawal 
(see Schedule of Activities) at the time they terminate study participation. Additionally, the safety 
follow up approximately 20 weeks after the last study intervention administration, which may be 
conducted at a site visit or by telephone, applies to all participants, including those who 
discontinued study intervention before Week 24 or who have otherwise terminated study 
participation (eg, through withdrawal of consent), unless they do not consent to this follow up by 
study-site staff.
When a participant withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study intervention assigned to a withdrawn 
participant may not be assigned to another participant. Participants who withdraw will not be 
replaced. If the reason for withdrawal from the study is withdrawal of consent, then no additional 
assessments are allowed.
If a participant is withdrawn from the study for any reason, the early termination assessments 
indicated in the Schedule of Activities should be performed as close as possible to the time of 
study discontinuation. If the reason for withdrawal from the study is withdrawal of consent, then 
no additional assessments are allowed.
7.2.1.
Withdrawal From the Use of Research Samples
A participant may withdraw consent for 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 research 
samples and to request sample destruction. The sponsor study site contact will, in turn, contact the 
appropriate sponsor representative to execute sample destruction. If requested, the investigator will 
receive written confirmation from the sponsor that the samples have been destroyed.
A participant may also withdraw consent for use of samples in future research (refer to Long-Term 
Retention of Samples for Additional Future Research in Section 10.6, Appendix 6). 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.


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7.3.
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented. Refer to Section 7.2 for further details on 
participant discontinuation/withdrawal from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The eligibility of participants will be assessed during a 5-week screening period, at which written 
informed consent must be obtained prior to conducting any protocol-specific assessments or 
procedures. Study assessments will be conducted at baseline (Week 0) and at Weeks 8, 16 and 24, 
or at early termination. All participants will have a follow-up for evaluation of safety performed 
at a site visit or by telephone approximately 20 weeks after their last study intervention 
administration (ie, Week 36 for participants who complete the final study intervention visit at 
Week 16). The Schedule of Activities summarizes the frequency and timing of safety, efficacy, 
ileocolonoscopy, PK, and immunogenicity measurements at screening and during the study. The 
following sections provide additional details on the evaluations to be conducted during the study.
During the screening period, participants will receive training in diary card completion for 
recording CDAI and information on concomitant medications. For calculation of CDAI at Week 0, 
the hematocrit value obtained during screening will be used.
Where participants agree for this procedure, a baseline, video ileocolonoscopic evaluation should 
be performed within 14 days before Week 0 (see Section 8.1.7). An ileocolonoscopy performed 
≤3 months before baseline may be used as a measure of secondary LoR (in combination with CDAI 
score; see Section 5.1, Inclusion Criterion 3), and may also be used as the baseline 
ileocolonoscopy, provided a video recording of the procedure is available . For these participants, 
a final endoscopy should be performed at the Week 16 visit.
All study-specific PRO assessments should be conducted/completed before any tests, procedures, 
or other consultations to prevent influencing participant perceptions. The PRO instruments will be 
provided in the local language in accordance with local guidelines.
Study site personnel must remind participants of the need to provide stool samples at the visits 
indicated in the Schedule of Activities.
All female participants of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline and prior to each administration of study 
intervention. Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or as required by local regulation, to establish the absence of 
pregnancy at any other time during study participation.
The total blood volume to be collected from each participant will be approximately 180 mL.


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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
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 Schedule of Activities 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.
Study-Specific Materials
The investigator will be provided with the following supplies:

Investigator's Brochure for ustekinumab.

EU SmPC/US Package Insert for ustekinumab.

Pharmacy Manual/Site Investigational Product and Procedures Manual.

Laboratory Manual.

IWRS Manual.

Manual for electronic data capture (eDC).

Sample ICF.

Contact information page.

Participant diary cards.

Participant study card.

Paper PRO questionnaires.
8.1.
Efficacy Assessments
8.1.1.
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy assessments during 
the study.
Efficacy evaluations will include the following:

CDAI (the primary tool for assessing disease activity response to ustekinumab).

PRO-2 (the CDAI components of the total number of liquid or very soft stools and the 
abdominal pain score).

IBDQ.


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
Inflammatory markers including serum CRP and fCal.

Fistula assessment.

Endoscopic assessments of the intestinal mucosa based on the presence and absence of 
mucosal ulcerations and the SES-CD.
8.1.2.
Crohn’s Disease Activity Index
The CDAI will be assessed by collecting information on 8 specific Crohn’s disease-related 
variables4: 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 four variables are scored over 7 days by the participant on a diary card. At 
each visit, the most recent hematocrit value before the current visit will be used for the calculation 
of CDAI.
For participants who agree for the ileocolonoscopy procedure, the CDAI should be completed 
before participants begin their preparation for this procedure, to prevent the ileocolonoscopy 
preparation from interfering with the CDAI results. If ileocolonoscopies coincide with visit dates 
or the 7 days before, the CDAI scores should be calculated using the closest previous 7 days not 
impacted by the ileocolonoscopy and/or its preparation.
The PRO-2 includes the unweighted CDAI components of the total number of liquid or very soft 
stools and the abdominal pain score.
Note: Fistulas that are only visible during an ileocolonoscopy procedure should not be included in 
the calculation of the CDAI score, as fistulas seen only on endoscopy cannot be evaluated at all 
visits (ie, not at Week 8 or Week 24).
A sample CDAI is presented in Section 10.10, Appendix 10. A standard weight table for CDAI is 
presented in Section 10.11, Appendix 11.
8.1.3.
C-reactive Protein
C-reactive protein has been demonstrated to be useful as a marker of inflammation in patients with 
inflammatory bowel disease. In Crohn’s disease, elevated CRP concentrations have been 
associated with severe clinical activity, elevated sedimentation rate, and active disease as detected 
by colonoscopy.24,30
Blood samples for the measurement of CRP will be collected from all participants at visits 
indicated in the Schedule of Activities. C-reactive protein will be assayed by the central laboratory 
using a validated, high sensitivity CRP assay. Results of postbaseline CRP measurements will not 
be released to the investigators.


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8.1.4.
Calprotectin
Fecal calprotectin has been demonstrated to be a sensitive and specific marker in identifying 
intestinal inflammation and response to treatment in patients with inflammatory bowel disease.7
Stool samples for determination of fCal concentrations will be collected from all participants at 
visits indicated in the Schedule of Activities; those stool samples should not be collected on days 
impacted by ileocolonoscopy preparation.
The assay for fCal concentration will be performed using a validated method by the central 
laboratory. Additional tests may also be performed on the stool samples for additional markers 
related to intestinal inflammation and treatment response. Results of post-baseline fCal tests will 
not be released to the investigators.
8.1.5.
Inflammatory Bowel Disease Questionnaire
The IBDQ14 is a validated, 32-item self-report questionnaire for participants with inflammatory
bowel disease to evaluate 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.
The IBDQ should be administered before any other study-specific procedures are performed.
Participants who do not remain in the study at Week 16, due to discontinuation of study 
intervention and/or termination of study participation, should have their follow-up IBDQ at the 
early termination visit.
A sample IBDQ is presented in Section 10.12, Appendix 12.
8.1.6.
Fistula Assessment
All participants will be assessed for fistulas. For participants 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). Only those fistulas 
that can be assessed during a normal physical examination should be included as part of the fistula 
assessment.
8.1.7.
Video Ileocolonoscopy
At the physician’s discretion, where participants agree for this procedure, ileocolonoscopy should 
be performed at baseline and at Week 16, for exploratory assessment of SES-CD and to determine 
the presence or absence of mucosal inflammation and ulceration.
All ileocolonoscopies should be performed as close to the applicable study visit as possible. The 
baseline (Week 0) ileocolonoscopy should be performed within 14 days before or at the Week 0 
visit. The Week 16 ileocolonoscopy should be performed within 14 days before or 28 days after 


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the Week 16 visit. Where ileocolonoscopy impacts the 7 days used for CDAI evaluations, see 
Section 8.1.2 for details on how those CDAI scores should be calculated.
Participants who do not remain in the study at Week 16 (due to discontinuation of study 
intervention and/or termination of study participation) should have their follow-up 
ileocolonoscopy at the early termination visit, where possible.
The ileocolonoscopy procedures should be video-recorded, following the more detailed directions 
provided in the separate study reference (or ileocolonoscopy) manual. Video endoscopies will be 
assessed by a central facility that will be blinded to intervention group.
SES-CD Scoring System
The SES-CD scoring system, which ranges from 0 to 60, includes 4 variables, each considered in 
5 segments of the bowel (the ileum, ascending colon, transverse colon, descending colon, and 
rectum):
Ulcer size: 
0.1–0.5 cm; 0.5–2 cm; >2 cm.
Extent of ulcerated surface:
<10%; 10%–30%; >30%.
Extent of affected surface:
<50%; 50%–75%; >75%.
Stenosis: 
Single or multiple and partially or totally occluded.
8.2.
Safety Assessments
Safety and tolerability evaluations will be performed as summarized in the Schedule of Activities.
In cases of self-administration of SC study intervention, participants are requested to contact their 
treating physician as soon as possible to consider reporting of an adverse event.
Adverse events will be reported and followed by the investigator as specified in Section 8.3 and in 
Section 10.7, Appendix 7.
Any clinically relevant changes occurring during the study must be recorded in 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 condition is reached.
8.2.1.
Physical Examination
Physical examinations will be performed as specified in the Schedule of Activities. Any 
abnormalities or changes in severity noted during the review of body systems should be 
documented in the source document.
8.2.2.
Vital Signs
Vital signs (temperature, pulse/heart rate, and systolic and diastolic blood pressure) will be 
obtained immediately before the initial IV infusion, approximately every 30 minutes during the IV 
infusion, and twice (at approximately 30-minute intervals) after the completion of the IV infusion. 


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Vital signs will also be obtained before and approximately 30 minutes after completion of each SC 
injection.
8.2.3.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Section 10.5, 
Appendix 5. 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. 
The laboratory reports must be filed with the source documents.
For some tests related to screening criteria, existing local or central laboratory results are 
acceptable to satisfy study requirements (eg, QuantiFERON-TB test, stool pathogens) provided 
they were performed in the required time windows. Appropriateness may be discussed with the 
medical monitor.
8.3.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, 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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study.
Anticipated events will be recorded and reported as described in Section 10.4, Appendix 4.
For further details on adverse events and serious adverse events (definitions and classifications; 
attribution definitions; severity criteria; special reporting situations; procedures) as well as product 
quality complaints, refer to Section 10.7, Appendix 7.


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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the participant'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 20 weeks after the last dose of 
study intervention (ie, up to Week 36), must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site and
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse 
event should be made by facsimile (fax).
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire 
about adverse event occurrence.
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by participants in their diary.
Unsolicited Adverse Events
Unsolicited adverse events are adverse events for which the participant is not specifically 
questioned in the participant diary.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Section 10.7, Appendix 7.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 


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sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence and 
the sponsor has determined there is a reasonable possibility that the intervention caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the institute where required). The sponsor assumes responsibility for appropriate reporting 
of anticipated events to the regulatory authorities according to requirements of the countries in 
which the studies are conducted.
8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes 
(eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any participant who becomes pregnant during the study must discontinue further study 
intervention. Follow-up information regarding the outcome of the pregnancy and any postnatal
sequelae in the infant will be required.
8.3.6.
Infusion/Injection Site Reactions and Allergic Reactions
Infusion Reactions
An infusion reaction is defined as an adverse event that occurs during or within 1 hour following 
the infusion of study intervention, 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 intervention 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, the infusion may be restarted 
with caution.
Injection Site Reactions
An injection site reaction is any adverse reaction at a study intervention injection site. The injection 
sites will be evaluated for reactions and any injection site reactions will be recorded as an adverse 
event.
Allergic Reactions
Before IV infusion, appropriately trained personnel and medications to treat allergic reactions, 
including anaphylaxis, must be available. Appropriate medical personnel must be in attendance at 
the time of the infusion and 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 
duration of the infusion, and for 1 hour after the end of the infusion in case emergency resuscitation 
is required. All participants must be observed carefully for symptoms of an allergic reaction (eg, 
urticaria, itching, hives).


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If a mild or moderate allergic reaction is observed, acetaminophen, 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 infusion or injections are 
being given.
Participants who receive an incomplete administration of the IV dose, due to any safety 
observation requiring intervention, should be discontinued from further injections of study 
intervention.
Participants who experience any systemic reaction following an IV infusion or SC injection of 
ustekinumab that requires ventilatory support or treatment with epinephrine will not be permitted 
to receive additional injections.
8.3.7.
Infections
Study intervention should not be administered to a participant with a clinically important, active 
infection. Investigators are required to evaluate participants for any signs or symptoms of infection, 
and also review participants’ diary cards for signs of infection, at scheduled visits.
If a participant develops a serious infection, including but not limited to sepsis or pneumonia, 
discontinuation of study treatment must be considered. For active varicella-zoster infection or a 
significant exposure to varicella-zoster infection in a participant without a history of chickenpox, 
study intervention should be interrupted until the symptoms have resolved and no active infection 
is present.
Assessments for TB infection will be performed at the visits specified in the Schedule of Activities. 
Refer to Section 10.3, Appendix 3 for details of tuberculin skin testing.
8.3.8.
Malignancies
Any participant who develops a malignancy, including squamous cell skin cancer, will be 
withdrawn from study intervention. Consideration may be given to allow participants who develop 
1 to 2 basal cell skin cancers to continue to receive study intervention if they are adequately treated 
with no evidence of recurrence or residual disease.
8.3.9.
Disease-Related Events and Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments or not.
8.4.
Treatment of Overdose
Single IV doses of ustekinumab up to approximately 6 mg/kg have been administered in clinical 
studies without dose-limiting toxicity. In case of overdose, it is recommended that the patient be 
monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic 
treatment be instituted immediately.


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8.5.
Pharmacokinetics and Immunogenicity
Serum samples will be used to evaluate the PK of ustekinumab and to detect and characterize
anti-ustekinumab antibodies. Serum collected for PK and immunogenicity evaluations may 
additionally be used to explore safety or efficacy aspects arising during or after the study period. 
Participant confidentiality will be maintained.
At all visits, PK and immunogenicity blood samples must be drawn PRIOR to the administration 
of ANY study intervention (IV or SC), except for the Week 0 post-infusion PK sample which 
should be drawn approximately 60 minutes after completion of the IV infusion. Pharmacokinetic 
and immunogenicity blood samples must also be drawn prior to the administration of any standard-
of-care therapy at Week 24.
8.5.1.
Evaluations
A venous blood sample of sufficient volume will be drawn at each blood sampling time point. At
Week 0, a pre-dose PK blood sample must be drawn before ANY study intervention (IV or SC) 
and approximately 60 minutes after completion of the IV infusion. At all other times, blood 
samples should be collected before administration of study intervention.
With the exception of the post-infusion blood sample at Week 0, which will be for PK evaluation 
only, each serum sample will be divided into 3 aliquots (1 each for pharmacokinetics, antibodies 
to study intervention, and a back-up sample).
8.5.2.
Analytical Procedures
All PK serum samples collected will be evaluated by a central laboratory for ustekinumab serum 
concentrations and anti-ustekinumab antibodies to enable interpretation of the data.
Pharmacokinetics
Serum concentrations of ustekinumab will be determined using a validated, specific, and sensitive 
method by or under the supervision of the sponsor.
Immunogenicity
The detection and characterization of anti-ustekinumab antibodies will be performed using a 
validated, drug-tolerant assay method by or under the supervision of the sponsor.
8.5.3.
Pharmacokinetic Parameters and Evaluations
Serum samples will be used to evaluate various pharmacokinetic parameters, including trough and 
peak ustekinumab concentrations.
8.6.
Genetics
Pharmacogenomics or other genetic measures are not evaluated in this study.
8.7.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this study.


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8.8.
Biomarkers
Biomarker assessments will be conducted to examine the biologic response to treatment and to 
identify biomarkers that are relevant to ustekinumab treatment and/or Crohn’s disease. 
Assessments may include the evaluation of relevant biomarkers in serum, blood, and/or stool 
samples collected as specified in the Schedule of Activities. Data collected from these samples 
will be used for exploratory research, which will include the following objectives:

To understand the molecular effects of ustekinumab.

To understand the pathogenesis of Crohn’s disease.

To develop new laboratory tests that could be used clinically in Crohn’s disease or other 
conditions.

