Clinical trial NCT03107793
Conditions: Crohn Disease
Sponsor: Janssen-Cilag Ltd.
Start date: 2017-04-19; Completion date: 2021-07-20
Enrollment: 500 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven (routine care) approach in achieving endoscopic response.

Detailed description:
Study investigates benefit of treat to target maintenance treatment strategy versus routine care to test hypothesis that 'treat to target' ustekinumab (UST) maintenance treatment strategy coupled with early endoscopic assessment will result in higher endoscopic response rate after 48 weeks of treatment, compared to pragmatic maintenance treatment strategy. It consists of screening (5 weeks); treatment period (Week 0 to 48); extension period (Weeks 48 to 104) and safety follow up visit (16 weeks after last dose). Participants will be given an option to enter ultrasound sub-study to assess intestinal ultrasound (IUS) parameters indicating transmural changes in response to treatment with UST in participants with Crohn's disease. Study treatment will be unaffected by participation in sub-study which is optional for participants of main study.

Arms: arm 1: At Week (Wk) 0, all eligible participants will initiate intravenous (IV) induction treatment with ustekinumab (UST) on a weight-tiered basis at a dose of approximately 6 milligram per kilogram (mg/kg). At Week 8, all participants will receive a 90 milligram (mg) subcutaneous (SC) injection of ustekinumab. At Week 16, participants who do not achieve a Crohn's Disease Activity Index (CDAI) improvement of greater than or equal to (\>=) 70 points versus Week 0 (CDAI 70) will leave the study. Remaining participants will be randomized in a 1:1 ratio to either one of two arms for open label maintenance treatment up to Week 48: the treat to target arm or the routine care arm. From Week 48, participants will continue ustekinumab treatment in the study extension period, up to Week 104. Dosing frequency will be adjusted in the extension period for the participants failing to meet the treatment target. arm 2: In the routine care arm, assessment visits will be scheduled according to the timing of maintenance treatment injections up to Week 48, which will be in compliance with the EU SmPC for ustekinumab for the treatment of Crohn's disease, in which dosing every 12 weeks is recommended. At Week 16, (that is, 8 weeks after the first SC dose) participants continuing in the study will have demonstrated a CDAI-70 response. Nonetheless, participants who have not shown adequate response based on the investigator's judgment may receive a second SC dose at Week 16. During the routine care maintenance treatment period, in case of clinical worsening reported by the participant, consistent with disease flare in the investigator's judgment, clinical assessments of disease flare will be performed at the investigator's discretion. arm 3: UST maintenance treatment assignment will be based on centrally-read colonoscopy (at Wk16). Participants with \<25% improvement in SES-CD score at Wk16 will be assigned to Q8 (8-weekly) treatment and will receive UST 90mg SC at Wk16. In contrast, participants with \>=25% improvement in SES-CD score at Wk16 will be assigned to Q12 treatment and will receive next UST dose (90 mg SC) at Wk20. At assessment visits (from Wk24 for participants assigned to the Q8 regimen or from Wk20 for the Q12 group) UST maintenance treatment (up to Wk 48) will be directed by T2T assessments. Participants meeting target will continue with same UST dosing frequency. The dosing frequency will be optimized for all participants failing to meet the target at assessment visit. Those previously on Q12 regimens will be adjusted to Q8 dosing; those previously on Q8 regimens will be adjusted to Q4 dosing. Participants subsequently failing to meet the target will not be able to adjust further and will leave the study. arm 4: At Week 48, dose de-escalation will be implemented for participants with both endoscopic remission (SES-CD score \<=2) and corticosteroid-free clinical remission of at least 16 weeks duration. Participants receiving 12 weekly dosing frequency (Q12) ustekinumab will maintain this dosing frequency. Participants with either clinical remission or endoscopic remission, but not both, at Week 48 will continue with same dosing frequency or de-escalate provided maintenance of corticosteroid-free clinical remission and biomarker remission at 2 consecutive visits. Participants with neither corticosteroid-free clinical remission nor endoscopic remission will escalate dose or leave study if already on 4 weekly dosing frequency (Q4) dose. If neither clinical remission nor biomarker remission is evident at the next visit, participant will leave study. Later in the extension period, only those who achieve corticosteroid-free clinical remission and biomarker remission will undergo dose de-escalation.
Interventions: intervention 1: Ustekinumab
Intervention descriptions: intervention 1: Participants will receive IV induction treatment with ustekinumab on a weight-tiered basis at a dose of approximately 6 milligram per kilogram (mg/kg) IV. At Week 8, all participants will receive a 90 mg SC injection of ustekinumab. During the routine care maintenance treatment period, in case of clinical worsening reported by the participant, consistent with disease flare in the investigator's judgment, clinical assessments of disease flare will be performed at the investigator's discretion.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL
1
Status: Approved,  Date: 14 April 2020
Janssen EMEA*
Clinical Protocol
Appendix - Guidance on Study Conduct during the COVID-19 Pandemic
Study of Treat to Target Versus Routine Care Maintenance Strategies in Crohn’s Disease 
Patients Treated with Ustekinumab
STARDUST
Protocol CNTO1275CRD3005; Phase 3b
Amendment 4
STELARA (ustekinumab)
* Janssen EMEA is an organization in Europe, the Middle East, and Africa that operates through different legal entities 
in various countries. The legal entity acting as the sponsor for Janssen EMEA studies may vary, such as, but not 
limited to Janssen Pharmaceutica NV or Janssen-Cilag International. 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:         2016-002918-43
Status:
Approved
Date:
14 April 2020
Prepared by:
Janssen-Cilag Ltd.
EDMS number:
EDMS-ERI-125725400, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice and applicable regulatory 
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT03107793