Genetic analyses will not be performed on biological samples obtained for this study.
8.8.1.
Serum-based Biomarkers
Blood samples for serum-based biomarker analyses will be collected from all participants. Assays 
to be performed may include proteins associated with proinflammatory and anti-inflammatory 
effects, the recruitment and proliferation of cells associated with inflammation and repair, and 
markers associated with tissue injury or repair.
8.8.2.
Whole Blood-based Biomarkers
Whole blood samples will be collected from all participants to assess the effect of study 
intervention on RNA expression profiles. Whole blood analyses may also examine RNA 
expression associated with the pathogenesis of Crohn’s disease.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be conducted by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the statistical analysis plan.
9.1.
Statistical Hypothesis
The study hypothesis is that in patients with secondary LoR to SC q8w 90 mg ustekinumab
maintenance treatment, a single weight-tiered based IV re-induction dose of 6 mg/kg ustekinumab 
will result in a higher clinical response rate (defined as a ≥100-point reduction from the baseline 
CDAI score, or a CDAI score <150) after 16 weeks of treatment, compared with continuous SC 
q8w 90 mg ustekinumab maintenance treatment.
It is expected that the difference in the proportion of participants who achieve a clinical response 
after receiving the 6 mg/kg IV re-induction of ustekinumab compared with participants receiving 
continuous SC q8w 90 mg ustekinumab maintenance treatment will be at least 20 percentage 
points. The study is powered based on this difference in the level of response.


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9.2.
Sample Size Determination
The assumptions that form the basis for sample size and power calculations incorporated into this 
protocol to support the primary endpoint are based on the dose adjustment data from the IMUNITI 
Phase 3 study. In IMUNITI, 17 of 29 (59%) participants attained clinical response 16 weeks after 
LoR in the q12w adjusted to q8w group, while 11 of 28 (39%) participants attained clinical 
response 16 weeks after LoR in the sham dose adjustment group (ie. continually remaining on SC 
q8w dosing). The hypothesis for the sample size determination is that the IV ustekinumab group
in this study will perform similarly to, if not better than, the q12w adjusted to q8w group in the 
IMUNITI study, given that the participants in this group will receive a higher dose of ustekinumab 
than those in the IMUNITI study, who received an adjustment from q12w to q8w.
Assuming a 60% clinical response rate at Week 16 in the ustekinumab IV re-induction group and 
40% in the continuous SC q8w 90mg group, 100 participants per intervention group will yield an 
overall power above 80%, at a significance level of 0.05 (2-sided, Mantel-Haenszel test).
Table 2 provides the power for detecting a treatment difference between the IV ustekinumab group
and the continuous SC q8w 90mg ustekinumab group (for 100 participants per group) under 
varying assumptions for the clinical response rates.
Table 2:
Power to Detect a Treatment Effect Based on Different Proportions of Participants Achieving 
Clinical Response at Week 16 (Each Group)
Clinical response at Week 16 (%)
SC q8w 90 mg
(n=100)
IV re-induction
(n=100)
Power
40%
55%
59%
-
60%
83%
-
65%
95%
9.3.
Populations for Analysis
For purposes of analysis, the following populations are defined:
Table 3:
Populations for Analysis
Population
Description
Intent-to-treat population
(ITT)
All participants randomized to 1 of the 2 intervention groups.
Treated population
(safety, PK)
All participants in the ITT population who receive at least one dose of 
study intervention.
9.4.
Statistical Analysis
9.4.1.
Efficacy Analysis
Efficacy analyses will be based on an intent-to-treat principle; the efficacy data for each participant 
will be analyzed according to the assigned treatment regardless of the actual treatment received.
For the primary endpoint, the proportion of participants in clinical response at Week 16 will be 
compared between the IV group and the continuous SC q8w group using a 2-sided 


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Cochran-Mantel-Haenszel-chi-square test, stratified by baseline CDAI score (≤300 or >300) and 
prior biologic failure status at baseline (yes or no) at a significance level of 0.05.
Participants with missing data, defined as those who terminate the study before the designated visit 
or participants who have a missing value at the designated visit, will be considered to not have 
achieved their dichotomous efficacy endpoints. For continuous endpoints, the last available value 
will be carried forward for participants with missing data.
Treatment failure rules will override the response status (eg, clinical response, clinical remission, 
and mucosal healing). Participants who meet any of the following criteria for treatment failure will 
be considered to not have achieved their dichotomous efficacy endpoints from the time the 
treatment failure occurs onwards:

Had a Crohn’s disease-related surgery due to lack of efficacy; OR

Discontinued study intervention due to an adverse event of worsening Crohn’s disease or due 
to lack of efficacy; OR

Had a prohibited change in concomitant medications (to be detailed in the statistical analysis 
plan).
For continuous efficacy endpoints, the baseline value will be carried forward from the time the 
treatment failure occurs onwards.
The study endpoints (as listed in Section 3) will be compared between the IV group and the 
continuous SC q8w group. Analyses suitable for categorical data (eg, chi-square test or Cochran-
Mantel-Haenszel chi-square test, as appropriate) will be used to compare the proportion of 
participants achieving selected endpoints (eg, clinical remission) between the IV group and the 
continuous SC q8w group. In the case of rare events, Fisher’s exact test will be used for treatment 
comparisons. Continuous variables will be compared between the IV group and the continuous SC 
q8w group using an analysis of variance/covariance.
9.4.2.
Safety Analysis
Safety will be assessed through Week 24 by evaluating adverse events, clinical laboratory changes, 
physical examination, and vital signs. Adverse events will also be evaluated at a safety follow up 
performed at a site visit or by telephone approximately 20 weeks after the last study intervention 
administration (ie, Week 36 for participants who complete the final study intervention visit at 
Week 16). All participants who receive at least 1 administration of study intervention will be 
included in the safety analyses. Participants will be analyzed according to the actual treatment 
received.
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). Intervention-emergent adverse 
events are adverse events with onset during the intervention phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of participants who experience at 


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least 1 occurrence of the given event will be summarized by intervention group. In addition, 
comparisons between intervention groups will be provided if appropriate.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an adverse event, or who experience a 
severe or a serious adverse event.
Adverse events will be assessed by evaluating summaries of the following:

Adverse events.

Serious adverse events.

Reasonably related adverse events (very likely, probable, possible, as assessed by the 
investigator).

Discontinuation of study intervention due to adverse event(s).

Adverse events of clinical interest:

Injection site reactions.

Infusion-related adverse events (during or within 1 hour of the IV infusion).

Infections and serious infections.

Malignancies.
Clinical Laboratory Tests
The following clinical laboratory measures will be used to assess the safety of participants:

Laboratory parameters (hematology and chemistry) and change from baseline in these 
laboratory parameters.

The incidence of markedly abnormal laboratory parameters.
Definitions for markedly abnormal results for each laboratory parameter will be defined in the 
statistical analysis plan.
9.4.3.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics of serum ustekinumab concentrations will be calculated at each sampling 
time point. Serum ustekinumab concentrations over time will be summarized separately for the 
ustekinumab IV group and the continuous maintenance group.
Concentrations below the lowest quantifiable concentration will be treated as zero in the summary 
statistics.
Immunogenicity Analyses
The incidence of anti-ustekinumab antibodies will be summarized for all participants who have at 
least one sample obtained after their first dose of ustekinumab for detection of antibodies to 
ustekinumab.


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Pharmacokinetic/Pharmacodynamic Analyses
Analyses of the PK, immunogenicity, and pharmacodynamics of study intervention will include:

Characterization of the PK and immunogenicity of ustekinumab in participants.

Assessment of the relationship between systemic ustekinumab exposure and:

clinical outcomes, including CDAI measures.

changes in CRP and fCal.

endoscopic outcomes.

Correlation of the PK data in this study with the PK data of the UNITI trials.
9.5.
Interim Analysis
An interim analysis will be performed in the study after 40 randomized participants have 
completed the efficacy assessment at Week 16. The purpose of this interim analysis will be to 
ensure the study is not futile and to assess sample size. 
Details of the interim analyses and futility criteria will be presented in a separate statistical analysis 
plan. The sites and the study team will remain blinded, the only unblinded person will be an 
independent statistician who is not part of the study team.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Definition of Terms
Abbreviations
ALT
Alanine aminotransferase
5-ASA
5-aminosalicylic acid
AST
Aspartate aminotransferase
AZA
Azathioprine
BCG
Bacille Calmette-Guérin
CDAI
Crohn’s Disease Activity Index
Cmax
Maximum serum concentration
CRF
Case report form
CRP
C-reactive protein
eDC
Electronic data capture
EU
European Union
fCal
Fecal calprotectin
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
-hCG
-human chorionic gonadotropin
HRT
Hormonal replacement therapy
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IgG1k
Human immunoglobulin G1 kappa
IL
Interleukin
ITT
Intent-to-treat
IV
Intravenous
IWRS
Interactive web response system
LoR
Loss of response
MedDRA
Medical Dictionary for Regulatory Activities
6-MP
6-mercaptopurine
MTX
Methotrexate
PFS
Prefilled syringe(s)
PK
Pharmacokinetic(s)
PPD
Purified protein derivative
PQC
Product quality complaint
PRO
Patient-reported outcome
qXw
Every X weeks (where X=4, 8 or 12)
SC
Subcutaneous
SES-CD
Simple endoscopic score for Crohn’s disease
SmPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reactions
TB
Tuberculosis
TNF
Tumor necrosis factor
TU
Tuberculin units
US
United States
WBC
White blood cell
Definition of Terms
Study intervention
Ustekinumab administered as an 6 mg/kg IV infusion or a 90 mg SC injection.


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10.2.
Appendix 2: Definition of Ustekinumab Initial Response and Current 
Therapy
Eligible participants must:

Be on SC 90 mg ustekinumab q8w maintenance dose regimen and have received at least 
2 doses of per label SC 90 mg ustekinumab treatment 8 weeks apart.
AND

Have demonstrated previous clinical remission OR previous clinical response within 
20 weeks after receiving ustekinumab induction therapy given as a single IV dose of ~6 mg/kg 
followed by 90 mg SC injection at Week 8, based on either the clinical remission or clinical 
response criteria specified below.

Note: Participants may have initially received SC 90 mg q12w maintenance and subsequently 
escalated to SC 90 mg ustekinumab q8w maintenance, but must have demonstrated previous 
clinical remission OR previous clinical response within 20 weeks after initiation of 
ustekinumab induction therapy, as above.
Evidence of previous ustekinumab doses and measures of initial response or remission should be 
documented by medical records, letter provided by a referring physician, patient diaries, reliable 
patient history with subsequent documentation or by other ‘reason for referral’ documents 
(eg, insurance authorization forms), if available, and recorded in the eCRF. If such documentation 
is not available, investigators can confirm the ustekinumab doses and initial response/remission in 
the eCRF according to their best knowledge and clinical judgement.
Evidence of Clinical Remission to Ustekinumab Treatment:
Any of the following available criteria should be documented and noted in the eCRF:

Documented CDAI <150 (if score is available).

Documented Harvey Bradshaw Index of <5 (if score is available).

No more than mild abdominal pain with 3 or less soft or loose stools per day, on average, for 
at least a 1-week period.

No abdominal pain, with an average of 5 or less soft or loose stools per day, for at least a 
1-week period.
Evidence of Clinical Response to Ustekinumab Treatment:
Any of the following available criteria should be documented and noted in the eCRF:
PROs:

Reduction of 3 points in total HBI score or reduction of at least 70 points in overall CDAI 
score, if documentation of these scores are available. Where documented in a patient’s medical 
records, the scores for the individual components of these indexes should also be recorded.

Meaningful reduction of stool frequency.

Reduction of rectal bleeding.


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
Meaningful reduction of daily abdominal pain/discomfort.

Resolution of one or more extra-intestinal manifestations (eg arthralgia, pyoderma 
gangrenosum, etc).
Objective Measures of Disease Activity:

Resolution of drainage from prior draining fistula(s).

Improvement in ileocolonoscopy (resolution of all ulcerations in at least one ileocolonic 
segment).

Normalization of CRP (<3 mg/L) or fCal (<250 mg/kg) in participants with elevated 
CRP/fCal at initiation of ustekinumab.

Reduction in steroid dose (or elimination of corticosteroids) after initiation of ustekinumab.
Acceptable documentation
Evidence of previous ustekinumab doses and measures of initial response or remission should be 
documented by medical records, letter provided by a referring physician, patient diaries, reliable 
patient history with subsequent documentation or by other ‘reason for referral’ documents 
(eg, insurance authorization forms), if available. If such documentation is not available, 
investigators can confirm the ustekinumab doses and initial response/remission in the eCRF 
according to their best knowledge and clinical judgement.


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10.3.
Appendix 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. Participants should never be allowed to read their own tuberculin skin 
test results. If a participant fails to show up for the scheduled reading, a positive reaction may still 
be measurable up to 1 week after testing. However, if a participant 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 participants, and this definition is to be applied in 
this study to maximize the likelihood of detecting latent TB, even though the participants 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 
participants should be consulted for the interpretation of tuberculin skin test results. If no local 
country guidelines for immunocompromised participants exist, US guidelines must be followed.


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Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised participants should be consulted for acceptable 
antituberculous treatment regimens for latent TB. If no local country guidelines for 
immunocompromised participants exist, US guidelines must be followed.
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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10.4.
Appendix 4: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events:
Adverse Events Associated with the Study Population

Adverse events related to symptoms of Crohn’s disease.

Adverse events related to worsening or progression of Crohn’s disease.
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated 
events and will be reported to the sponsor as described under ‘All Adverse Events’ in Section 8.3.1. 
Any anticipated event that meets the serious adverse event criteria will be reported to the sponsor 
as described under ‘Serious Adverse Events’ in Section 8.3.1. 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 intervention, 
the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee
An Anticipated Event Review Committee will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The Anticipated Event Review Committee is a safety 
committee within the sponsor’s organization that is independent of the sponsor’s study team and 
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 intervention.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold 
to trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated
Events Safety Monitoring Plan.


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10.5.
Appendix 5: Clinical Laboratory Tests
The following tests will be performed by a central laboratory, unless otherwise specified or 
approved by the medical monitor:

Follicle stimulating hormone (for assessment of postmenopausal state, where applicable).a

Stool sample tests for enteric pathogens.a

Stool fecal calprotectin.

Serum C-reactive protein.

Serum pregnancy testing for women of childbearing potential.

Serology for HIV antibody, HBsAg, anti-HBs, anti-HBc, hepatitis C virus antibody.a
a
For some tests related to screening criteria, existing local or central laboratory results are acceptable to satisfy 
study requirements provided they were performed in the required time windows. Appropriateness of such tests 
may be discussed with the medical monitor.

Hematology:
- hemoglobin
- hematocrit (to enable CDAI evaluations)
- WBC count with differential
- platelet count

Serum Chemistry:
- sodium
- total and direct bilirubin
- potassium
- alkaline phosphatase
- chloride
- calcium
- blood urea nitrogen/urea
- phosphate
- creatinine
- albumin
- aspartate aminotransferase (AST)
- total protein
- alanine aminotransferase (ALT)
Hematology and clinical chemistry tests should be repeated at Week 0 if the screening tests were 
done >2 weeks previously.
The following tests will be performed by a local laboratory, unless otherwise specified or approved 
by the medical monitor:

Urine pregnancy testing for women of childbearing potential.

If required, SARS-CoV-2 (COVID-19) test may be performed at a local lab (per Exclusion 
Criterion 27).


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10.6.
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
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, 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 participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
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 participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) 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.
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.


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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator.

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable.

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.

Documentation of investigator qualifications (eg, curriculum vitae).

Completed investigator financial disclosure form from the principal investigator, where 
required.

Signed and dated Clinical Trial Agreement, which includes the financial agreement.

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first 
participant:

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.


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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 participants).

Investigator's Brochure (or equivalent information) and amendments/addenda.

Sponsor-approved participant recruiting materials.

Information on compensation for study-related injuries or payment to participants 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 participants.

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 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant 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 participants, data or study conduct).

Revision(s) to ICF and any other written materials to be provided to participants.

If applicable, new or revised participant recruiting materials approved by the sponsor.

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable.

New edition(s) of the Investigator's Brochure and amendments/addenda.

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually).

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
intervention.


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
New information that may adversely affect the safety of the participants or the conduct of the 
study.

Deviations from or changes to the protocol to eliminate immediate hazards to the participants.

Report of deaths of participants under the investigator's care.

Notification if a new investigator is responsible for the study at the site.

Development Safety Update Report and Line Listings, where applicable.

Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution)
FINANCIAL DISCLOSURE
Where appropriate, investigators and subinvestigators will provide the sponsor with sufficient, 
accurate financial information in accordance with local regulations to allow the sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. Investigators are responsible for providing information on financial interests during 
the course of the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
INFORMED CONSENT PROCESS
Each participant 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 participant 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 participants the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Participants 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 participant will receive. Finally, they will be told that the investigator will 


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maintain a participant 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 participant, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the 
participant agrees to allow his or her study physician to recontact the participant for the purpose 
of obtaining consent for additional safety evaluations, if needed.
The participant 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 participant's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF, will be assigned a new participant 
number, and then restart a new screening phase.
DATA PROTECTION
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant 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 participant 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.
Pharmacokinetic, immunogenicity and biomarker research is not conducted under standards 
appropriate for the return of data to participants. In addition, the sponsor cannot make decisions as 
to the significance of any findings resulting from this research. Therefore, such research data will 
not be returned to participants 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.


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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 ustekinumab, to understand 
Crohn’s disease, to understand differential intervention responders, and to develop tests/assays 
related to 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. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1).
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding ustekinumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory 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, to 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 ustekinumab and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from clinical studies to be used, the investigator is obligated to provide the sponsor with all data 
obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of 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 participant 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 (ICMJE) 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 


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writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. If issues arise regarding scientific integrity or regulatory compliance, 
the sponsor will review these issues with the investigator. The sponsor will not mandate 
modifications to scientific content and does not have the right to suppress information. For
multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, 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.


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CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in 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.
The study data will be transcribed by study-site personnel from the source documents onto the
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 participant's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
All participative measurements will be completed by the same individual who made the initial 
baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a 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.
SOURCE DOCUMENTS
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: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study intervention administration information; and 
date of study completion and reason for early discontinuation of study intervention or withdrawal 
from the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study, and will be described in the monitoring guidelines 
(or other equivalent document).


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The following data will be recorded directly into the CRF and will be considered source data:

Investigator-completed scales and assessments.

PROs.
The minimum source documentation requirements for the inclusion and exclusion criteria that 
specify a need for documented medical history (see Sections 5.1 and 5.2) are as follows:

Referral letter from treating physician.

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 participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource 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 eSource is utilized, references made to the CRF in the protocol include the 
eSource system, but information collected through eSource may not be limited to that found in the 
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques, central, remote, or on-site 
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into
the 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.


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In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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. Participant 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/she has been 
contacted by a regulatory agency concerning an upcoming inspection.
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 participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.


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STUDY AND SITE CLOSURE
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 participants by the investigator.

Discontinuation of further study intervention development.


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10.7.
Appendix 7: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to ‘All 
Adverse Events’ under Section 8.3.1 for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death.

Is life threatening(ie, participant was at risk of death at the time of the event - 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 participant or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study intervention and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint (eg, all-cause mortality).


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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ustekinumab, the expectedness of an adverse event will 
be determined by whether or not it is listed in the Investigator's Brochure.
Adverse Event Associated With the Use of the Intervention
An adverse event is considered associated with the use of the intervention if the attribution is at 
least possible (ie, possible, probable, or very likely) based on the definitions listed below.
ATTRIBUTION DEFINITIONS
Not Related
An adverse event that is not related to the use of the intervention.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant treatment(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the intervention. An alternative explanation, 
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the intervention. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant treatment(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant treatment(s), concomitant disease(s). The 
relationship in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).


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SEVERITY CRITERIA
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention.

Suspected abuse/misuse of a sponsor study intervention.

Accidental or occupational exposure to a sponsor study intervention.

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
intervention.

Unexpected therapeutic or clinical benefit from use of a sponsor study intervention.

Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 
Johnson medicinal product; eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors).

Exposure to a sponsor study intervention from breastfeeding.
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.


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PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
‘upper respiratory infection’). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
For all studies with an outpatient phase, including open-label studies, the participant 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 participant 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.

Participant number.

Any other information that is required to do an emergency breaking of the blind.
Serious Adverse Events
The cause of death of a participant in a study within 90 days of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the participant'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 intervention or to factors unrelated 
to study conduct.

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts).


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Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a participant's participation in a study must be reported as a serious adverse 
event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the CRF)
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the participant for the duration of 
the intervention period.
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.
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 participants, 
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.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to ‘Serious 
Adverse Events’under Section 8.3.1). A sample of the suspected product should be maintained for 
further investigation if requested by the sponsor.
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.


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10.8.
Appendix 8: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy information 
will be collected and reported as noted in Section 8.3.5.
Definitions
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

Premenarchal
A premenarchal state is one in which menarche has not yet occurred.

Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study.

Permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
NOTE: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.


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Examples of Contraceptives
Contraceptive use by men or women should be consistent with local regulations regarding the use 
of contraceptive methods for participants participating in clinical studies.
Examples of highly effective contraceptives (ie, failure rate ≤1% per year when used consistently 
and correctly, which may differ from typical use failure rates) allowed during the study include:
USER INDEPENDENT:

Implantable progestogen-only hormone contraception associated with inhibition of ovulationa

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomized partner (considered a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm 
has been confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT:

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationa
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationa
oral
injectable

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 intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)
a. Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal 
contraception may interact with the study intervention.


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Examples of contraceptives that are not considered to be highly effective (ie, failure rate >1% per 
year) and that are not allowed during the study include:

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action

Male or female condom with or without spermicidea

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)a

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a. Male condom and female condom should not be used together (due to risk of failure with friction)
Pregnancy During the Study
A female participant who becomes pregnant during the study must discontinue further study 
intervention. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.
Because the effect of the study intervention on sperm is unknown, pregnancies in partners of male 
participants included in the study will be reported. A male study participant is not required to 
discontinue study intervention if their partner becomes pregnant during the study.
Pregnancy Testing
A woman of childbearing potential must have a negative serum pregnancy test at screening and a 
negative urine pregnancy test at all dosing visits prior to administration of study intervention.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participation in the study.


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10.9.
Appendix 9: Protocol Amendment History
This is the fourth global amendment. The summary of changes table for the current amendment is 
located directly before the Table of Contents (TOC). The summary of changes tables for the 
previous amendments are presented below:
Amendment 3, 19 May 2020
Overall Rationale for the Amendment: To allow subcutaneous injections of study intervention at Week 8 
and Week 16 to be self-administered outside a study site, in cases where a site visit is not possible.
Section Number
and Name
Description of Changes and Brief Rationale
1.1 Synopsis; 1,3 Schedule of 
Activities; 6.1 Study 
Intervention; 6.2.2 Drug 
Accountability; 6.4 Study 
Intervention Compliance; 
Description of Change:
Added text to allow subcutaneous injections of study intervention at Week 8 
and Week 16 to be self-administered outside a study site in exceptional cases, 
where a study site visit is not possible, provided those participants have the 
appropriate experience or have received the required training to perform self-
administration of SC injections and have received instructions for storage and 
handling of study materials.
Rationale:  To provide flexibility of dose administration in exceptional cases 
where a study site visit is not possible.
5.2. Exclusion Criteria
Description of Change:
Added exclusion criterion 27, to document exclusion of patients with confirmed 
or suspected SARS-CoV-2 infection or who have had close contact with a 
person with confirmed or suspected SARS-CoV-2 infection within 6 weeks 
before baseline and to provide COVID-19-related guidance on study 
participation and exclusion.
Rationale:  To exclude patients with confirmed or potential SARS-CoV-2 
infection.
8.2 Safety Assessments
Description of Change:  Added instructions on adverse event reporting for 
participants who self-administer SC study intervention.
Rationale: To provide safety reporting guidance outside the study site.
Appendix 7: Adverse Events: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, and Reporting
Description of Change:  Clarified the special reporting situation ‘Medication 
error’ to also include intercepted and potential medication errors for a Johnson 
& Johnson medicinal product.
Rationale: To be consistent with safety reporting requirements.
Investigator Agreement Page
Description of Change:  Changed the name of the Sponsor’s Responsible 
Medical Officer.
Rationale:  To reflect the new assignment of the responsible physician for this 
study.
Amendment 2, 8 April 2020
Overall Rationale for the Amendment: To allow for self-administration of subcutaneous study 
intervention at Weeks 8 and 16 outside a study site (eg, at home), in cases where a study site visit is not 
possible under restrictions and limitations during the COVID-19 pandemic. Guidance on other aspects of 
study conduct during the COVID-19 pandemic is also included.
Section Number
and Name
Description of Changes and Brief Rationale
Added 10.13. Appendix 13 -
Guidance on Study Conduct 
During the COVID-19 
Pandemic
Description of Change:  Added appendix as guidance on changes to study 
conduct and assessments due to restrictions and limitations during the 
COVID-19 pandemic.
Rationale: To provide guidance on study conduct and assessments during the 
COVID-19 pandemic.


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Amendment 1, 19 July 2019
Overall Rationale for the Amendment: To include information regarding the planned primary endpoint 
database lock at Week 16 and the final database lock. Other clarifications and changes were made to address 
investigator and site questions surrounding operational elements of the study.
Section Number
and Name
Description of Changes and Brief Rationale
4.2 Scientific Rationale for 
Study Design
Description of Change:  Added information regarding the planned primary 
endpoint database lock at Week 16 (when all participants have completed 
Week 16 or have terminated study participation prior to Week 16) and the final 
database lock (when all participants have completed Week 36 or have 
terminated study participation prior to Week 36).
Rationale:  Clarify the planned database locks, the first for periodic 
summarization of the primary endpoint and selected data at Week 16 and the 
second for the final analysis.
1.3 Schedule of Activities; 
5.1 Inclusion Criteria
Description of Change:  Increased the time window during which a prior 
radiograph taken within normal clinical practice may be used for tuberculosis 
and infection screening from 3 months to 6 months before Week 0.
Rationale:  Eligible patients would have been on ustekinumab therapy for at 
least 4 months at screening. The initial 3-month window before Week 0 within 
which a prior radiograph taken within normal clinical practice may be used for 
screening was not reflective of the study design; all patients eligible for the 
study will have received ustekinumab treatment for at least 16 weeks at study 
baseline and, as such, all eligible patients would require an additional study-
specific radiograph prior to enrollment. To reflect local standard-of-care for 
tuberculosis screening of patients on ustekinumab therapy and potentially 
reduce radiation exposure, this window was increased to 6 months before 
Week 0.
5.1 Inclusion Criteria
(Inclusion Criterion 6)
Description of Change:  Changed the window for a negative TB test result 
before the first study intervention from 8 to 5 weeks and added computed 
tomography of the chest as an alternative to a chest radiograph.
Rationale:  To align with the 5-week screening period and allow an alternative 
method of TB screening, according to standard-of-care practices at study sites.
1.3 Schedule of Activities.
Description of Change:  Addressed the following corrections in the Schedule 
of Activities for consistency with existing protocol text:
Stool sample for fecal calprotectin added at screening.
Preplanned surgery/procedures removed after baseline.
Clarified measurement of vital signs at time of SC injections.
Moved collection of height from baseline to screening.
Removed collection of weight from screening measures (collected at 
baseline)
Clarified collection of IBDQ at the early termination visit for patients who 
discontinued before Week 16.
Rationale: To clarify the Schedule of Activities, to align with protocol text and 
address questions from investigators.
1.1 Synopsis; 3. Objectives 
and Endpoints
Description of Change:  Removed vital signs from listed endpoints.
Rationale:  Vital signs will be collected and reported as safety evaluations or 
adverse events, but changes in vital signs will not be assessed as study 
endpoints.


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Section Number
and Name
Description of Changes and Brief Rationale
1.1 Synopsis; 1.2 Schema; 
1.3 Schedule of Activities 
(footnote b); 4.1. Overall 
Design; 7.2 Participant 
Discontinuation/Withdrawal 
From the Study; 8. Study 
Assessments and Procedures; 
Description of Change:  Clarified timing of safety follow up as 20 weeks after 
a participant’s last study intervention administration (ie, Week 36 for 
participants who complete the final study intervention visit at Week 16).
Rationale:  Allow early follow-up for participants who discontinue before 
Week 16.
1.3 Schedule of Activities; 
8.5 Pharmacokinetic and 
Immunogenicity
Description of Change:  Clarified collection of pharmacokinetic and 
immunogenicity blood samples in relation to study intervention.
Rationale:  Clarification of timing of blood sampling.
1.1 Synopsis; 4.1. Overall 
Design; 5.1 Inclusion Criteria
Description of Change:  Clarified definition of secondary loss of response 
based on endoscopy as within 3 months before or at baseline and removed less 
specific wording that this is to be during the current disease flare.
Rationale:  To provide more specific definition of secondary loss of response.
1.1 Synopsis; 6.1. Study 
Interventions Administered
Description of Change:  Added clarification that either the IV infusion or SC 
injection may be administered first at Week 0 and provided guidance on 
minimum time windows between study interventions at Week 0.
Rationale:  Clarification of initial study intervention.
4.4 End of Study Definition
Description of Change: Corrected the definition for completion of the primary 
efficacy period (from Week 24 to Week 16).
Rationale:  Correction of primary efficacy period.
1.3 Schedule of Activities; 
8.1.5 Inflammatory Bowel 
Disease Questionnaire
Description of Change: Indicated that participants who do not remain in the 
study until Week 16 or do not perform the IBDQ at Week 16 should complete 
the IBDQ at the early termination visit.
Rationale:  Clarification of early termination assessment of IBDQ.
8.8 Biomarkers
Description of Change: Added information on serum/whole-blood-based 
biomarkers. 
Rationale:  Additional details and clarification of biomarker assessments.
10.11 Appendix 11: CDAI 
Standard Weight Table
Description of Change: Added a standard weight table for CDAI.
Rationale:  Provided additional information for CDAI determination.
Throughout the protocol
Description of Change: Minor grammatical/spelling changes and clarifications 
made.
Rationale: Minor changes only, therefore are not summarized.


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10.10. Appendix 10: Sample Crohn’s Disease Activity Index






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10.12. Appendix 12: Sample Inflammatory Bowel Disease Questionnaire
Copyright © 1989 McMaster University, Hamilton, Ontario, Canada
The Inflammatory Bowel Disease Questionnaire (IBDQ), authored by Dr. Jan Irvine et al, is the copyright of 
McMaster University (Copyright ©1989, McMaster University). The IBDQ has been provided under license 
from McMaster University and must not be copied, distributed or used in any way without the prior written 
consent of McMaster University. Contact the McMaster Industry Liaison Office at McMaster University, email: 
milo@mcmaster.ca for licensing details.
Updated from: IBDQ - United Kingdom-English - Version of 09 May 08 - Mapi Research Institute.
ID4529/IBDQ_AU2 0_eng-GB.doc
IBDQ (enGB) 03JUN2016 FINAL – ICON Language Services


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INSTRUCTIONS FOR SELF-ADMINISTERED INFLAMMATORY BOWEL 
DISEASE QUESTIONNAIRE (IBDQ)
This questionnaire is designed to measure the effects of your inflammatory bowel 
disease on your daily function and quality of life. You will be asked about 
symptoms you have been having as a result of your bowel disease, the way you 
have been feeling in general, and how your mood has been.
There are 2 versions of this questionnaire, the IBDQ and IBDQ-Stoma. If you 
have a colostomy or ileostomy, you should complete the IBDQ-Stoma. 
Questions 1, 5, 17, 22, 24 and 26 are slightly different in each version. Be sure 
you have the correct questionnaire.
On this questionnaire there are 32 questions. Each question has graded 
response choices numbered from 1 to 7. Please read each question carefully and 
answer the number which best describes how you have been feeling in the past 
2 weeks.
EXAMPLE
How often have you felt unwell as a result of your bowel problem in the 
past 2 weeks?
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
If you are having trouble understanding a question, STOP for a moment!
Think about what the question means to you. How is it affected by your bowel 
problem? Then answer the question as best you can. You will have the chance to 
ask the research assistant questions after completing the questionnaire. This 
takes only a few minutes to complete.