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 4
Appendix - Guidance on Study Conduct during the COVID-19 Pandemic
CONFIDENTIAL
2
Status: Approved,  Date: 14 April 2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4 (COVID-19 Appendix)
14 April 2020
Amendment 3
23 November 2017
Amendment 2
13 September 2017
Amendment 1
22 March 2017
Original Protocol
04 November 2016
Amendment 4, 14 April 2020
Overall Rationale for the Amendment: To provide guidance on changes to study conduct and 
assessments due to restrictions and limitations during the COVID-19 pandemic.
Section Number
and Name
Description of Changes and Brief Rationale
Appendix - Guidance on 
Study Conduct During the 
COVID-19 Pandemic
Description of Change:  Added 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.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 4
Appendix - Guidance on Study Conduct during the COVID-19 Pandemic
CONFIDENTIAL
3
Status: Approved,  Date: 14 April 2020
BACKGROUND
This document applies to all current versions of Protocol CNTO1275CRD3005.
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 subjects 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 subject management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government guidelines or requirements or the clinical judgement 
of the investigator to protect the health and well-being of subjects and site staff. If at any time a 
subject’s safety is considered to be at unacceptable risk, study drug 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, subjects will be interviewed to collect safety data. Key efficacy endpoint 
assessments should be performed if required and as feasible. Subjects will also be questioned 
regarding general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
drug, including follow up. Modifications to protocol-required assessments may be permitted after
consultation between the subject 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 subject has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer or designee to discuss plans for study drug and follow-up.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 4
Appendix - Guidance on Study Conduct during the COVID-19 Pandemic
CONFIDENTIAL
4
Status: Approved,  Date: 14 April 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
Study Drug 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.

Remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions between 
site staff (or designees) and patients for study procedures (eg, those related to safety 
monitoring / efficacy evaluation / study drug storage and administration, including training 
where pertinent)

Application of study drug at home and central lab assessment sample collection and efficacy 
assessments can also be performed by a Home Health Care service provider if agreed by the 
sponsor, investigator and subject.
Drug Accountability and Compliance (Protocol Section 14.5)
Notes on Shipment of Study Drug to Subjects
If it is necessary to ship the study drug directly to study subjects, 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 subject 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 drug), 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 subjects to the 
sponsor using appropriate measures. Both the transport and handover conditions for study drug
should be part of the contractual arrangements, so that pharmaceutical drug safety of study drug
as well as protection of the privacy and personal data of subjects are adequately safeguarded. The 
study drug must be delivered directly to the subject or a person authorized by the subject 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 drug to subjects, written instructions on storage and return of used 
and unused study drug should be provided to subjects. When shipped by study sites, the receipt, 
consumption and return of study drug 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.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 4
Appendix - Guidance on Study Conduct during the COVID-19 Pandemic
CONFIDENTIAL
5
Status: Approved,  Date: 14 April 2020
Study Assessments and Analyses
Safety Assessments (Protocol Section 9.6.)
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 drugs and withdrawal from the study should be documented 
with the prefix “COVID-19-related” in the CRF.
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).


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 4
Appendix - Guidance on Study Conduct during the COVID-19 Pandemic
CONFIDENTIAL
6
Status: Approved,  Date: 14 April 2020
INVESTIGATOR AGREEMENT


1
Status: Approved, Date: 23 November 2017
Janssen EMEA *
Clinical Protocol
Study of Treat to Target Versus Routine Care Maintenance Strategies in Crohn’s Disease 
Patients Treated with Ustekinumab
STARDUST
Protocol CNTO1275CRD3005; Phase 3b
AMENDMENT 3
STELARA  (ustekinumab)
* Janssen EMEA is an organization in Europe, the Middle East, and Africa that operates through different legal
entities in various countries. The legal entity acting as the sponsor for Janssen EMEA studies may vary, such as, but
not limited to Janssen Pharmaceutica NV or Janssen-Cilag International. 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:         2016-002918-43
Status:
Approved
Date:
23 November 2017
Prepared by:
Janssen-Cilag Limited  
EDMS number:
EDMS-ERI-125725400, 5.0  
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.
NCT03107793


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
2
Approved, Date: 23 November 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULE -ROUTINE CARE ARM ....................................................................... 19
TIME AND EVENTS SCHEDULE -TREAT TO TARGET ARM ................................................................. 22
TIME AND EVENTS SCHEDULE -EXTENSION PERIOD ........................................................................ 25
ABBREVIATIONS ...................................................................................................................................... 27
DEFINITIONS OF TERMS.......................................................................................................................... 28
1.
INTRODUCTION................................................................................................................................ 29
1.1.
Background .................................................................................................................................... 29
1.2.
Overall Rationale for the Study...................................................................................................... 30
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 31
2.1.
Objectives and Endpoints .............................................................................................................. 31
2.2.
Hypothesis ..................................................................................................................................... 35
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 35
3.1.
Overview of Study Design.............................................................................................................. 35
3.2.
Study Design Rationale.................................................................................................................. 43
4.
SUBJECT POPULATION.................................................................................................................. 46
4.1.
Inclusion Criteria ............................................................................................................................ 46
4.2.
Exclusion Criteria ........................................................................................................................... 50
4.3.
Prohibitions and Restrictions ......................................................................................................... 53
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 53
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 54
7.
TREATMENT COMPLIANCE............................................................................................................ 56
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 56
9.
STUDY EVALUATIONS .................................................................................................................... 58
9.1.
Study Procedures........................................................................................................................... 58
9.1.1.
Overview..................................................................................................................................... 58
9.1.2.
Screening Phase ........................................................................................................................ 59
9.1.3.
Open-Label Treatment Phase .................................................................................................... 60
9.1.4.
Posttreatment Phase (Follow Up)............................................................................................... 64
9.2.
Efficacy Evaluations....................................................................................................................... 65
9.2.1.
Crohn’s Disease Activity Index ................................................................................................... 65
9.2.2.
C-reactive Protein....................................................................................................................... 65
9.2.3.
Fecal Calprotectin....................................................................................................................... 65
9.2.4.
Video Ileocolonoscopy................................................................................................................ 66
9.2.5.
Fistula Assessment..................................................................................................................... 66