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QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (IBDQ)
This questionnaire is designed to find out how you have been feeling during the last 
2 weeks. You will be asked about symptoms you have been having as a result of your 
inflammatory bowel disease, the way you have been feeling in general, and how your mood 
has been.
1.
How frequent have your bowel movements been during the last 2 weeks? Please indicate 
how frequent your bowel movements have been during the last two weeks by picking one 
of the options from
1
BOWEL MOVEMENTS THE MOST FREQUENT YOU HAVE EVER EXPERIENCED
2
EXTREMELY FREQUENT
3
VERY FREQUENT
4
MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
5
SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
6
SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
7
NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2.
How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? Please indicate how often the feeling of fatigue or tiredness has 
been a problem for you during the last 2 weeks by picking one of the options from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
3.
How often during the last 2 weeks have you felt frustrated, impatient or restless? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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4.
How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
5.
How much of the time during the last 2 weeks have your bowel movements been loose?
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
6.
How much energy have you had during the last 2 weeks? Please choose an option from
1
NO ENERGY AT ALL
2
VERY LITTLE ENERGY
3
A LITTLE ENERGY
4
SOME ENERGY
5
A MODERATE AMOUNT OF ENERGY
6
A LOT OF ENERGY
7
FULL OF ENERGY
7.
How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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8.
How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
9.
How often during the last 2 weeks have you been troubled by cramps in your abdomen? 
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
10.
How often during the last 2 weeks have you felt generally unwell? Please choose an option 
from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
11.
How often during the last 2 weeks have you been troubled because of fear of not finding 
a toilet? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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12.
How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks? Please choose 
an option from
1
A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
2
A LOT OF DIFFICULTY
3
A FAIR BIT OF DIFFICULTY
4
SOME DIFFICULTY
5
A LITTLE DIFFICULTY
6
HARDLY ANY DIFFICULTY
7
NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR LEISURE 
ACTIVITIES
13.
How often during the last 2 weeks have you been troubled by pain in the abdomen? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
14.
How often during the last 2 weeks have you had problems getting a good night’s sleep or 
been troubled by waking up during the night? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
15.
How often during the last 2 weeks have you felt depressed or discouraged? Please choose 
an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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16.
How often during the last 2 weeks have you had to avoid attending events where there 
was no toilet close at hand? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
17.
Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of wind? Please choose an option from
1
A MAJOR PROBLEM
2
A BIG PROBLEM
3
A SIGNIFICANT PROBLEM
4
SOME TROUBLE
5 
A LITTLE TROUBLE
6
HARDLY ANY TROUBLE
7
NO TROUBLE
18.
Overall, in the last 2 weeks, how much of a problem have you had maintaining or getting 
to the weight you would like to be at? Please choose an option from
1
A MAJOR PROBLEM
2
A BIG PROBLEM
3
A SIGNIFICANT PROBLEM
4
SOME TROUBLE
5 
A LITTLE TROUBLE
6
HARDLY ANY TROUBLE
7
NO TROUBLE
19.
Many patients with bowel problems often have worries and anxieties related to their illness. 
These include worries about getting cancer, worries about never feeling any better, and 
worries about having a relapse. In general, how often during the last 2 weeks have you 
felt worried or anxious? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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20.
How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
21.
How often during the last 2 weeks have you felt relaxed and free of tension? Please 
choose an option from
1
NONE OF THE TIME
2
A LITTLE OF THE TIME
3
SOME OF THE TIME
4
A GOOD BIT OF THE TIME
5
MOST OF THE TIME
6
ALMOST ALL OF THE TIME
7
ALL OF THE TIME
22.
How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
23.
How much of the time during the last 2 weeks have you felt embarrassed as a result of 
your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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24.
How much of the time during the last 2 weeks have you been troubled by a feeling of 
having to go to the toilet even though your bowels were empty? Please choose an option 
from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
25.
How much of the time during the last 2 weeks have you felt tearful or upset? Please choose 
an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
26.
How much of the time during the last 2 weeks have you been troubled by accidental soiling 
of your underpants? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
27.
How much of the time during the last 2 weeks have you felt angry as a result of your bowel 
problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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28.
To what extent has your bowel problem limited sexual activity during the last 2 weeks? 
Please choose an option from
1
NO SEX AS A RESULT OF BOWEL DISEASE
2
MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
3
MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
4
SOME LIMITATION AS A RESULT OF BOWEL DISEASE
5
A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
6
HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
7
NO LIMITATION AS A RESULT OF BOWEL DISEASE
29.
How much of the time during the last 2 weeks have you been troubled by nausea or an 
upset stomach? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
30.
How much of the time during the last 2 weeks have you felt irritable? Please choose an 
option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
31.
How often during the past 2 weeks have you felt a lack of understanding from others? 
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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32.
How satisfied, happy, or pleased have you been with your personal life during the past 2 
weeks? Please choose one of the following options from
1
VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
2
GENERALLY DISSATISFIED, UNHAPPY
3
SOMEWHAT DISSATISFIED, UNHAPPY
4
GENERALLY SATISFIED, PLEASED
5
SATISFIED MOST OF THE TIME, HAPPY
6
VERY SATISFIED MOST OF THE TIME, HAPPY
7
EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR PLEASED


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10.13. Appendix 13: Guidance on Study Conduct during the COVID-19 Pandemic
BACKGROUND
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/or study-site personnel; travel restrictions and limited access to public places, including 
hospitals; and study site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government guidelines or requirements or the clinical judgement 
of the investigator to protect the health and well-being of participants and site staff. If at any time 
a participant’s safety is considered to be at 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 will be delayed until such time that on-site visits can be resumed. 
At each contact, participants will be interviewed to collect safety data. Key efficacy endpoint 
assessments should be performed if required and as feasible. Participants will also be questioned 
regarding general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted 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 health authorities according to local guidance.
If a participant has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer or designee to discuss plans for study intervention and follow-up.


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GUIDANCE SPECIFIC TO THIS PROTOCOL
Study Population
Exclusion Criteria (Protocol Section 5.2)
A potential participant with the following features will be excluded from participating in the study.
27.
Criterion added per Amendment 2:
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

obtained at least 2 weeks after conditions (a), (b), or (c) above (timed from 
resolution of key clinical features if present, eg, fever, cough, dyspnea)
AND

with absence of ALL conditions (a), (b) and (c) above during the period between 
the negative test result and the baseline study visit.
Notes on COVID-related Exclusion

If a patient is excluded due to recent COVID-19-related features, the reason for screen failure 
should be documented in the case report form (CRF) under the exclusion criterion of having 
a condition for which participation would not be in the participant’s interest or could confound 
study assessments.

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, or standards of care.
Precautions
For those patients who may carry a higher risk for severe COVID-19 illness (eg, patients aged over 
65 years), follow the guidance from local health authorities when considering the potential benefits 
and risks of enrolling patients into the study and during study participation.


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Study Interventions and Assessments
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 patient 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.
Administration of Study Intervention
In cases where a site visit is not possible under restrictions and limitations due to the COVID-19 
pandemic, participants may self-administer subcutaneous (SC) injections of study intervention 
outside a study site (eg, at home) at Weeks 8 and 16. Those participants will receive instructions 
on compliance, storage, disposal of used syringes, handling of unused study material, and adverse 
event reporting. The specific protocol changes are documented below:
Study Interventions Administered (Protocol Section 6.1)
Subcutaneous injections at Week 0 will be administered by qualified staff at the study site. At 
Weeks 8 and 16, SC injections should be administered by qualified study site staff during the study 
visit, if possible. However, in cases where a site visit is not possible, participants who have 
adequate experience or have been trained how to self-inject may self-administer SC study 
intervention (in compliance with the SmPC or local label) at the times instructed by the 
investigator.
Study-site personnel will instruct participants on how to store study intervention for at-home use. 
For each administration of study intervention, the time and date of injection, whether study 
intervention was self-administered, and if so, whether SC administration was complete (based on 
the returned syringe[s]) will be recorded in the CRF.
Drug Accountability and Compliance (Protocol Sections 6.2.2 and 6.4)
Study intervention at Week 0 will be administered with the assistance of a staff member at the 
study site who will be supervising study intervention administration at this visit. Study intervention 
at Week 8 and Week 16 will be administered at the study visit, whenever possible, with the 
assistance of a staff member. For any study intervention administration performed by the 
participant outside of a study site, participants will receive a sharps container to dispose of used 
syringes and will be instructed to return the sharps container and cartons to the study site with the 
diary at their next visit.
Participants will record the time and date of study intervention administrations in the diary. Study 
site personnel will utilize participant’s diaries to ensure compliance and record at-home study 
intervention administrations in the eCRF.
Any participant who will be self-administering study intervention at home at Weeks 8 and 16 will 
receive detailed instructions on storage of study intervention, disposal of used syringes, and 
handling of unused study material.


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Notes on Shipment of Study Intervention to Participants
If it is necessary to ship the study intervention directly to study participants, shipment by the study 
site itself is preferred under this exception due to the COVID-19 pandemic. Shipment should be 
made in a manner that allows tracking of both transport and delivery. The participant should 
acknowledge receipt of the shipment to the site (eg, by returning a dated and signed receipt form).
In case adequate shipment by the study site is not possible (for example, owing to capacity 
limitations, logistics, or special transport conditions for the study intervention), direct transport by 
the sponsor may be accepted in justified exceptional cases, provided that the sponsor appoints a 
suitably qualified service provider as trustee. The sponsor must contractually oblige this service 
provider to maintain the pseudonymization and, if necessary, blinding of study participants to the 
sponsor using appropriate measures. Both the transport and handover conditions for study 
intervention should be part of the contractual arrangements, so that pharmaceutical drug safety of 
study intervention as well as protection of the privacy and personal data of participants are 
adequately safeguarded. The study intervention must be delivered directly to the participant or a 
person authorized by the participant, and must not be given to neighbors or deposited at a storage 
location. Written confirmation of dose and dose regimens by the investigator should also be 
obtained prior to shipment.
The personnel of the service provider in charge of the transport should be trained and instructed 
accordingly. As personal data are transferred to the service provider, this requires a contract of 
assignment with the sponsor or legal representative.
For direct shipment of study intervention to participants, written instructions on storage and return 
of used and unused study intervention should be provided to participants. When shipped by study 
sites, the receipt, consumption and return of study intervention must be documented in a form that 
allows the study site to meet its documentation requirements (ie, drug accountability), as defined 
in ICH GCP 4.6.3.
Study Assessments and Analyses
Safety Assessments (Protocol Section 8.2)
In cases of self-administration of SC study intervention at home, participants are requested to 
contact their treating physician as soon as possible to consider reporting of an adverse event.
Clinical laboratory safety monitoring may be performed at a certified local laboratory identified 
by the study site rather than at the central laboratory; for selected measures (eg, urine pregnancy), 
home testing may be employed.
Missed Assessments
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 CRF.


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Other relevant study data elements impacted by the COVID-19 pandemic should also be 
documented/labeled as “COVID-19-related” in CRFs and/or other study systems, as directed by 
sponsor guidance; these may include missed/delayed/modified study visits/assessments/dosing, 
and instances where temporary measures such as those above are implemented.
Where applicable, other study procedures may be conducted at an appropriate facility identified 
by the study site.
Study Analyses
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 the statistical analysis plan(s).


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11.
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Adalimumab SmPC.
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Adedokun OJ, Zhenhua X, Gasink C, Jacobstein D, Szapary P, Johanns J, Gao L-L, Davis H, Hanuauer S, 
Fegan BG, Ghosh S Sandborn WJ. Pharmacokinetics and Exposure-Response Relationships of Ustekinumab in 
Patients with Crohn's Disease. Gastroenterology. 2018; https://doi.org/10.1053/j.gastro.2018.01.043.
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Amiot A, Serrero M, Peyrin-Biroulet L, Filippi J, Pariente B, Roblin X, Buisson A, Stefanescu C, Trang-
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Pharmacology and Therapeutics. 2017; 46:310-321.
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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.
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Certolizumab US PI.
6.
Claire, P, Severine, B, Nicolas, D, Nicolas D, Maria N, Pierre D, Julien B, Romain G, Medina B, Myriam L,
Benjamin P. Trough levels and antibodies to ustekinumab are not correlated to response to ustekinumab 
treatment in Crohn's disease patients. ECCO 2017 #P360.
7.
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.
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D’Haens GR, Panaccione R, Higgins P, Vermeire S, Gassull M, Chowers Y, Hanauer S, Herfarth H, Hommes 
D, Kamm M, Lofberg, R, Quary A, Sands B, Sood A, Watermayer G, Lashner B, Lemann M, Plevy S, 
Reinisch W, Schreiber S, Siegel C, Targan S, Watanabe M, Feagan B, Sandborn WJ, Colombel J-F, Travis S. 
The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD 
with the European Crohn’s and Colitis Organization: When to Start, When to Stop, Which Drug to Choose and 
How to Predict Respsnse. American Journal of Gastroenterology. 2011;106, 199-212.
9.
Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, Blank MA, Johanns J, Gao L-L, 
Miao Y, Adedokun OJ, Sands BE, Hanauer SB, Vermeire S, Targan S, Ghosh S, de Villiers WJ, Colombel J-F, 
Tulassay Z, Seidler U, Salzberg BA, Desreumaux P, Lee SD, Loftus Jr EF, Dieleman LA, Katz S, Rutgeerts P. 
Ustekinumab as Induction and Maintenance. Therapy for Crohn’s Disease. NEJM. 2016;375:1946-60. Online 
Supplement.
10.
Feagan BG, Sandborn WJ, Gasink C, Group U-I-US, et al. Ustekinumab as induction and maintenance therapy 
for Crohn’s Disease. N Engl J Med. 2016;375:1946–1960.
11.
Gomollón F, Dignass A, Annese V et al. Journal of Crohn’s and Colitis. 3rd European Evidence-based 
Consensus on the GTiagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical 
Management. 2017;3-25.
12.
Heron V, Restellini S, Bessissow T, Lemieux C, Lakatos P, Wild G, Seidman E, Bitton A, Afif W. Re-
induction with ustekinumab in Crohn’s disease patients with a loss of response to treatment. ECCO 2018 
Abstract 438.
13.
Infliximab SmPC.
14.
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.
15.
Khorrami S, Ginard D, Marín-Jiménez I, Chaparro M, Sierra Monica, Aguas M, Sicilia B, Garcia-Sanchez V, 
Suarez C, Villoria A, Taxonera C, Velasco-Guardado An, Martinez-Gonzalez J, Gisbert JP. Ustekinumab for 
the Treatment of Refractory Crohn's Disease: The Spanish Experience in a Large Multicentre Open-label 
Cohort. Inflamm Bowel Dis. 2016 Jul;22(7):1662-9.
16.
Kopylov U, Afif W, Cohen A, Bitton A, Wild G, Bessissow T, Wyse J, Al-Taweel T, Szilagyi A, Seidman E. 
Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience. J 
Crohn’s Colitis. 2014 Nov;8(11):1516-22.
17.
Lichtenstein GR et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J 
Gastroenterol. 2018 Mar;113(4):481-517.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3008 Amendment 4
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18.
Ma, C, Fedoera RN, Kaplan G, Dieleman LA, Devlin SM, Stern N, Kroeker KI, Seow CH, Leung Y, Novak 
KL, Halloran BP, Huang VW, Wong K, Blustein PK, Ghosh S, Panaccione R. Long-term Maintenance of 
Clinical, Endoscopic and Radiographic Response to Ustekinimab in moderate-to-Server Crohn’s Diease: Real-
world Experience from a Multicenter Cohort Study. Inflammatory Bowel Disease. 2017. DOI 
10.1097/MIB.0000000000001074.
19.
Park S, Evans E, Sandborn WJ, Boland B. Ustekinumab IV 6 mg/kg Loading Dose Re-induction Improves 
Clinical and Endoscopic Response in Crohn’s disease: A Case Series. American Journal of Gastroenterology. 
2018; 113:627-629.
20.
Qiu Y, Chen B-L, Mao R, Zhang S-H, He Y, Zeng Z-R, Ben-Horin S, Chen M-H. Journal of Gastroenterology. 
2017;52:535-554.
21.
Sandborn W, Rutgeerts P, Gasink C, Jacobstein D, Gao L.-L, Johanns J, Sands B, Hanauer SB, Targan S, 
Ghosh S, de Villiers WJS, Colombe J-F, Feagan BG. ECCO 2017, Abstract OP010.
22.
Sandborn WJ et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 
2014;369(8):711-721.
23.
Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, Hoffman I, Van Steen K, Vermeire S, 
Rutgerrts PJ. Long-term Outcome of Treatment with Infliximab in 614 Crohn’s Disease Patients: Results from 
a Single Centre Cohort. Gut. 2008; doi:10.1136/gut.2008.155812.
24.
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.
25.
Srinavasan A, VasudevanA, McFarlane A, Sparrow M, Gibson P, Van Langenberg DR. Anti-TNF-Re-
induction is as Effective, Simpler and Cheaper Compared with Dose Interval Shortening for Secondary Loss of
Response in Crohn’s Diseaes. Journal of Crohn’s and Colitis. 2017: doi:10.1093/ecco-jcc/jjx144.
26.
Stallmach A, Langbein C, Atreya T, Dignass A, Ende K, Hampe J, Hartmann F, Neurath MF, Maul J, Preiss 
JC, Schmelz R, Siegmund B, Schulze H, Teich N, van Arnim U, Baumgart CD, Schmidt C. Alimentary 
Pharmacology and Therapeutics. 2016; 44:1199-1212.
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STELARA [EU SmPC]. Beerse, Belgium: Janssen-Cilag International NV; 2016.
28.
Summary of Clinical Pharmacology Studies, ustekinumab. Treatment of Adults with Moderately to Severely 
Active Crohn’s Disease. EDMS-ERI-92904905, 1.0. 2015.
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Vedolizumab SmPC.
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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.
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Wils P, Bouhnik Y, Michetti P, Flourie B, Brixi H, Bourrier A, Allez M, Duclos B, Grimaud J-C, Buisson A, 
Amiot A, Fumery M, Roblin X, Peryin-Biroulet L, Filippi J, Bougeuen G, Abitbol V. Subcutaneous 
Ustekinumab Provides Clinical Benefit for Two-Thirds of Patients With Crohn's Disease Refractory to Anti-
Tumor Necrosis Factor Agents. Clin Gastroenterol Hepatol. 2016 Feb;14(2):242-50.e1-2.
32.
Wils P, Bouhnik Y, Michetti P, Flourie B, Brixi H, Bourrier A, Allez M, Duclos B, Serrero M, Buisson A, 
Amiot A, Fumery M, Roblin X, Peryin-Biroulet L, Filippi J, Bouguen G, Abitbol V, Coffin B, Simon M, 
Laharie D, Pariente G. Long-term efficacy and safety of ustekinumab in 122 refractory Crohn's disease 
patients: a multicentre experience. Aliment Pharmacol Ther. 2018 Jan 8. [Epub ahead of print].



SAP_001.pdf: 
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Janssen Research & Development *
Statistical Analysis Plan
A Phase 3b, Randomized, Double-blind, Multicenter Study to Evaluate the Safety and 
Efficacy of Intravenous Re-induction Therapy With Ustekinumab in Patients with 
Moderately to Severely Active Crohn’s Disease
POWER
Protocol CNTO1275CRD3008; Phase 3b
Stelara®  (Ustekinumab)
Version: Final
Status:
Approved
Date:
17 October 2022
Prepared by:
Janssen Scientific Affairs, LLC.  
Document No.: EDMS-ERI-177328556, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03782376


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 5
DEFINITIONS OF TERMS............................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 7
1.5.
Randomization and Blinding ............................................................................................................ 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Visit Windows................................................................................................................................... 9
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 10
2.3.
Analysis Sets.................................................................................................................................. 10
2.3.1.
Efficacy Analysis Set(s) .............................................................................................................. 10
2.3.2.
Safety Analysis Set..................................................................................................................... 10
2.3.3.
Pharmacokinetics Analysis Set .................................................................................................. 10
2.3.4.
Immunogenicity Analysis Set...................................................................................................... 10
2.4.
Definition of Subgroups.................................................................................................................. 10
2.5.
Study Day and Relative Day .......................................................................................................... 13
2.6.
Baseline ......................................................................................................................................... 13
2.7.
Imputation Rules for Missing AE Date ........................................................................................... 13
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 14
4.
SUBJECT INFORMATION................................................................................................................ 14
4.1.
Demographics and Baseline Characteristics ................................................................................. 14
4.1.1.
Demographics............................................................................................................................. 14
4.1.2.
Baseline Characteristics ............................................................................................................. 15
4.2.
Disposition Information................................................................................................................... 15
4.3.
Extent of Exposure......................................................................................................................... 16
4.4.
Protocol Deviations ........................................................................................................................ 16
4.5.
Prior and Concomitant Medications ............................................................................................... 16
5.
EFFICACY ......................................................................................................................................... 17
5.1.
General Method of Analysis........................................................................................................... 17
5.1.1.
Data Handling Rules................................................................................................................... 17
5.1.1.1.
Missing Data Imputation.......................................................................................................... 17
5.1.2.
Estimand..................................................................................................................................... 17
5.1.2.1.
Composite Estimand ............................................................................................................... 18
5.2.
Analysis Specifications................................................................................................................... 18
5.2.1.
Level of Significance................................................................................................................... 18
5.2.2.
Multiplicity Adjustment for Testing Procedures .......................................................................... 19
5.3.
Primary Endpoint Analysis ............................................................................................................. 20
5.3.1.
Definition of the Endpoints.......................................................................................................... 20
5.3.1.1.
CDAI ........................................................................................................................................ 20
5.3.2.
Analysis Methods........................................................................................................................ 20
5.3.3.
Sensitivity Analyses for Primary Endpoint.................................................................................. 21
5.3.4.
Subgroup analyses..................................................................................................................... 21
5.3.5.
Summary of Analyses Related to the Primary Endpoint ............................................................ 21
5.4.
Major Secondary Endpoints Analyses ........................................................................................... 23


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5.4.1.
Definitions of Major Secondary Endpoints (in corresponding order).......................................... 23
5.4.1.1.
C-reactive Protein.................................................................................................................... 23
5.4.1.2.
Calprotectin.............................................................................................................................. 23
5.4.2.
Analyses method for the Major Secondary Endpoints ............................................................... 24
5.4.3.
Summary of Analyses Related to Major Secondary Endpoints.................................................. 24
5.5.
Other Endpoints ............................................................................................................................. 26
5.5.1.
Secondary Efficacy Endpoints at Week 24................................................................................. 26
5.5.2.
Other Efficacy Endpoints: ........................................................................................................... 26
5.5.3.
Definitions ................................................................................................................................... 28
5.5.3.1.
Inflammatory Bowel Disease Questionnaire ........................................................................... 28
5.5.3.2.
Fistula Assessment ................................................................................................................. 28
5.5.3.3.
Video Ileocolonoscopy............................................................................................................. 28
5.5.4.
Analysis Methods........................................................................................................................ 29
6.
SAFETY............................................................................................................................................. 30
6.1.
Adverse Events .............................................................................................................................. 30
6.2.
Clinical Laboratory Tests................................................................................................................ 31
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 33
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 33
7.1.1.
Pharmacokinetics and Immunogenicity...................................................................................... 33
7.1.2.
Pharmacokinetic and Immunogenicity Analyses ........................................................................ 34
7.2.
Biomarker....................................................................................................................................... 34
7.2.1.
Serum-based Biomarkers........................................................................................................... 34
7.2.2.
Whole Blood-based Biomarkers ................................................................................................. 35
REFERENCES............................................................................................................................................ 36
ATTACHMENTS......................................................................................................................................... 38
ATTACHMENT 1:
SAMPLE INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (IBDQ) .......... 38
ATTACHMENT 2:  CROHN’S DISEASE ACTIVITY INDEX...................................................................... 49
ATTACHMENT 3:  STANDARD WEIGHT TABLE .................................................................................... 50
ATTACHMENT 4: PROTOCOL-PROHIBITED MEDICATIONS................................................................ 51
ATTACHMENT 5: CONCOMITANT CORTICOSTEROIDS AND IMMUNOMODULATOR
CHANGE............................................................................................................................................ 52
ATTACHMENT 6:  Statistical Hypothesis ............................................................................................... 53


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AMENDMENT HISTORY
N/A


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ABBREVIATIONS
Abbreviation
Definition
6-MP
6-mercaptopurine
6-TG
6-thioguinine
-hCG
-human chorionic gonadotropin
AE
adverse event
ALT
alanine transaminase
AST
aspartate transaminase
AZA
azathioprine
BCG
Bacille Calmette-Guérin
BUN
blood urea nitrogen
CD
Crohn’s disease
CDAI
Crohn’s disease activity index
CRF
case report form(s) (paper or electronic as appropriate for this study)
CRP
C-reactive protein
eCRF
electronic case report form
eDC
electronic data capture
ER
emergency room
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG1k
immunoglobulin G1 kappa
IL
Interleukin
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
JAK
Janus kinase
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MTX
methotrexate
PFS
pre-filled syringe
PQC
Product Quality Complaint
PRO
patient-reported outcome
PROMIS
Patient Reported Outcome Measurement Information System
q2w
every 2 weeks
RNA
ribonucleic acid
SAE
SC
serious adverse event
subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TNF
tumor necrosis factor 
TPN
total parenteral nutrition
ULN
upper limit of normal
WBC
white blood cells


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DEFINITIONS OF TERMS
Term
Definition
Clinical remission
CDAI score < 150
Clinical response
Decrease in CDAI score of ≥ 100 from baseline or CDAI score <150
IBDQ remission
Score of >= 170
Normalization of C-reactive protein or 
Fecal Calprotectin
C-reactive protein (CRP) ≤3 ug/L or Fecal Calprotectin (<250 
mg/kg) (among subjects with abnormal CRP or Fecal  Calprotectin at 
baseline)
Endoscopic improvement                                  Change in SES-CD score of at least 3 points 
Endoscopic remission                                        SES-CD score ≤3, or SES-CD =0 for subjects who enter the study 
                                                                           with an SES-CD =3
Endoscopic response                                        Reduction in SES-CD score by 50% from baseline or SES-CD score
                                                                           ≤3, or SES-CD =0 for subjects who enter the study with an SES-CD
                                                                           =3


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods to compare the efficacy and safety of Intravenous Re-induction Therapy with
Ustekinumab in Patients with Moderately to Severely Active Crohn’s Disease
1.1.
Trial Objectives
The primary objective is to evaluate the achievement of clinical response at Week 16 following a 
single IV re-induction dose of ~6 mg/kg Ustekinumab, compared with continuing regular SC q8w 
90 mg Ustekinumab administration, in participants with secondary loss of response (LoR) to SC 
q8w 90 mg Ustekinumab maintenance therapy. 
Secondary objectives are to: 

Evaluate the achievement of clinical response and clinical remission, as well as the reduction 
in inflammatory biomarkers (serum C-reactive protein [CRP] and fecal calprotectin [FeCa] 
levels), after IV Ustekinumab re-induction. 

Assess the overall safety of IV Ustekinumab re-induction. 
The exploratory objectives are to explore endoscopy and patient-reported assessment of bowel
inflammation following IV Ustekinumab re-induction, and to assess the steroid-sparing effect and
pharmacokinetics following a single IV re-induction dose of  ~6 mg/kg Ustekinumab.
1.2.
Trial Design
This is a randomized, double-blind, placebo-controlled, multicenter, 24-week, Phase 3b study in
adult patients with active moderate to severe Crohn’s disease who initially responded to
Ustekinumab induction therapy per label followed, at any time, by secondary LoR to SC q8w
Ustekinumab maintenance therapy. The benefit of a single weight-tiered based IV re-induction
dose of ~6 mg/kg body weight Ustekinumab versus continuous SC q8w maintenance treatment
will be evaluated.
1.3.
Statistical Hypotheses for Trial Objectives
The study hypothesis is that in patients with secondary LoR to SC q8w 90 mg Ustekinumab
maintenance treatment, a single weight-tiered based IV Ustekinumab re-induction dose of
~6 mg/g (ie, IV Ustekinumab/SC placebo at Week 0) followed by q8w 90 mg Ustekinumab
maintenance will result in a higher clinical response rate (defined as a ≥100-point reduction from
the baseline CDAI score, or a CDAI score <150) compared with continuous SC q8w 90 mg
Ustekinumab maintenance treatment (ie, IV placebo /SC Ustekinumab at Week 0) after 16 weeks.
1.4.
Sample Size Justification
The assumptions that form the basis for sample size and power calculations incorporated into this 
protocol to support the primary endpoint are based on the dose adjustment data from the 
IMUNITI Phase 3 study. In IMUNITI, 17 of 29 (59%) participants attained clinical response 
16 weeks after LoR in the q12w adjusted to q8w group, while 11 of 28 (39%) participants 
attained clinical response 16 weeks after LoR in the sham dose adjustment group (ie. continually 


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Approved, Date: 17 October 2022
remaining on SC q8w dosing). The hypothesis for the sample size determination is that the IV 
Ustekinumab re-induction group in this study will perform similarly to, if not better than, the 
q12w adjusted to q8w group in the IMUNITI study, given that the participants in this group will 
receive a higher dose of Ustekinumab than those in the IMUNITI study, who received an 
adjustment from q12w to q8w.
Assuming a 60% clinical response rate at Week 16 in the IV Ustekinumab re-induction group 
and 40% in the continuous SC q8w 90mg group, 100 participants per treatment group will yield 
an overall power above 80%, at a significance level of 0.05 (2-sided, Mantel-Haenszel test).
Table 1 provides the power for detecting a treatment difference between the IV Ustekinumab
re-induction group and the continuous SC q8w 90mg Ustekinumab group (for 100 participants 
per group) under varying assumptions for the clinical response rates.
Table 1:
Power to Detect a Treatment Effect Based on Different Proportions of Participants Achieving 
Clinical Response at Week 16 (Each Group)
Clinical response at Week 16 (%)
SC q8w 90 mg
(n=100)
IV re-induction
(n=100)
Power
40%
55%
59%
-
60%
83%
-
65%
95%
1.5.
Randomization and Blinding
Treatment Allocation
Following clinical assessments at baseline, all enrolled participants will be randomized in a 1:1 
ratio to one of two re-induction groups to receive either IV Ustekinumab 6 mg/kg and SC 
placebo or IV placebo and SC Ustekinumab 90 mg in a blinded manner.
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to one of two re-induction groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. Permuted block 
randomization with stratification variables, including the participant’s baseline CDAI score 
(≤300 or >300) and whether the participant had failed a prior biologic at baseline (yes or no), 
will be used. The interactive web response system (IWRS) will assign a unique intervention 
code, which will dictate the intervention assignment and matching study intervention kit for the 
participant. The requestor must use his or her own user identification and personal identification 
number when contacting the IWRS, together with the relevant unique participant details to 
identify the participant.


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Blinding
At Week 0 participants will receive a single IV administration of study intervention 
(Ustekinumab 6 mg/kg or placebo) plus a single SC administration of study intervention 
(Ustekinumab 90 mg or placebo) in a double-blinded manner. During study visits at Weeks 8 and 
16, all participants will receive SC maintenance injections of 90 mg Ustekinumab.
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 participant. Appropriate sponsor representatives will also have access to the IWRS to 
break the blind for an individual participant, if needed.
Data that may potentially unblind the intervention assignment (ie, treatment allocation, study 
intervention preparation/accountability, and administration of study intervention) will be handled 
with special care to ensure that the integrity of the blind is maintained and the potential for bias 
is minimized. This can include making special provisions, such as segregating the data in 
question from view by the investigators, clinical team, or others as appropriate until the time of 
database lock and unblinding.
Under normal circumstances, the blind should not be broken until the database is finalized. The 
investigator may in an emergency determine the identity of the intervention by contacting the 
IWRS. While the responsibility to break the intervention code in emergency situations resides 
solely with the investigator, it is recommended that the investigator contact the sponsor or its 
designee if possible to discuss the 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 and reason for the 
unblinding must be documented by the IWRS in the appropriate section of the CRF. The 
documentation received from the IWRS, indicating the code break, must be retained with the 
participant's source documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for 
scheduled evaluations.
2.
GENERAL ANALYSIS DEFINITIONS
This analysis plan provides the general analysis definitions and describes the planned subject 
information, efficacy, safety, pharmacokinetics, and antibody analyses for the two treatment 
groups.
2.1.
Visit Windows
Study visits are to occur at Screening (within 1- 5 weeks prior to Week 0), and Weeks 0, 8, 16 
(primary endpoint)  and visit at Week 24.
Study visits should occur at the week indicated ± 4days for each visit up to and including Week 
16 and ±7 days for Week 24 (Table 2). Note that while out of window visits should be recorded as 
protocol deviations, it is preferable to perform visits and procedures out of window than not 
perform them at all. One exception may be if sufficient time has passed that it is now in-window 


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Approved, Date: 17 October 2022
for the next, subsequent visit, in which case it is advised to contact the medical monitor for 
assistance in how to best manage the situation.
Table 2:
Visit Windows
Parameter
Analysis 
Period
Scheduled 
Visit 
Number
Time Interval
(label on 
output)
Time 
Interval
(Day)*
Target Time 
Point (Day)
[1]
[1]
[Screening]
[<1]
[-35 to -7]
[1]
[2]
[Week 0]
[<=1]
[1]
[1]
[3]
[Week 8]
[52 to 60]
[56]
[1]
[4]
[Week 16]
[108 to 116]
[112]
telephone call or 
on-site
[1]
[5]
[Week 24]
[161 to 175]
[168]
2.2.
Pooling Algorithm for Analysis Centers
There is no pooling algorithm for analysis centers.
2.3.
Analysis Sets
2.3.1.
Efficacy Analysis Set(s)
In this study, the efficacy analyses will be based on intent-to-treat principle.  That means efficacy 
analyses will be performed on the full analysis set, which is defined as all randomized subjects. 
The full analysis set will be used for all primary and secondary efficacy analyses. 
2.3.2.
Safety Analysis Set
All subjects in the ITT population who receive at least 1 administration of study agent will be 
included in the safety analyses. Subjects will be analyzed according to the actual treatment 
received.
2.3.3.
Pharmacokinetics Analysis Set
The PK analysis set is defined as all subjects who have received at least 1 administration of study 
agent and have at least one valid blood sample drawn for PK analysis. Subjects will be analyzed 
according to the actual treatment received.
2.3.4.
Immunogenicity Analysis Set
The immunogenicity analysis set is defined as all subjects who have received at least 1 
administration of study agent and have at least one valid blood sample drawn for detection of 
antibodies to study agent. Subjects will be analyzed according to the actual treatment received.
2.4.
Definition of Subgroups
To evaluate the consistency of efficacy in the primary endpoint over demographic, baseline disease 
characteristics, and CD medication history, subgroup analyses will be performed when the number 
of subjects in the subgroups permits.