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
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Approved, Date: 23 November 2017
9.2.6.
Inflammatory Bowel Disease Questionnaire............................................................................... 66
9.2.7.
EQ-5D-5L.................................................................................................................................... 66
9.2.8.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)..................................... 67
9.2.9.
Hospital Anxiety and Depression Scale (HADS) ........................................................................ 67
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 67
9.4.
Additional Biomarkers .................................................................................................................... 67
9.4.1.
Analytical Procedures................................................................................................................. 67
9.4.2.
Pharmacokinetic Parameters ..................................................................................................... 68
9.4.3.
Immunogenicity Assessments (Anti-ustekinumab antibodies) ................................................... 68
9.5.
Medical Resource Utilization and Health Economics .................................................................... 68
9.5.1.
Work Productivity and Activity Impairment (WPAI) .................................................................... 68
9.5.2.
Time Lost From Work ................................................................................................................. 68
9.6.
Safety Evaluations ......................................................................................................................... 68
9.7.
Sample Collection and Handling.................................................................................................... 71
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 72
10.1.
Completion ..................................................................................................................................... 72
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 72
10.3.
Withdrawal From the Use of Samples in Future Research............................................................ 74
11.
STATISTICAL METHODS................................................................................................................. 74
11.1.
Subject Information ........................................................................................................................ 75
11.2.
Sample Size Determination ........................................................................................................... 75
11.3.
Efficacy Analyses ........................................................................................................................... 75
11.3.1.
Primary Endpoint ........................................................................................................................ 75
11.3.2.
Secondary Endpoints.................................................................................................................. 76
11.4.
Pharmacokinetic/Immunogenicity/Pharmacodynamic Analyses ................................................... 78
11.5.
Safety Analyses ............................................................................................................................. 78
11.6.
Interim Analysis.............................................................................................................................. 79
11.7.
Steering Committee ....................................................................................................................... 79
12.
ADVERSE EVENT REPORTING ...................................................................................................... 80
12.1.
Definitions ...................................................................................................................................... 80
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 80
12.1.2.
Attribution Definitions.................................................................................................................. 81
12.1.3.
Severity Criteria .......................................................................................................................... 81
12.2.
Special Reporting Situations.......................................................................................................... 82
12.3.
Procedures..................................................................................................................................... 82
12.3.1.
All Adverse Events...................................................................................................................... 82
12.3.2.
Serious Adverse Events ............................................................................................................. 83
12.3.3.
Events of Special Interest........................................................................................................... 84
12.3.4.
Pregnancy................................................................................................................................... 84
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 85
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 85
13.1.
Procedures..................................................................................................................................... 85
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 85
14.
STUDY DRUG INFORMATION......................................................................................................... 85
14.1.
Physical Description of Study Drug(s) ........................................................................................... 85
14.2.
Packaging ...................................................................................................................................... 86
14.3.
Labeling.......................................................................................................................................... 86
14.4.
Preparation, Handling, and Storage............................................................................................... 86
14.5.
Drug Accountability ........................................................................................................................ 86
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 87
16.
ETHICAL ASPECTS ......................................................................................................................... 88


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
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Approved, Date: 23 November 2017
16.1.
Study-Specific Design Considerations........................................................................................... 88
16.2.
Regulatory Ethics Compliance....................................................................................................... 88
16.2.1.
Investigator Responsibilities ....................................................................................................... 88
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 89
16.2.3.
Informed Consent ....................................................................................................................... 90
16.2.4.
Privacy of Personal Data ............................................................................................................ 91
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 91
16.2.6.
Country Selection ....................................................................................................................... 92
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 92
17.1.
Protocol Amendments.................................................................................................................... 92
17.2.
Regulatory Documentation ............................................................................................................ 92
17.2.1.
Regulatory Approval/Notification ................................................................................................ 92
17.2.2.
Required Prestudy Documentation............................................................................................. 92
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 93
17.4.
Source Documentation................................................................................................................... 94
17.5.
Case Report Form Completion ...................................................................................................... 94
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 95
17.7.
Record Retention ........................................................................................................................... 95
17.8.
Monitoring ...................................................................................................................................... 96
17.9.
Study Completion/Termination....................................................................................................... 96
17.9.1.
Study Completion/End of Study.................................................................................................. 96
17.9.2.
Study Termination....................................................................................................................... 96
17.10.
On-Site Audits ................................................................................................................................ 97
17.11.
Use of Information and Publication................................................................................................ 97
REFERENCES............................................................................................................................................ 99
INVESTIGATOR AGREEMENT ............................................................................................................... 131
LIST OF ATTACHMENTS
Attachment 1:
QuantiFERON-TB Gold Testing ............................................................................... 101
Attachment 2:
Tuberculin Skin Testing............................................................................................ 103
Attachment 3:
Crohn’s Disease Activity Index (Sample) ................................................................. 104
Attachment 4:
Standard Weight Table (Sample) ............................................................................. 105
Attachment 5:
Inflammatory Bowel Disease Questionnaire (IBDQ) ................................................ 106
Attachment 6:
EuroQoL-5D-5L Health Questionnaire (EQ-5D-5L) – Sample UK English 
Version...................................................................................................................... 117
Attachment 7:
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
[Sample].................................................................................................................... 120
Attachment 8:
Hospital Anxiety and Depression Scale (HADS) [Sample]....................................... 121
Attachment 9:
Work Productivity and Activity Impairment (WPAI) [Sample]................................... 123
Attachment 10:
Anticipated Events.................................................................................................... 125
Attachment 11: 
Risk/Benefit Assessment of the Investigational Medicinal Product Dossier ............ 126
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Extension Period Ustekinumab Dosing From Week 48............................................................ 39
FIGURES
Figure 1:
Schematic Overview of the Study Design................................................................................. 41
Figure 2:
Ustekinumab Maintenance Dosing in the Treat to Target Arm (Week 16 to Week 48) ........... 42