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Baseline demographics:

Baseline age (≤median age, >median age)

Sex (male, female)

Race (White, non-White)

Baseline weight (≤ median, > median)

Baseline smoking status (smoking, non-smoking)
Baseline disease characteristics:

Baseline CDAI score (≤300 or >300)

Crohn’s disease duration (years) (<2 years, >=2 to <5 years, or >=5 years)

Involved gastrointestinal areas (ileum only, colon only, ileum & colon)

CRP (≤ 3 mg/L, > 3 mg/L)

Fecal Calprotectin (≤250 mg/kg, > 250 mg/kg)
Concomitant medication using at baseline:

Oral corticosteroids (including budesonide) (receiving, not receiving)

6-MP/AZA/MTX (receiving, not receiving)

Oral corticosteroids (including budesonide) and (6-MP/AZA/MTX ) (receiving, not receiving)

Oral corticosteroids (including budesonide) or (6-MP/AZA/MTX ) (receiving, not receiving)
Surgery history:

Prior intra-abdominal surgeries 

0 (i.e. NO prior intra-abdominal surgeries)

1

≥1

≥2

Prior total or subtotal colectomy (independent of CD-related surgeries)

Prior other CD related partial bowel resection

Current or prior fistula

Current draining fistula

Previous fistula history

Prior perianal CD related Surgery


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Baseline endoscopy information

Endoscopic disease severity per SES-CD score

No ulcers (0-2)

Mild (3-6)

Moderate (7-16)

Severe (>16)

Ulceration location

None

Ileum only

Colon only

Ileum and colon
Pre-Study Ustekinumab trough concentration 

By level

Undetectable

>0 – 0.8

0.8 – 1.3

>1.3

By quartiles
Antibodies to Ustekinumab

Yes/no
Number of Biologics Failed Prior to Ustekinumab

None

1 Biologic

2 Biologics

3 Biologics

4 Biologics
    
Prior response to Ustekinumab

Remission

Yes/no


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
Response (Subjects with normalization of)

CRP (≤3 mg/L)

FeCa (≤250 mg/kg)
Total length of time using Ustekinumab for CD

≤ 24 weeks

> 24 weeks to ≤ 52 weeks

> 52 weeks to ≤ 104 weeks

> 104 weeks      
Other 

CDAI > 300 and receiving corticosteroids and/or 6-MP/AZA/MTX at baseline (Yes, 
    No)
2.5.
Study Day and Relative Day
Study Day 1 refers to the first study agent administration. The study day for an event is defined 
as:

Event date - (date of Study Day 1) +1, if event date is ≥ date of Day 1

Event date - date of Day 1, if event date < date of Day 1 
2.6.
Baseline
In general, the baseline measurement is defined as the closest measurement taken prior to or at the 
time of the first study agent administration date unless otherwise specified. 
2.7.
Imputation Rules for Missing AE Date 
Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event 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

The day of study agent start, if the month/year of the onset of AE is the same as 
month/year of the study agent start date and month/year of the AE resolution date is 
different

The day of study agent start or day of AE resolution date, whichever is the earliest, if 
month/year of the onset of AE and month/year of the study agent start date and 
month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:

January 1 of the year of onset, as long as this date is on or after the study agent start date


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
Month and day of the study agent start date, if this date is in 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 adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution or the date of AE, if the AE occurred in 
that month.

If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of AE, if the AE occurred 
in that year.
Completely missing resolution dates will not be imputed.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Interim analysis is planned at Week 16 database lock.  There is no Data Monitoring Committee 
(DMC) for this study.
4.
SUBJECT INFORMATION
The full analysis set will be used for the subject information analyses as specified below unless 
otherwise noted. 
Descriptive statistics, such as mean, median, standard deviation, interquartile range, maximum, 
and minimum for continuous variables, and counts and percentages for discrete variables will be 
used to summarize most data. In addition, subject listings will also be used to present the data.
4.1.
Demographics and Baseline Characteristics
4.1.1.
Demographics
Table 3 presents a list of the demographic variables that will be summarized for the full analysis 
set.  


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Table 3: 
Demographic 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) 
Categorical Variables:
Age (≤ median age, >median age)
Frequency distribution with the 
number and percentage of 
subjects in each category.
Sex (male, female)
Weight (≤ median, > median)
Racea (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or other Pacific Islander, 
White, Other, Multiple, Unknown, Not reported)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not 
Reported, Unknown)
a
If multiple race categories are indicated, then Race is recorded as “Multiple.”
4.1.2.
Baseline Characteristics
Crohn’s disease baseline disease characteristics (i.e., Crohn’s disease duration [years], surgery 
history, age at diagnosis [years], baseline CDAI scores, baseline SES-CD score [0-56], baseline 
CRP and Fecal Calprotectin, baseline IBDQ [32-224] will be summarized for the full analysis 
set.
4.2.
Disposition Information
The number of subjects in the following disposition categories will be summarized throughout 
the study by treatment group and overall:

Subjects randomized

Subjects receiving study agent

Subjects completing the study

Subjects who discontinued study agent

Reasons for discontinuation of study agent

Subjects who terminated study prematurely

Reasons for termination of study
The above categories will include summaries over the period of Week 16 and through Week 36
if appropriate. The reasons for discontinuation of study agent and termination of study due to 
COVID-19 will be included in the summary tables.


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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

Treatment Compliance

Study agent compliance with the number of missing SC injections (1, 2, 3, more than 3) will 
be summarized descriptively through Week 16 for the full analysis set. 
4.3.
Extent of Exposure
The exposure data will be summarized through week 8/16 for week 16/end of study database lock
separately. The number, cumulative dose and percentage of subjects who receive study agents will 
be summarized by treatment group for the safety analysis set. Descriptive statistics will be 
presented for the following parameters:

Number of study agent injections or Infusions
4.4.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations will be identified prior to week 16/end of study database lock and 
the subjects with major protocol deviations will be summarized by category through Week 36 for 
the full analysis set.

Entered but did not satisfy criteria

Developed withdrawal criteria but not withdrawn

Received a disallowed concomitant treatment

Received a wrong treatment or an incorrect dose

Other
Subjects with major protocol deviations will also be listed. A listing will also be provided for 
subjects who had any COVID-19 related protocol deviations.
4.5.
Prior and Concomitant Medications
Prior medications are defined as any therapy used before the day of first dose of study agent. 
Subjects’ prior CD medication history with immunomodulators (MTX, AZA, and 6-MP) or oral 
corticosteroids or other non-biologic systemic therapies or CD-related biologic medication 
history will be summarized by treatment groups. 


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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. The number of subjects who received oral corticosteroid treatment at baseline and 
the doses over time of these subjects will be summarized. 
Subjects who received concomitant corticosteroids for indications other than CD will be listed.
5.
EFFICACY
In general, efficacy data summaries will be provided for the full analysis set. All efficacy analyses 
will be based on intent-to-treat principle.
5.1.
General Method of Analysis
Descriptive statistics (eg, mean, median, standard deviation, interquartile range, minimum, and 
maximum) will be used to summarize continuous variables. Counts and percentages will be used 
to summarize categorical variables. Graphical data displays (eg, line plots) may also be used to 
summarize the data whenever appropriate. Listings may also be utilized to present data at a subject 
level. 
All endpoints will be based on a superiority comparison between the 2 randomized groups (~6 
mg/kg IV re-induction of Ustekinumab and SC q8w 90 mg Ustekinumab). All efficacy analyses 
will be based on intent-to-treat principle. Therefore, the efficacy data for each subject randomly 
assigned to treatment group will be analyzed according to the assigned treatment regardless of the 
actual treatment received. All randomized subjects will be included in the efficacy analyses.
5.1.1.
Data Handling Rules
5.1.1.1.
Missing Data Imputation
Subjects with missing data, defined as those who terminated the study prior to the designated 
visit or subjects who have a missing value at the designated visit, will be considered to not have 
achieved their dichotomous efficacy endpoints. For continuous endpoints, the last available value 
will be carried forward for subjects with missing data.
5.1.2.
Estimand
Composite Strategy
The Composite Strategy assesses the treatment effects not only based on the variable 
measurements, but also based on intercurrent events (ICE(1-4)) defined in Section 5.1.2.1. If a 
participant met any of the ICE criteria the subject will be a non-responder for response variables 
and will have a score of no improvement for continuous variables for signs and symptoms. This 
estimand acknowledges that meeting the ICE (TF) criteria is an unfavorable outcome. 


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5.1.2.1.
Composite Estimand 
The Composite Estimand is defined by the 5 components:

Population: Subjects with moderately-to-severely active CD who have previously responded 
to Ustekinumab induction therapy, followed by a secondary LoR to SC q8w 90 mg 
Ustekinumab maintenance treatment

Treatment: 

Ustekinumab IV re-induction

Ustekinumab SC q8w

Variable: 

Binary: The endpoint (e.g. Clinical Response) is defined as responders who had not met 
any TF criteria prior to the specific visit at which the endpoint was assessed.  

Continuous: The endpoint is defined as change from baseline score prior to meeting TF 
criteria and 0 (no improvement) after meeting TF criteria. 

Intercurrent Events (ICEs): 
The following are the intercurrent events considered for this trial:
1.
A Crohn’s disease-related surgery due to lack of efficacy
2.
Discontinuation of study agent due to an AE of worsening CD or due to lack of efficacy
3.
Protocol-prohibited medications (Attachment 4)
4.
A change in corticosterioids and immunomodulator (Attachment 5)

Population level summary: 

Binary: difference in proportion of responders between Ustekinumab IV re-induction 
group and Ustekinumab SC group

Continuous: difference in mean changes between Ustekinumab IV re-induction group and 
Ustekinumab SC group
This estimand examines the difference through 24 weeks without increasing/initiating select 
background CD medications or discontinuing study intervention prior to that point, between 
Ustekinumab IV re-induction and Ustekinumab SC group.
5.2.
Analysis Specifications
5.2.1.
Level of Significance
Unless otherwise specified, a 2-sided significance level of 5% will be used.


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5.2.2.
Multiplicity Adjustment for Testing Procedures
This study has 1 primary endpoint (proportion of participants who achieved a clinical response at 
Week 16) and 4 major secondary endpoints.  With 5 endpoints and 2 treatment comparisons for 
each of these endpoints, there are a total of 5 hypotheses to be tested. The 5 hypotheses for the 
endpoints are explicitly listed in attachment 6. 
The overall Type I error of the 5 hypotheses in attachment 6 will be controlled at a significance 
level of ≤ 0.05. The testing procedure tests the primary and 4 major secondary endpoints for the 
two regimens of Ustekinumab IV re-induction vs Ustekinumab SC, in a fixed sequence and each 
endpoint is tested at the two-sided 0.05 level of significance. The fixed sequence testing method 
tests an endpoint only if the null hypotheses of no difference between the Ustekinumab IV re-
induction and Ustekinumab SC was rejected at the 0.05 level for all the endpoints above it in the 
sequence. This is shown visually in Figure 1 below.
Figure 1:
Multiplicity Control
Primary Endpoint
Major Secondary Endpoints
Clinical Response at Week 16 (IV Reinduction vs SC 90mg)
Clinical Remission at Week 16 (IV Reinduction vs SC 90mg)
Clinical Response at Week 8 (IV Reinduction vs SC 90mg)
If p ≤ 0.05
If p ≤ 0.05
If p ≤ 0.05
Clinical Remission at Week 8 (IV Reinduction vs SC 90mg)
Normalization of CRP and/or Fecal Calprotectin Concentration (s) at Week 16 (IV 
Reinduction vs SC 90mg)
If p ≤ 0.05


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5.3.
Primary Endpoint Analysis
5.3.1.
Definition of the Endpoints
The primary endpoint of the study is the proportion of subjects with clinical response (defined as 
a ≥100-point reduction from the baseline CDAI score, or a CDAI score <150) at Week 16.
5.3.1.1.
CDAI
The CDAI will be assessed by collecting information for 8 different CD-related variables: 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.4,9  
The last 4 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 wellbeing, if only 5 days or 6 days 
of data are available for the calculation, the weights of 7/5 and 7/6 will be used for the calculation 
respectively; if the values are recorded for less than 5 days, the subscore will not be calculated.
When at least 4 of the 8 components are available, missing components will be imputed. For 
missing hematocrit at baseline, the hematocrit value obtained closest and prior to the date of the 
Week 0 administration will be used. For all other visits, the hematocrit value obtained closest to 
the date of the visit will be used provided it was obtained within ± 10 days of the visit. If the 
laboratory value is obtained outside the ± 10-day window, then the closest previous hematocrit 
value will be carried forward.
5.3.2.
Analysis Methods
The primary efficacy analysis of the primary endpoint will be analyzed at the Week16 database 
lock based on the Composite Estimand (Table 4).
Intercurrent Events and Corresponding Strategies: 
Intercurrent events (ICEs) in categories 1-4 in 5.1.2 will be handled by the composite strategy.  
The estimand for the primary endpoint acknowledge that having any intercurrent event  is an 
unfavorable outcome. If a subject had any of the ICE categories 1-4 at or prior to Week 16, the 
subject will be considered not to be in clinical response at Week 16.  
In the primary efficacy analysis (i.e. the main estimator for the primary estimand), data from all 
subjects in the FAS (Section 2.3.1) will be analyzed according to the randomized study 
intervention regardless of the study intervention they actually received.
In the primary efficacy analysis, the number and proportion of subjects achieving a clinical 
response (defined as a ≥100-point reduction from the baseline CDAI score, or a CDAI score <150) 
at Week 16 will be summarized. The clinical response endpoints as measured by the CDAI score 
will be determined based on these CDAI scores. The CDAI score will be calculated as described 
in Section 5.3.1.1. If any CDAI score is collected after experiencing ICE1-4, subject will be 
considered not having clinical response regardless of their CDAI score. If the CDAI score cannot 
be calculated (ie, <4 components available) at Week 16, the CDAI score will be considered missing 
for Week 16. Subjects who have a missing CDAI score at Week 16 will be considered not to be in 


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clinical response as measured by the CDAI score (ie, Nonresponder Imputation (NRI)). The 
endpoint will be compared between the Ustekinumab IV re-induction treatment group and 
continuous SC q8w treatment group using 2-sided Cochran-Mantel Haenszel-chi-square test, 
stratified by baseline CDAI score (≤300 or > 300), and prior biologic failure status at baseline 
(yes or no) at a significance level of 0.05. Strata adjusted proportion difference from CMH method 
will be calculated. 95% asymptotic confidence interval for strata-adjusted proportion difference 
based on Wald-type statistic will be calculated as well.
5.3.3.
Sensitivity Analyses for Primary Endpoint
To assess the robustness of the primary endpoint analysis, the following three sensitivity analyses 
will be conducted.
(1)  Per protocol: exclude randomized, never treated subjects
(2)  Observed case: exclude subjects from the analysis if they have a missing CDAI score at Week 
16 (ie, the CDAI score is missing at Week 16)
(3)  Last observation carried forward: subjects who have a missing CDAI score at Week 16 (ie, the 
CDAI score is missing at Week 16) will have their last CDAI score carried forward.
The same ICE strategies as those used for the primary endpoint analysis in 5.3.2 will be applied
on the above three sensitivity analyses. 
5.3.4.
Subgroup analyses  
To evaluate the consistency of the efficacy of the primary endpoint over demographic, baseline 
disease characteristics, Crohn’s disease medication use at baseline, surgery history and baseline 
endoscopy information, subgroup analyses are planned when the number of subjects in the 
subgroups permits.  The same data handling rules and ICE strategies will be applied as were used 
for the primary endpoint analysis in 5.3.2.  The odds ratios of Ustekinumab IV re-induction group 
vs. continuous SC q8w and corresponding 95% confidence intervals will be provided for each of 
the subgroups in Section 2.4.
5.3.5.
Summary of Analyses Related to the Primary Endpoint 
Table 4:
Summary of Analyses Related to the Primary Endpoint of Clinical Response at Week 16
Analysis 
(Analysis Set)
Missing data
Analysis method/Summary statistics
All analyses in this table are based on Composite Estimand. 
Primary Analysis
(Full Analysis 
Set-FAS)
Missing data due to missed 
visits or missed data 
collection (missing CDAI 
score). Subjects with missing 
data are considered not to be
in clinical response
·      Summaries of the proportion of 
subjects who achieved the endpoint 
·      Strata adjusted proportion  difference 
(Ustekinumab IV re-induction group-
Ustekinumab SC q8w group) and 95% CI 
·      P-value from the CMH test (stratified by 
baseline CDAI score (≤300 or > 300 ), 


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Table 4:
Summary of Analyses Related to the Primary Endpoint of Clinical Response at Week 16
and prior biologic failure status at 
baseline (yes or no))
Subgroup 
Analyses 
(Individual 
subgroup levels 
defined in 
Section 2.4, FAS)
Missing data due to missed 
visits or missed data 
collection (missing CDAI 
score).  Subjects with 
missing data are considered 
not to be in clinical response
·      Summaries of the proportion of 
subjects who achieved the endpoint 
·      Odds ratios and 95% CIs 
·      P-value from the logistic regression 
(stratified by baseline CDAI score 
(≤300 or > 300 ), and prior biologic 
failure status at baseline (yes or no)
Sensitivity 
Analysis 1 
Full Analysis Set 
excluding 
Randomized, 
never treated 
subjects
Same as Primary Analysis
Same as Primary Analysis
Sensitivity 
Analysis 2 
Observed case: 
Full Analysis Set-
Exclude subjects 
from the analysis 
if they have a 
missing CDAI 
score at week 16
(ie. < 4 
components of the 
CDAI score are 
available at Week 
16)
No missing data on CDAI at 
Week 16
Same as Primary Analysis
Sensitivity 
Analysis 3 (FAS)
Last observation 
carried forward: 
subjects who have 
a missing CDAI 
score at Week 16
will have their last 
CDAI score 
For missing CDAI score due 
to missed visits or missed 
data collection (< 4 
components of the CDAI 
score), CDAI score will have 
the last non-missing value 
carried forward. If any of 
ICE 1-4 occurs prior to 
Week 16, then subject  is 
considered as not to be in 
Same as Primary Analysis


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Table 4:
Summary of Analyses Related to the Primary Endpoint of Clinical Response at Week 16
carried forward
clinical response at Week 16. 
Otherwise, clinical response
status will be determined by 
observed or carried forward 
CDAI score.
5.4.
Major Secondary Endpoints Analyses
The 4 major secondary endpoints are: 

Clinical remission at Week 16

Clinical response at Week 8

Clinical remission at Week 8       

Normalization of CRP and/or FeCal calprotectin concentration(s) at Week 16, among 
participants with an elevated CRP and/or FeCa at baseline
5.4.1.
Definitions of Major Secondary Endpoints (in corresponding order)
The proportion of subjects with:

Clinical remission is defined as a CDAI score < 150 

Clinical response is defined as a CDAI score decrease ≥100 from baseline or CDAI score 
<150 

Normalization of CRP is defined as CRP <3 mg/L and normalization of FeCal calprotectin 
concentration is defined as fecal calprotectin ≤250 mg/kg
5.4.1.1.
C-reactive Protein
C-reactive protein has been demonstrated to be useful as a marker of inflammation in patients 
with irritable bowel disease. In Crohn’s disease, elevated CRP concentrations have been 
associated with severe clinical activity, elevated sedimentation rate, and active disease as 
detected by colonoscopy 7, 15. 
Blood samples for the measurement of CRP will be collected from all participants at visits 
indicated in the Schedule of Activities. CRP will be assayed by the central laboratory using a 
validated, high sensitivity CRP assay. Results of postbaseline CRP measurements will not be 
released to the investigators.
5.4.1.2.
Calprotectin
Fecal calprotectin has been demonstrated to be a sensitive and specific marker in identifying 
intestinal inflammation and response to treatment in patients with irritable bowel disease 6. 