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
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Approved, Date: 23 November 2017
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
04 November 2016
Amendment 1
22 March 2017
Amendment 2
13 September 2017
Amendment 3
23 November 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (23 November 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To extend study treatment to Week 104, to explore the effectiveness of 
longer-term ustekinumab treatment, and to explore de-escalation of ustekinumab dosing.
Applicable Section(s)
Description of Change(s)
Rationale: To extend the study to Week 104, and to examine the effectiveness of de-escalated ustekinumab dosing.
Synopsis, Objectives, 
Endpoints and 
Hypothesis; 
2.1 Objectives and 
Endpoints; 
11.3.2 Secondary 
Endpoints
Added exploratory objectives and endpoints relating to the extension of ustekinumab 
treatment to Week 104, and to dose de-escalation.
Synopsis, Overview of 
Study Design, Dosage 
and Administration;
3.1 Overview of Study 
Design; Figure 1; 
6 Dosage and 
Administration; 
9.1.3 Open-Label 
Treatment Phase
Added text describing continuation of study treatment after Week 48 in an extension 
period up to Week 104. Modified the Schematic Overview of Study Design. Added details 
of ustekinumab dose de-escalation to be applied depending on endoscopic and clinical 
findings at Week 48, and subsequently on clinical remission and biomarker (CRP and FC) 
findings.
Time and Events 
Schedules
Added a Time and Events Schedule for the extension period. Amended the Time and 
Events Schedules and footnotes to allow for ustekinumab dosing at or after Week 48. 
Indicated that safety, efficacy, health economics, pharmacokinetic and immunogenicity 
assessments will be performed up to Week 104. Clarified the timing of urine pregnancy 
testing, and injection site evaluation.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
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Approved, Date: 23 November 2017
Applicable Section(s)
Description of Change(s)
Synopsis, Objectives, 
Endpoints and 
Hypothesis, Overview 
of Study Design, 
Efficacy Evaluations; 
Time and Events 
Schedule – Extension 
Period; 2.1 Objectives 
and Endpoints; 
3.1 Overview of Study
Design; 3.2 Study 
Design Rationale; 
9.1.3 Open-Label 
Treatment Phase; 
9.2.4. Video 
Ileocolonoscopy; 
11.3.2 Secondary 
Endpoints
Added ileocolonoscopic assessments at Week 104. Indicated that endoscopic endpoints at
Week 104 will be explored.
Synopsis, Overview of 
Study Design; Time 
and Events Schedules, 
footnotes; 
3.1 Overview of Study 
Design; 
9.1.3 Open-Label 
Treatment Phase; 
9.1.4 Posttreatment 
Phase (Follow Up); 
10.1 Completion; 
10.2 Discontinuation 
of Study 
Treatment/Withdrawal 
from the Study; 
16.1 Study-Specific 
Design Considerations
Amended text to indicate a 104-week study duration, and that subjects continuing 
treatment to Week 104 will be considered to have completed the study. Modified reasons 
for discontinuation of study treatment to address discontinuations from Week 48.
3.2 Study Design 
Rationale; References
Added text discussing the rationale for the extension period.
Time and Events 
Schedule - Routine 
Care Arm, footnote w; 
9.2.2 C-reactive 
Protein; 9.2.3 Fecal 
Calprotectin
Added text to indicate that CRP and FC may be used to guide ustekinumab dosing (eg, for 
demonstration of biomarker remission for second de-escalation of dosing frequency) in 
the extension period. Modified Time and Events Schedule footnote to align with this.
9.1.1 Overview
Amended estimated blood volume collected to accommodate assessments up to 
Week 104.
11.1 Subject 
Information; 
11.3.2 Secondary 
Endpoints
Added text regarding the final analysis population and exploratory analyses for subjects 
treated during the extension period.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
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Approved, Date: 23 November 2017
Applicable Section(s)
Description of Change(s)
Rationale: To add that serum collected for PK and immunogenicity analyses, and stool samples collected for FC 
assessments may also be used for other analyses.
9.3 Pharmacokinetics 
and Immunogenicity; 
9.4 Additional 
Biomarkers; 
10.3 Withdrawal From 
the Use of Samples in 
Future Research; 
16.2.4 Privacy of 
Personal Data. 
16.2.5 Long-Term 
Retention of Samples 
for Additional Future 
Research
Modified the text to state that serum collected for PK and immunogenicity analyses may 
also be used for further characterization of immunogenicity or for the evaluation of 
relevant biomarkers. Added Section 9.4 (Additional Biomarkers) and specified that stool 
samples collected for FC assessments may also be used for testing for additional markers. 
Added that exploratory biomarker and immunogenicity research is not conducted under 
standards appropriate for the return of data to subjects. Added Section 16.2.5 to indicate 
that there may be long-term retention of samples for additional future research. Added 
Section 10.3 to indicate that subjects may withdraw consent for long-term retention of 
samples for additional future research.
Rationale: To update the introductory text.
1.1 Background
Updated text regarding the approval status of ustekinumab for Crohn’s disease.
Rationale: Minor editorial corrections were needed.
Throughout the 
protocol
Minor editorial corrections/clarifications were added.


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Amendment 2 (13 September 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To redefine the treatment target for subjects who do not have elevated 
CRP at baseline.
Applicable Section(s)
Description of Change(s)
Rationale: To redefine the treatment target for subjects within the treat to target arm who do not have elevated 
CRP at baseline, to adopt a scientifically more valid treat to target strategy in that subgroup of subjects.
Synopsis, Overview 
of Study Design; 
3.1 Overview of 
Study Design; 
9.1.3 Open-label 
Treatment Phase, 
Treat to Target Arm: 
Weeks 16 to 48
For subjects who do not have elevated CRP at baseline in the presence of active disease, 
the treatment target was redefined to indicate that CRP would not be considered a 
biomarker target.
Rationale: To clarify that potential subjects with either ileal or colonic Crohn’s disease (or both) will be eligible 
for inclusion.
Synopsis, Overview 
of Study Design, 
Subject Population; 
3.1 Overview of 
Study Design; 
4.1 Inclusion Criteria 
Added text to clarify that subjects with ileal and/or colonic disease will be studied.
Rationale: To inform that an ultrasound substudy will be performed at selected centers.
Synopsis, Overview 
of Study Design; 
3.1 Overview of 
Study Design
Added text to indicate that an ultrasound substudy will be performed, which will be 
described in a separate substudy protocol.
Rationale: To clarify that the information used to identify subjects will be in accordance with local regulations.
17.3 Subject 
Identification, 
Enrollment, and 
Screening Logs
Added text to clarify that the information used to identify subjects will be as allowed by 
local regulations.
Rationale: Minor editorial corrections were needed.
Throughout the 
protocol
Minor editorial corrections/clarifications were added.


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Approved, Date: 23 November 2017
Amendment 1 (22 March 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To redefine the treatment target according to more stringent CDAI and 
biomarker criteria as recommended by the study steering committee and considered scientifically more valid in the 
context of a treat to target strategy.
Applicable Section(s)
Description of Change(s)
Rationale: To redefine treatment targets for the treat to target arm.
Synopsis, Overview 
of Study Design;
Time and Events 
Schedule, Treat to 
Target Arm, footnote
pp; 3.1 Overview of 
Study Design;
3.2 Study Design 
Rationale;
9.1.3 Open-label 
Treatment Phase, 
Treat to Target Arm: 
Weeks 16 to 48
For the treat to target arm, the treatment target was redefined to stipulate both CDAI <220 
and ≥70-point improvement in CDAI score from baseline (Week 0), and CRP ≤10 mg/L or 
FC ≤250 µg/g.
Rationale: To correct the timing of the first serum sample for pharmacokinetic and immunogenicity assessments.
Time and Events 
Schedules, 
footnotes y and yy; 
9.3 Pharmacokinetics 
and Immunogenicity
Specified that a sample should be drawn prior to IV infusion at Week 0.
Rationale: To specify body weight measurement to enable CDAI assessment at the time of disease flare in the treat 
to target arm.
Time and Events 
Schedule, Treat to 
Target Arm
Body weight measurement was added at the disease flare visit for the treat to target arm.
Rationale: To specify that a steering committee will provide oversight during the study.
Synopsis, Overview 
of Study Design; 
3.1 Overview of 
Study Design;
11.7 Steering 
committee
Text was added to state that a steering committee will act as an expert advisory group to 
provide consulting oversight during the study.
Rationale: To enable direct reference to the risk/benefit assessment by attaching information from the 
investigational medicinal product dossier (IMPD) to the protocol.
1 Introduction; 
Attachment 11
A sentence referencing the risk/benefit assessment was added to the Introduction and the 
risk/benefit section of the IMPD was added to the Attachments.
Rationale: Minor editorial corrections were needed.
Throughout the 
protocol
Minor editorial corrections/clarifications were added.