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Stool samples for determination of FeCa concentrations will be collected from all participants at 
visits indicated in the Schedule of Activities; those stool samples should not be collected on days 
impacted by ileocolonoscopy preparation.
The assay for FeCa concentration will be performed using a validated method by the central 
laboratory. Additional tests may also be performed on the stool samples for additional markers 
related to intestinal inflammation and treatment response. Results of postbaseline FeCa tests will 
not be released to the investigators.
5.4.2.
Analyses method for the Major Secondary Endpoints
The major secondary endpoints, defined in Section 5.4.1 will be compared between Ustekinumab
IV re-induction group and continuous Ustekinumab SC q8w group and will use the full analysis 
set. The same data handling rule and ICE strategies as primary analysis in Section 5.4.2 will be 
used in analyses for major secondary endpoints related to CDAI score.  The endpoints will be 
estimated by differences between the Ustekinumab IV re-induction group and the Ustekinumab
SC q8w group in the percentages of subjects who meet each endpoint and their associated 95% 
CIs.  In addition, each endpoint will be compared between Ustekinumab IV re-induction group 
and Ustekinumab SC q8w group using the CMH chi-square test (2-sided) stratified by baseline 
CDAI score (≤300 or > 300), and prior biologic failure status at baseline (yes or no)) at a 
significance level of 0.05. The tests of superiority will be based on the p-values from the CMH 
test.
The CDAI score will be calculated as described in Section 5.3.1.1. The clinical response or 
remission endpoints as measured by the CDAI score will be determined based on these CDAI 
scores. If the CDAI score cannot be calculated (ie, <4 components available) at Week 8/16, the 
CDAI score will be considered missing for Week 8/16. Subjects who have a missing CDAI score 
at Week 8/16 will be considered not to be in clinical remission or clinical response as measured 
by the CDAI score (ie, Nonresponder Imputation (NRI)). 
If CRP or fecal concentration is missing at Week 16, CRP or fecal concentration will have their 
last non-missing value carried forward at Week 16. If any of ICE 1-4 occurs at or prior to week 
16, then the subject is considered as not to be normalization at week 16. Otherwise, normalization 
status will be determined by observed or carried forward CRP or Fecal value.
5.4.3.
Summary of Analyses Related to Major Secondary Endpoints
Table 5 below provides an overview of all the analyses related to the major secondary endpoints, 
the analysis sets, the data handling rules to be used, and the analysis methods and summary 
statistics.   
Table 5:
Summary of Analyses Related to Major Secondary Endpoints
Analysis 
(Analysis Set)
Missing data
Analysis method/Summary statistics
All analyses for major secondary endpoints are handled by the composite strategy


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Table 5:
Summary of Analyses Related to Major Secondary Endpoints
Clinical 
Remission at 
Week 16 (FAS)
Missing data due to missed 
visits or missed data 
collection (missing CDAI 
score). Subjects with missing 
data are considered not to be
in clinical remission
      Summaries of the proportion of 
subjects who achieved the endpoint
      Strata adjusted proportion difference 
(Ustekinumab IV re-induction group-
Ustekinumab SC q8w group) and 95% CI
      P-value from the CMH test (stratified by 
baseline CDAI score (≤300 or > 300), 
and prior biologic failure status at 
baseline (yes or no))
Clinical Response 
at Week 8 (FAS) 
Missing data due to missed 
visits or missed data 
collection (missing CDAI 
score).  Subjects with 
missing data are considered 
not to be in clinical response
      Summaries of the proportion of 
subjects who achieved the endpoint
      Strata adjusted proportion difference 
(Ustekinumab IV re-induction group-
Ustekinumab SC q8w group) and 95% CI
      P-value from the CMH test (stratified 
by baseline CDAI score (≤300 or 
> 300), and prior biologic failure 
status at baseline (yes or no))
Clinical 
Remission at 
Week 8 (FAS)
Missing data due to missed 
visits or missed data 
collection (missing CDAI 
score). Subjects with missing 
data are considered not to be
in clinical remission
      Summaries of the proportion of 
subjects who achieved the endpoint
      Strata adjusted proportion difference 
(Ustekinumab IV re-induction group-
Ustekinumab SC q8w group) and 95% CI
      P-value from the CMH test (stratified by 
baseline CDAI score (≤300 or > 300), 
and prior biologic failure status at 
baseline (yes or no))
Normalization of 
CRP and/or 
FeCal 
concentration(s) 
at Week 16
(Randomized 
Subjects with an 
elevated CRP 
and/or FeCa at 
baseline)
For missing CRP or Fecal, 
CRP or Fecal will have their 
last non-missing value 
carried forward. If any of 
ICE 1-4 occurs prior to week 
16, then the subject is 
considered as not to be 
normalized at Week 16. 
Otherwise, normalization
status will be determined by 
observed or carried forward 
CRP or Fecal value.
      Summaries of the proportion of 
subjects who achieved the endpoint 
      strata adjusted proportion difference 
(Ustekinumab IV re-induction group-
Ustekinumab SC q8w group) and 95% CI
      P-value from the CMH test (stratified by 
baseline CDAI score (≤300 or > 300), 
and prior biologic failure status at 
baseline (yes or no))


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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. 
5.5.1.
Secondary Efficacy Endpoints at Week 24
The secondary endpoints in the following list will be analyzed. 

The proportion of subjects with clinical response (defined as a CDAI score decrease ≥100 
from baseline or a CDAI score < 150) at Week 24

The proportion of subjects with clinical remission (defined as CDAI < 150) at Week 24

Normalization of CRP at Week 16, among participants with an elevated CRP 

Normalization of FeCal concentration(s) at Week 16, among participants with an elevated 
FeCal at baseline

Normalization of CRP and/or FeCal concentration(s) at Week 24, among participants with an
elevated CRP and/or FeCal at baseline

Normalization of CRP at Week 24, among participants with an elevated CRP 

Normalization of  FeCal concentration(s) at Week 24, among participants with an elevated 
FeCal at baseline

Safety endpoints, including the proportion of participants with at least one adverse event 
and subcategories of adverse events (all infections, all serious adverse events and serious 
infections), as well as changes in clinical laboratory test results.
5.5.2.
Other Efficacy Endpoints:

The proportion of subjects with endoscopic response (defined as a reduction in SES-CD score 
by 50% from baseline or SES-CD score ≤3 or SES-CD =0 for subjects who enter the study.
with an SES-CD =3) at Week 16

The proportion of subjects with endoscopic improvement (reduction of ≥3 points from 
baseline in SES-CD) at Week16.

The proportion of subjects with endoscopic remission (SES-CD score ≤3 or SES-CD =0 for 
subjects who enter the study with an SES-CD =3) at Week 16.

Complete absence of mucosal ulcerations in any ileocolonic segment (score=0 for all 
segments for the “Presence and size of ulcers” component) at Week 16

Change from baseline in SES-CD score at Week 16.

The proportion of subjects with a minimum of 25% improvement from baseline in SES-CD 
score at Week 16

The change from baseline in the sum of the number of stools and the abdominal pain scores 
in the prior 7 days, without weighting (PRO-2) at Week 16


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
The change in the weighted sum of the abdominal pain and stool frequency scores of the CDAI
(PRO-2 weighted) from baseline at Week 16 

The change from baseline in the IBDQ score (including IBDQ domains) at Week 16

The proportion of subjects with IBDQ remission (IBDQ score ≥170) at Week 16

The proportion of subjects with corticosteroid-free response at Week 24 (defined as a CDAI 
score decrease ≥ 100 from baseline or a CDAI score < 150 and not taking any corticosteroids 
for at least 30 days prior to Week 24)

The proportion of subjects with corticosteroid-free response at Week 24 (defined as a CDAI 
score decrease ≥ 100 from baseline or a CDAI score < 150 and not taking any corticosteroids 
for at least 30 days prior to Week 24) among subjects who were on corticosteroids at baseline

The proportion of subjects with corticosteroid-free remission at Week 24 (defined as a CDAI 
score < 150 and not taking any corticosteroids for at least 30 days prior to Week 24) among 
subjects who were on corticosteroids at baseline 

The proportion of subjects with clinical remission and ≥50% reduction from baseline in CRP 
or fecal calprotectin at Week 16 

The proportion of subjects with clinical remission and ≥50% reduction from baseline in CRP 
or fecal calprotectin at Week 16 where fecal calprotectin assessed, among participants with 
elevated CRP (>3 mg/L) or fecal calprotectin >250 mg/kg at baseline

The proportion of subjects with clinical remission and CRP <3 mg/L and fecal calprotectin 
≤250 mg/kg at 16 where fecal calprotectin assessed at baseline

The proportion of subjects with clinical remission and CRP <3 mg/L and fecal calprotectin 
≤250 mg/kg at 16 where fecal calprotectin assessed, among participants with elevated CRP 
(>3 mg/L) or fecal calprotectin >250 mg/kg at baseline

The proportion of subjects with clinical biomarker response (clinical response and ≥50% 
reduction from baseline in CRP or fecal calprotectin) at Week 16 

The proportion of subjects with clinical biomarker response (clinical response and ≥50% 
reduction from baseline in CRP or fecal calprotectin) at Week 16 where fecal calprotectin 
assessed, among participants with elevated CRP (>3) or fecal calprotectin (>250 mg/kg) at 
baseline

The proportion of subjects with clinical response and CRP <3 mg/L and fecal calprotectin 
≤250 mg/kg at Week 16 

The proportion of subjects with clinical response and CRP <3 mg/L and fecal calprotectin 
≤250 mg/kg at Week 16 where fecal calprotectin assessed, among participants with elevated 
CRP (>3 mg/L) or fecal calprotectin >250 mg/kg at baseline

The proportion of subjects with fistula resolution (closure of all perianal/perirectal fistulas) at 
Week 8 and Week 16 among subjects with one or more open/draining perianal or perirectal 
fistulas at baseline 


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5.5.3.
Definitions
5.5.3.1.
Inflammatory Bowel Disease Questionnaire
The IBDQ is a validated, 32-item self-report questionnaire for participants with irritable bowel 
disease to evaluate patient-reported outcomes 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.
5.5.3.2.
Fistula Assessment
All participants will be assessed for fistulas. For participants 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).
5.5.3.3.
Video Ileocolonoscopy
An ileocolonoscopy will be used to assess SES-CD at baseline (Week 0) and at the Week 16 visit 
to determine the presence or absence of mucosal inflammation and ulceration. An ileocolonoscopy 
was done as an optional procedure and is not available for all patients. The baseline (Week 0) 
ileocolonoscopy should be performed within 14 days before or at the Week 0 visit. The Week 16 
ileocolonoscopy should be performed within 28 days before or after the Week 16 visit. 
Participants who do not remain in the study at Week 16 (due to discontinuation of study 
intervention and/or termination of study participation) should have their follow-up 
ileocolonoscopy at the early termination visit. 
The ileocolonoscopy procedures will be video-recorded, following the more detailed directions 
provided in the separate study reference (or ileocolonoscopy) manual. Video endoscopies will be 
assessed by a central facility that will be blinded to the treatment group.
Simplified endoscopic activity score for Crohn’s disease (SES-CD)
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/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.


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Table 6
Sample score sheet and scoring definitions for the Simple Endoscopic Score for Crohn’s Disease 
(SES-CD)
The total SES-CD score at a visit will be calculated based on all segments scored at the visit. If the 
total SES-CD score cannot be calculated (i.e., no segments are scored) at a visit, the total SES-CD 
score will be considered missing.
5.5.4.
Analysis Methods
Other efficacy endpoints except endoscopy endpoints related to SES-CD score listed and defined 
in Sections 5.5.1 and 5.5.2 will be analyzed based on the FAS according to randomized treatment 
group regardless of the treatment actually received.
Endoscopy endpoints related to SES-CD score will be analyzed on subjects with total SES-CD 
score ≥3 at baseline.
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.
The data handling rule and ICE strategies as defined above for the major secondary endpoints 
(Section 5.4.3) will also be used for these endpoints.
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 narrowings (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.


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Binary Endpoints
Subjects who have any intercurrent event (as specified in section 5.3.2) will be considered to not 
have achieved the binary endpoints. Subjects with missing data for an endpoint will be considered 
to have not achieved the associated binary endpoint. 
The proportions will be compared between the Ustekinumab IV re-induction group and continuous 
Ustekinumab SC q8w group using 2-sided Cochran-Mantel Haenszel-chi-square test, stratified by 
baseline CDAI score (≤300 or > 300), and prior biologic failure status at baseline (yes or no) 
unless otherwise specified. In case of rare events, Fisher’s exact test will be used for treatment 
comparisons.
Continuous Endpoints
Baseline values (at Week 0) will be assigned from the point of an intercurrent event categories 1-
4 onward, regardless of the observed data if a subject has any intercurrent event (as specified in 
Section 5.3.2).  Missing data for scores will be carried forward from last non-missing observed 
value prior to missing visits.
The continuous variables (such as changes from baseline) will be compared between the 
Ustekinumab IV re-induction group and Ustekinumab SC q8w group using an analysis of 
covariance on van der Waerden normal scores with baseline value, baseline CDAI score (≤300 
or > 300), and prior biologic failure status at baseline (yes or no)  as stratification factors unless 
otherwise specified. For the change from baseline in CDAI score, the baseline CDAI 
(continuous)will be used as a covariate instead of baseline CDAI score (<=300 or >300). 
6.
SAFETY
Safety will be assessed by summarizing the incidence and type of AEs, and examining changes in 
laboratory parameters (hematology and chemistry).
In all safety analyses, subjects who received at least 1 (partial or complete) dose of study agent 
will be included. No formal hypothesis testing is planned.
Depending on the safety data categories, the cumulative safety data will be analyzed through 
different study periods which include through Week 16 for the primary endpoint and through Week 
36 for the final follow-up of the study as appropriate.
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). 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. Any AE occurring at or after the initial administration of study agent 
through the end of the trial is considered to be treatment emergent. 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 


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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 (including COVID-19 related 
AEs) will be included in the analysis.  For each AE, the number and percentage of subjects who 
experience at least 1 occurrence of the given event will be summarized by treatment group. In 
addition, comparisons between treatment groups will be provided if appropriate.
Summary tables will be provided for:

Adverse events (AEs)

Serious adverse events (SAEs)

Reasonably related AEs (very likely, probable, possible as assessed by the investigator)

Discontinuation of study agent due to AEs

Infections and serious infections

Injection site reactions

Infusion-related AEs (during or within 1 hour of a study agent infusion)
In addition to the summary tables above, listings will be provided for subjects who:

Had SAEs

Discontinuation of study agent due to AEs

Had serious infections

Had Malignancies
Since safety should be assessed relative to exposure and follow-up, most AE summary tables will 
include average weeks of follow-up and average number of study agent administrations for each 
treatment group.
Additional summaries, listings, or narratives will be provided for any deaths.
6.2.
Clinical Laboratory Tests
All clinical laboratory tests will be displayed for the subjects included in the safety analysis set. 
The clinical laboratory parameters to be evaluated by the central laboratory include but are not 
limited to:

Hematology assessments will include but are not limited to the following: hemoglobin, 
hematocrit, platelet count, total and differential WBC count.