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SYNOPSIS
Study of Treat to Target Versus Routine Care Maintenance Strategies in Crohn’s Disease Patients Treated 
with Ustekinumab
Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal antibody to human 
IL-12/23p40 that binds with high affinity to the p40 subunit of human IL-12 and IL-23. Inhibition of 
IL-12 and IL-23 and associated inflammatory pathways via blockade of the shared p40 subunit constitutes 
a novel mechanism of action for the treatment of Crohn’s disease.
A ‘treat to target’ strategy as an optimized management approach has been shown to be successful in 
chronic, immune-mediated inflammatory disorders. The goal of this study of adult Crohn’s disease 
subjects treated with ustekinumab is to demonstrate that a maintenance strategy based on early endoscopy 
followed by regular assessment of biomarkers (fecal calprotectin [FC], C-reactive protein [CRP]) and 
clinical symptoms (Crohn’s disease activity index [CDAI]) with subsequent adjustment of treatment in 
case of persistent inflammatory disease activity (failure to achieve the target) is more successful in 
achieving endoscopic improvement than a pragmatic maintenance strategy driven by the EU SmPC for 
the use of ustekinumab in Crohn’s disease.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
The endpoints listed below will be observed values at all visits assessed and at endpoint (last observation 
carried forward [LOCF]) and changes from baseline for continuous/ordinal variables unless otherwise 
specified.
Objectives
Endpoints
Primary

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) 
approach 
in 
achieving 
endoscopic 
response.

Endoscopic response at Week 48, defined 
as showing (yes or no) a reduction from 
baseline in simple endoscopic score for 
Crohn’s disease
(SES-CD)
of ≥50%.
Randomized subjects who stop treatment 
before reaching Week 48 due to any 
reason, or subjects without endoscopic 
data at Week 48, will be analyzed as 
nonresponders.
Secondary

To examine the robustness of the primary 
endpoint analysis, sensitivity analyses of the 
primary endpoint will be conducted.

Endoscopic response at Week 48, defined 
as showing (yes or no) a reduction from 
baseline in SES-CD score of ≥50%. 
Randomized subjects who stop treatment 
before reaching Week 48 due to reasons 
other than lack/loss of efficacy will be
excluded from the analysis.

Endoscopic 
response 
defined 
as 
a 
reduction from baseline in SES-CD score
of ≥50% at endpoint (LOCF).

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) 
approach 
in 
achieving 
endoscopic 
remission.

Endoscopic remission defined as SES-CD 
score ≤2 at Week 48 and endpoint 
(LOCF).


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Objectives
Endpoints

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving mucosal healing.

Mucosal healing defined as the complete 
absence of mucosal ulcerations in any 
ileocolonic segment at Week 48 and 
endpoint (LOCF).

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving clinical remission.

Clinical remission defined as a CDAI 
score of <150 points.

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving clinical response.

Clinical response defined as a ≥100-point 
reduction from the baseline CDAI score, 
or a CDAI score <150.

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in eliminating the need for 
corticosteroids 
while 
maintaining 
disease 
control.

Corticosteroid-free clinical remission.

Corticosteroid-free endoscopic response 
(endoscopic response defined as a 
reduction from baseline in SES-CD score 
of ≥50%).

To evaluate the effect of a treat to target strategy 
coupled with early endoscopic assessment 
versus a clinically driven (routine care) approach 
on serum CRP and FC levels.

Serum CRP.

FC.

To evaluate the effect of a treat to target strategy 
coupled with early endoscopic assessment 
versus a clinically driven (routine care) approach 
on 
health-related 
quality 
of 
life 
(QoL),
patient-reported 
outcomes 
and 
pharmacoeconomics.

Percentage of subjects with a 16-point 
change from baseline for Inflammatory 
bowel disease questionnaire (IBDQ).

Percentage of subjects with a 7-point 
change 
from 
baseline 
in 
work 
productivity and activity impairment 
(WPAI) scores for each domain.
Changes from baseline for:

IBDQ,

European quality of life 5 dimensions 5 
level (EQ-5D-5L),

Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-F),

Hospital anxiety and depression scale 
(HADS),

WPAI,

Time lost from work.


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Objectives
Endpoints

To describe the safety of two subcutaneous (SC)
ustekinumab 
maintenance 
regimens 
in 
a 
randomized population.

Adverse events.

Clinical laboratory data.

Vital signs.

Physical examination findings.
Exploratory

To explore the effect of a treat to target strategy 
coupled with early endoscopic assessment 
versus a clinically driven (routine care) approach 
on fistula response.
For subjects with fistulas at baseline:

≥50% reduction from baseline in the 
number of draining fistulas at Week 48, 
Week 104, and endpoint (LOCF).

To explore the pharmacokinetics (PK), and 
immunogenicity of ustekinumab therapy

To explore the pharmacodynamics (PD) of 
ustekinumab therapy, correlating the PK with 
clinical outcomes, including CDAI measures, 
changes in CRP and FC, and endoscopic 
outcomes.

Serum ustekinumab concentrations.

Antibodies to ustekinumab.

To explore the benefit of a treat to target strategy 
coupled with early endoscopic assessment 
versus a clinically driven (routine care) approach 
on Crohn's disease-related hospitalizations and 
surgeries.

Crohn’s disease-related hospitalizations.

Crohn’s disease-related surgery.

To explore the effectiveness of maintenance of 
ustekinumab treatment up to Week 104.

Endoscopic response at Week 104 and 
endpoint (LOCF), defined as showing 
(yes or no) a reduction from baseline in 
SES-CD of ≥50%. Randomized subjects 
who
stop treatment before reaching 
Week 104 due to any reason, or subjects 
without endoscopic data at Week 104, 
will be analyzed as nonresponders.

Endoscopic 
response 
at 
Week 104, 
defined as showing (yes or no) a 
reduction from baseline in SES-CD score 
of ≥50%. Randomized subjects who stop 
treatment before reaching Week 104 due 
to reasons other than lack/loss of efficacy 
will be excluded from the analysis.

Endoscopic remission defined as SES-CD 
score ≤2 at Week 104 and endpoint 
(LOCF).

Mucosal healing defined as the complete 
absence of mucosal ulcerations in any 
ileocolonic segment at Week 104 and 
endpoint (LOCF).


STELARA (ustekinumab)
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Objectives
Endpoints

Clinical remission defined as a CDAI 
score of <150 points.

Clinical response defined as a ≥100-point 
reduction from the baseline CDAI score, 
or a CDAI score of <150 points.

Corticosteroid-free clinical remission.

Corticosteroid-free endoscopic response 
(endoscopic response defined as a 
reduction from baseline in SES-CD score 
of ≥50%).

Serum CRP.

FC.

PROs and pharmacoeconomics (IBDQ, 
EQ-5D-5L, FACIT-F, HADS, time lost 
from work, WPAI).

Clinical and biomarker remission (CDAI 
score of <150 points, CRP ≤10 mg/L, and 
FC ≤250 µg/g) at Week 104 and endpoint 
(LOCF).

To explore the effectiveness of de-escalated 
ustekinumab dosing after Week 48.

Durations of corticosteroid-free clinical 
remission and biomarker remission,

Durations of corticosteroid-free clinical 
remission and biomarker remission after 
dose de-escalation,

Duration of de-escalated doses.
Hypothesis
The hypothesis is that a ‘treat to target’ ustekinumab maintenance treatment strategy coupled with early 
endoscopic assessment will result in a higher endoscopic response rate (defined as the percentage of 
subjects achieving ≥50% reduction in SES-CD versus baseline) after 48 weeks of treatment, compared 
with a pragmatic (per EU SmPC) maintenance treatment strategy in subjects with Crohn’s disease. 
This study is designed to show that the percentage of subjects with endoscopic response at Week 48 in the 
treat to target arm is 15% higher compared with the routine care arm. Based on results of the Phase 3 
IM-UNITI study, endoscopic response in the routine care arm is estimated at 30% of subjects. Endoscopic 
response in the treat to target arm is estimated at 45% of subjects.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, parallel-group, multicenter, multinational, Phase 3b interventional study 
of ustekinumab in adult subjects with active, moderate to severe, ileal and/or colonic Crohn’s disease. The 
benefit of a treat to target maintenance treatment strategy versus routine care will be investigated. For the 
treat to target strategy, ustekinumab treatment will be adjusted based on the regular assessment of disease 
activity by objective clinical and biological outcome measures and clinical symptoms. Maintenance 


STELARA (ustekinumab)
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treatment in the routine care arm will be pragmatic, in compliance with the EU SmPC for ustekinumab in 
Crohn’s disease. 
A target of 650 adult male and female subjects with endoscopic evidence of active disease will be 
enrolled. Subjects enrolled will have previously had an inadequate response with, lost response to, been 
intolerant to, or had medical contraindications to either conventional therapy, or one previous biologic 
therapy approved for the treatment of Crohn’s disease in the countries in which the study is conducted. 
Study subjects may be biologic-naïve or biologic-experienced, having received no more than one prior 
biologic approved for the treatment of Crohn’s disease.
During a screening period of up to 5 weeks, eligibility of subjects will be evaluated, and centrally-read 
endoscopic assessments at screening will be used for baseline evaluation. At Week 0, all eligible subjects 
will initiate intravenous (IV) induction treatment with ustekinumab, in line with the EU SmPC, on a 
weight-tiered basis at a dose of approximately 6 mg/kg IV. At Week 8, all subjects will receive a 90 mg 
SC injection of ustekinumab.
At Week 16, subjects who do not achieve a CDAI improvement of ≥70 points versus Week 0 (CDAI-70)
will leave the study. Subjects who remain in the study will be randomized in a 1:1 ratio to either one of 
two arms for open-label maintenance treatment up to Week 48: the treat to target arm or the routine care 
arm. Randomized subjects will be stratified according to whether biologic-naïve at baseline versus prior 
exposure to 1 biologic for the treatment of Crohn’s disease, and according to baseline SES-CD score ≤16
or SES-CD >16.
Routine care arm up to Week 48
In the routine care arm, assessment visits will be scheduled according to the timing of maintenance 
treatment injections, which will be in compliance with the EU SmPC for ustekinumab for the treatment of 
Crohn’s disease, in which dosing every 12 weeks is recommended. At Week 16, (ie, 8 weeks after the 
first SC dose), subjects who have not shown adequate response based on the investigator’s judgment may 
receive a second SC dose at that time. During the routine care maintenance treatment period up to 
Week 48, clinical assessments in case of disease flare will be at the investigator’s discretion. Consistent
with the EU SmPC for ustekinumab, subjects who lose response during 12-weekly dosing may benefit 
from an adjustment to 8-weekly maintenance treatment. Subjects may subsequently be dosed every 8 
weeks or every 12 weeks according to clinical judgment. In contrast, those subjects previously receiving 
8-weekly treatment will not be able to adjust the ustekinumab dose following disease flare and will leave
the study if they would not benefit from continuing study treatment in the investigator’s judgment.
Treat to target arm up to Week 48
In the treat to target arm, initial ustekinumab maintenance treatment assignment will be based on 
centrally-read ileocolonoscopy findings. Subjects with <25% improvement in SES-CD score at Week 16 
versus baseline will be assigned to 8-weekly maintenance treatment. Subjects with ≥25% improvement in 
SES-CD score at Week 16 versus baseline will be assigned to 12-weekly treatment. Subsequently, at 
assessment visits (from Week 24 for subjects assigned to the 8-weekly regimen or from Week 20 for the 
12-weekly group) ustekinumab maintenance treatment up to Week 48 will be directed by treat to target 
assessments.
Among the subgroup of subjects with elevated CRP at baseline (ie, CRP >2.87 mg/L at Week 0), the 
treatment target will be the achievement of:

CDAI <220 and ≥70-point improvement in CDAI score from baseline (Week 0) 
AND

CRP ≤10 mg/L or FC ≤250 µg/g.