Blood chemistry assessments will include but are not limited to the following: chemistry panel 
(total bilirubin, ALT, AST, alkaline phosphatase, albumin, total protein, calcium, phosphate, 
sodium, potassium, chloride, blood urea nitrogen (BUN)/urea, and creatinine).

Stool fecal calprotectin

C-reactive protein


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Descriptive statistics will be presented for all chemistry, hematology, and other laboratory tests at 
scheduled time points.
Box plots of laboratory measurements and change from baseline will be provided for selected 
laboratory analytes.
The proportion of subjects with any markedly abnormal post baseline laboratory values 
(hematology and chemistry) in selected laboratory measurements will be summarized. Markedly 
abnormal clinical laboratory will be summarized through Week 24 of the study. Markedly 
abnormal post baseline laboratory values will also be presented in listings.
Markedly abnormal changes from baseline are defined in Table 7. For a laboratory value to be 
considered markedly abnormal, the corresponding laboratory criteria below must be met. For 
example, for a platelet value to be markedly abnormal, the platelet value must be <100 x109/L and 
must be at least 50% decrease from the baseline platelet value. If the baseline value is missing for 
a parameter, the determination of whether the laboratory value is markedly abnormal will be based 
solely on the actual value (ie, the criterion for a specific increase or decrease from baseline will 
not be utilized).
Table 7:
Markedly Abnormal Criteria for Laboratory Parameters
Hematology Test
Criteria for Markedly Abnormal Status
Hemoglobin (g/L)
Decrease from baseline > 20 g/L 
& absolute value < 100 g/L
Hematocrit, fraction
absolute value < 0.3 fraction
WBC (x109/L)
Decrease absolute value < 3 x 109/L
Increase absolute value > 20 x 109/L
Neutrophils (x109/L)
Percent decrease from baseline ≥ 33% 
& absolute value < 1.5 x 109/L
Lymphocytes (x109/L)
Percent decrease from baseline ≥ 33% 
& absolute value < 1.5 x 109/L
Eosinphils (x109/L)
Percent increase from baseline ≥ 100 % 
& absolute value > 1.0 x 109/L
Platelets (x109/L)
Percent decrease from baseline ≥ 50% 
& absolute value < 100 x 109/L
Chemistry Test
ALT/SGPT (U/L)
Percent increase ≥ 100 & Value > 100
AST/SGOT (U/L) 
Percent increase ≥ 100 & Value > 100
Total Bilirubin (umol/L) 
Percent increase ≥ 100 & Value > 41.0


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Table 7:
Markedly Abnormal Criteria for Laboratory Parameters
Non-fasting glucose (mmol/L)
Percent decrease from baseline ≥ 33 & absolute value < 
3.05 mmol/L Percent increase from baseline ≥ 50 & value 
> 8.88 mmol/L
Creatinine (umol/L)
Percent increase from baseline >= 66 & absolute value > 
99 umol/L
Albumin (g/L) 
Decrease ≥ 10 & Value < 25
BUN/Urea (mmol/L) 
Percent increase ≥66 & Value > 14.28
Alkaline phosphatase (U/L)
Percent increase ≥100 & Value >250
Sodium (mmol/L)
(Increase ≥10 & Value >150) OR (Decrease ≥10 & Value 
< 120)
Potassium (mmol/L)
(Increase ≥0.8 & Value > 5.5) OR (Decrease ≥0.8 & Value 
< 3.0)
Chloride (mmol/L)
Value < 85 OR Value > 120
Calcium (mmol/L)
(Increase ≥0.37 & Value > 2.62) OR (Decrease ≥0.37 & 
Value < 1.87)
Phosphorus (mmol/L)
(Increase ≥0.81 & Value >1.94) OR (Decrease ≥0.32 & 
Value < 0.65)
Total protein (g/L)
Value < 45 OR Value > 100
6.3.
Vital Signs and Physical Examination Findings
Weight and weight changes from baseline will be summarized at each visit time point through 
Week 24.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
7.1.1.
Pharmacokinetics and Immunogenicity
At baseline, blood samples for measuring serum concentrations of Ustekinumab, and antibodies 
to Ustekinumab will be drawn before the IV infusion (for PK and antibodies) and approximately60 
minutes after completion of the IV infusion (for PK only). All other blood samples will be collected 
before administration of the study intervention at scheduled visits as indicated in the Time and 
Events Schedule in the protocol.
Serum concentrations and antibodies to study agent will be assessed at the following timepoints: 
       Serum concentrations:
       Ustekinumab
Weeks 0, 8, 16, 24, and early termination if 
applicable


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       Antibodies to study agent:
       Ustekinumab
Weeks 0, 8, 16, 24, and early termination if 
applicable
Serum concentrations will be determined using a validated, sensitive, specific, and drug-tolerant 
method by or under the supervision of the sponsor. Anti-drug assays will be performed for 
Ustekinumab using different, but drug-tolerant, validated assays by the sponsor or their designee. 
Any comparison of the data will be descriptive, only.
7.1.2.
Pharmacokinetic and Immunogenicity Analyses
The PK analysis will be based on subjects who received at least 1 administration of study agent 
and had at least one valid blood sample drawn for serum concentrations. No imputation of 
missing concentration data will be performed; that is, data summaries will be based on the 
observed data.
If there were multiple samples collected prior to an injection, the closest sample before the 
injection will be used. If a sampling time or an injection time was missing, the date will be used. 
If sampling date was the same as the injection date, the sample will be included in the statistical 
summary.
Descriptive statistics of the serum study agent concentrations will be calculated at each sampling 
time point.  Serum study agent concentrations over time will be summarized for each treatment 
group.
Concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics.
The incidence of antibodies to study agent (immunogenicity) will be summarized for all subjects 
who receive any study agent and have appropriate samples for detection of antibodies to 
Ustekinumab.
7.2.
Biomarker
The goal of the biomarker analyses is to examine the biologic response to treatment and to identify 
biomarkers that are relevant to Ustekinumab treatment and/or CD. Assessment will be performed 
including:
1.      To understand the molecular effects of Ustekinumab.
2.      To understand CD pathogenesis.
3.      To understand why an individual may respond differently to  Ustekinumab.
7.2.1.
Serum-based Biomarkers
Blood samples for serum-based biomarker analyses will be collected from all participants. 
Assays to be performed may include proteins associated with proinflammatory and anti-


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inflammatory effects, the recruitment and proliferation of cells associated with inflammation and 
repair, and markers associated with tissue injury or repair. 
7.2.2.
Whole Blood-based Biomarkers
Whole blood samples will be collected from all participants to assess the effect of study 
intervention on RNA expression profiles. Whole blood analyses may also examine RNA 
expression associated with the pathogenesis of CD.
The biomarker results will be reported in a separate report.


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14. Vergara-Gomez M, Montserrat A, Casellas F. Clinical outcomes assessment:  A new 
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ATTACHMENTS
ATTACHMENT 1:
SAMPLE INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE 
(IBDQ)
Copyright © 1989 McMaster University, Hamilton, Ontario, Canada 
The Inflammatory Bowel Disease Questionnaire (IBDQ), authored by Dr. Jan Irvine et al, is the copyright of 
McMaster University (Copyright ©1989, McMaster University).  The IBDQ has been provided under license 
from McMaster University and must not be copied, distributed or used in any way without the prior written 
consent of McMaster University.  Contact the McMaster Industry Liaison Office at McMaster University, 
email: milo@mcmaster.ca for licensing details.
Updated from: IBDQ - United Kingdom-English - Version of 09 May 08 - Mapi Research Institute.
ID4529/IBDQ_AU2 0_eng-GB.doc
IBDQ (enGB) 03JUN2016 FINAL – ICON Language Services
INSTRUCTIONS FOR SELF-ADMINISTERED INFLAMMATORY BOWEL 
DISEASE QUESTIONNAIRE (IBDQ)
This questionnaire is designed to measure the effects of your inflammatory 
bowel disease on your daily function and quality of life. You will be asked about 
symptoms you have been having as a result of your bowel disease, the way you 
have been feeling in general, and how your mood has been.
There are two versions of this questionnaire, the IBDQ and IBDQ-Stoma. If 
you have a colostomy or ileostomy, you should complete the IBDQ-Stoma. 
Questions 1, 5, 17, 22, 24 and 26 are slightly different in each version. Be sure 
you have the correct questionnaire.
On this questionnaire, there are 32 questions. Each question has graded 
response choices numbered from 1 to 7. Please read each question carefully and 
answer the number which best describes how you have been feeling in the past 
2 weeks.
EXAMPLE
How often have you felt unwell as a result of your bowel problem in the 
past 2 weeks?
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
If you are having trouble understanding a question, STOP for a moment! 
Think about what the question means to you. How is it affected by your bowel 


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problem? Then answer the question as best you can. You will have the chance to 
ask the research assistant questions after completing the questionnaire. This 
takes only a few minutes to complete.


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QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (IBDQ)
This questionnaire is designed to find out how you have been feeling during the 
last 2 weeks. You will be asked about symptoms you have been having as a result of your 
inflammatory bowel disease, the way you have been feeling in general, and how your mood 
has been.
1.
How frequent have your bowel movements been during the last two weeks? Please 
indicate how frequent your bowel movements have been during the last two weeks by 
picking one of the options from
1
BOWEL MOVEMENTS THE MOST FREQUENT YOU HAVE EVER EXPERIENCED
2
EXTREMELY FREQUENT
3
VERY FREQUENT
4
MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
5
SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
6
SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
7
NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2.
How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? Please indicate how often the feeling of fatigue or tiredness has 
been a problem for you during the last 2 weeks by picking one of the options from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
3.
How often during the last 2 weeks have you felt frustrated, impatient or restless?  Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME 


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4.
How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
5.
How much of the time during the last 2 weeks have your bowel movements been loose?
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
6.
How much energy have you had during the last 2 weeks? Please choose an option from
1
NO ENERGY AT ALL
2
VERY LITTLE ENERGY
3
A LITTLE ENERGY
4
SOME ENERGY
5
A MODERATE AMOUNT OF ENERGY
6
A LOT OF ENERGY
7
FULL OF ENERGY
7.
How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem?  Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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8.
How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
9.
How often during the last 2 weeks have you been troubled by cramps in your abdomen? 
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
10.
How often during the last 2 weeks have you felt generally unwell?  Please choose an 
option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
11.
How often during the last 2 weeks have you been troubled because of fear of not finding 
a toilet? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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12.
How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks? Please 
choose an option from
1
A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
2
A LOT OF DIFFICULTY
3
A FAIR BIT OF DIFFICULTY
4
SOME DIFFICULTY
5
A LITTLE DIFFICULTY
6
HARDLY ANY DIFFICULTY
7
NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR LEISURE 
ACTIVITIES
13.
How often during the last 2 weeks have you been troubled by pain in the abdomen? 
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
14.
How often during the last 2 weeks have you had problems getting a good night’s sleep or 
been troubled by waking up during the night? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
15.
How often during the last 2 weeks have you felt depressed or discouraged? Please choose 
an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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16.
How often during the last 2 weeks have you had to avoid attending events where there 
was no toilet close at hand? Please choose an option from 
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
17.
Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of wind? Please choose an option from
1
A MAJOR PROBLEM
2
A BIG PROBLEM
3
A SIGNIFICANT PROBLEM
4
SOME TROUBLE
5 
A LITTLE TROUBLE
6
HARDLY ANY TROUBLE
7
NO TROUBLE
18.
Overall, in the last 2 weeks, how much of a problem have you had maintaining or getting 
to the weight you would like to be at? Please choose an option from
1
A MAJOR PROBLEM
2
A BIG PROBLEM
3
A SIGNIFICANT PROBLEM
4
SOME TROUBLE
5 
A LITTLE TROUBLE
6
HARDLY ANY TROUBLE
7
NO TROUBLE
19.
Many patients with bowel problems often have worries and anxieties related to their illness. 
These include worries about getting cancer, worries about never feeling any better, and 
worries about having a relapse. In general, how often during the last 2 weeks have you 
felt worried or anxious? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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20.
How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
21.
How often during the last 2 weeks have you felt relaxed and free of tension?  Please 
choose an option from
1
NONE OF THE TIME
2
A LITTLE OF THE TIME
3
SOME OF THE TIME
4
A GOOD BIT OF THE TIME
5
MOST OF THE TIME
6
ALMOST ALL OF THE TIME
7
ALL OF THE TIME
22.
How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
23.
How much of the time during the last 2 weeks have you felt embarrassed as a result of 
your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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24.
How much of the time during the last 2 weeks have you been troubled by a feeling of 
having to go to the toilet even though your bowels were empty?  Please choose an option 
from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
25.
How much of the time during the last 2 weeks have you felt tearful or upset?  Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
26.
How much of the time during the last 2 weeks have you been troubled by accidental soiling 
of your underpants? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
27.
How much of the time during the last 2 weeks have you felt angry as a result of your bowel 
problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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28.
To what extent has your bowel problem limited sexual activity during the last 2 weeks? 
Please choose an option from
1
NO SEX AS A RESULT OF BOWEL DISEASE
2
MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
3
MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
4
SOME LIMITATION AS A RESULT OF BOWEL DISEASE
5
A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
6
HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
7
NO LIMITATION AS A RESULT OF BOWEL DISEASE
29.
How much of the time during the last 2 weeks have you been troubled by nausea or an 
upset stomach? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
30.
How much of the time during the last 2 weeks have you felt irritable?  Please choose an 
option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
31.
How often during the past 2 weeks have you felt a lack of understanding from others?   
Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME


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32.
How satisfied, happy, or pleased have you been with your personal life during the past 2 
weeks? Please choose one of the following options from
1
VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
2
GENERALLY DISSATISFIED, UNHAPPY
3
SOMEWHAT DISSATISFIED, UNHAPPY
4
GENERALLY SATISFIED, PLEASED
5
SATISFIED MOST OF THE TIME, HAPPY
6
VERY SATISFIED MOST OF THE TIME, HAPPY
7
EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR PLEASED


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ATTACHMENT 2:  CROHN’S DISEASE ACTIVITY INDEX


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ATTACHMENT 3:  STANDARD WEIGHT TABLE


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ATTACHMENT 4: PROTOCOL-PROHIBITED MEDICATIONS
a.    Immunomodulatory agents other than 6-MP, AZA or MTX (including but not limited 
to 6-TG, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil).
b. Immunomodulatory biologic agents (including but not limited to TNF antagonists,
vedolizumab, natalizumab, abatacept).
c. Experimental or investigational Crohn’s disease medications (including but not limited 
to thalidomide, briakinumab, traficet, AMG 827).


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ATTACHMENT 5: CONCOMITANT CORTICOSTEROIDS AND 
IMMUNOMODULATOR CHANGE 
Corticosteroid agents:
a. Receiving oral corticosteroids (excluding budesonide) at a dose of > 5 mg/day 
(prednisone equivalent) above the baseline dose for more than 3 consecutive days within 30 days 
prior to Week 16 due to worsening Crohn’s disease. This includes initiation of oral corticosteroids 
for subjects who were not receiving oral corticosteroids at baseline of this study.
b. Receiving oral budesonide at dose of >= 3 mg/day above the baseline dose for more than 
3 consecutive days within 30 days prior to Week 16 due to worsening Crohn’s disease. This 
includes initiation of oral budesonide for subjects who were not receiving oral budesonide at 
baseline.
c. Receiving oral corticosteroids (excluding budesonide) at a dose of > 5 mg/day
(prednisone equivalent) above the baseline dose for more than any 7 days in total within 30 days 
prior to Week 16 due to reasons other than worsening Crohn’s disease. This includes initiation of 
oral corticosteroids for subjects who were not receiving oral corticosteroids at baseline.
d. Receiving oral budesonide at dose of >= 3 mg/day above the baseline dose for more than 
any 7 days in total within 30 days prior to Week 16 due to reasons other than worsening Crohn’s 
disease. This includes initiation of oral budesonide for subjects who were not receiving oral 
budesonide at baseline.
e. Initiation IV corticosteroids within 30 days prior to Week 16 due to worsening Crohn’s 
disease.
Immunomodulator agents:
a. Initiation of oral 6-MP/AZA due to worsening Crohn’s disease during study and the total 
receiving days within 90 days prior to Week 16 are more than 14 days.
b. Initiation of oral, subcutaneous, or intramuscular MTX due to worsening Crohn’s disease 
during study and the total receiving days within 90 days prior to Week 16 are more than 14 days.