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For subjects who do not have elevated CRP at baseline (ie, CRP ≤2.87 mg/L at Week 0) in the presence 
of active disease, CRP would not be considered a biomarker target for dose adjustment, therefore the 
treatment target for these subjects will be the achievement of:

CDAI <220 and ≥70-point improvement in CDAI score from baseline (Week 0) 
AND

FC ≤250 µg/g.
Subjects meeting the treatment target will continue with the same ustekinumab dosing frequency. 
Maintenance dosing frequency will be optimized for subjects failing to meet the treatment targets: those 
subjects previously on 12-weekly regimens will be adjusted to 8-weekly dosing; those previously on 
8-weekly regimens will be adjusted to 4-weekly dosing. Subjects subsequently failing to meet treatment 
targets at the next assessment visit 4 weeks after dosing will not be able to optimize dosing further and 
will leave the study. In case of disease flare between scheduled assessment visits for the treat to target 
arm, subjects will undergo CDAI and biomarker (CRP and FC) assessments. Dosing frequency will be 
adjusted for subjects failing to meet the treatment target.
Extension period: Weeks 48 to 104
From Week 48, subjects will continue ustekinumab treatment in the study extension period, up to 
Week 104. The frequency of dosing will be based on endoscopic and/or clinical remission at Week 48, 
and subsequently on clinical remission and biomarker findings. From Week 48, ustekinumab dose de-
escalation will be implemented for subjects with both endoscopic remission (SES-CD score ≤2) at 
Week 48 and corticosteroid-free clinical remission (CDAI score of <150 points) of ≥16 weeks’ duration. 
Among such subjects, those receiving 8-weekly ustekinumab will adjust to 12-weekly dosing, whereas 
those receiving 4-weekly ustekinumab will adjust to 8-weekly dosing. In the latter case, further dose de-
escalation to 12-weekly ustekinumab will be applied for subjects with corticosteroid-free clinical 
remission (CDAI score of <150 points) and biomarker remission (CRP ≤10 mg/L and FC ≤250 µg/g) at 2 
subsequent, consecutive visits 8 weeks apart. Subjects receiving 12-weekly ustekinumab with endoscopic 
remission at Week 48 will maintain this 12-weekly dosing frequency.
Subjects with either clinical remission or endoscopic remission, but not both, at Week 48 will continue 
with the same dosing frequency. For those with only clinical remission, subsequent dosing de-escalation 
will be dependent on maintenance of corticosteroid-free clinical remission and demonstration of 
biomarker remission at 2 consecutive visits. For subjects with only endoscopic remission, subsequent 
dose de-escalation will be dependent on being in corticosteroid-free clinical remission and demonstrating 
biomarker remission at 2 consecutive visits.
Conversely, subjects with neither corticosteroid-free clinical remission nor endoscopic remission having 
received 12-weekly or 8-weekly ustekinumab up to Week 48 will undergo dose escalation to 8-weekly or 
4-weekly dosing, respectively. After dose escalation, if neither clinical remission nor biomarker remission 
is evident at the next visit, subjects will leave the study. Later in the extension period, only those who 
achieve corticosteroid-free clinical remission of ≥16 weeks’ duration and demonstrate biomarker 
remission over 2 consecutive visits will undergo dose de-escalation. Subjects with neither 
corticosteroid-free clinical remission nor endoscopic remission who have received ustekinumab at 
4-weekly intervals up to Week 48 will not be able to adjust dosing further and will leave the study.
Among the subgroup of subjects with elevated CRP at baseline (ie, CRP >2.87 mg/L at Week 0) disease 
flare during the extension period will be defined as:

CDAI ≥220 and <70-point improvement in CDAI score from baseline (Week 0)
AND


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
CRP >10 mg/L or FC >250 µg/g
Among subjects who do not have elevated CRP at baseline (ie, CRP ≤2.87 mg/L at Week 0) disease flare 
during the extension period will be defined as:

CDAI ≥220 and <70-point improvement in CDAI score from baseline (Week 0) 
AND

FC >250 µg/g.
In case of disease flare at any time during the extension period, dosing will be escalated/re-escalated 
(12-weekly to 8-weekly, or 8-weekly to 4-weekly). Subjects receiving 4-weekly ustekinumab during the 
extension period who experience disease flare will not be able to adjust dosing further and will leave the 
study.
Study visits
All subjects will have study visits at Weeks 0, 8, and 16, at each assessment visit at the times scheduled 
for study drug administration, at Week 48 and Week 104. In cases of disease flare arising between 
scheduled study visits, subjects will also be assessed at the time of disease flare. Ileocolonoscopic 
assessments will be performed at the Week 48 and Week 104 study visits. Subjects discontinuing 
treatment before Week 104 will have an early termination visit at the time of discontinuation, unless 
consent is withdrawn. Early termination assessments should include an ileocolonoscopic assessment.
Subjects will be allowed to enter the study on oral corticosteroids at a prednisone-equivalent dose of 
≤40 mg/day or ≤9 mg/day of budesonide. For subjects receiving corticosteroids who are randomized at 
Week 16 (CDAI-70 responders) corticosteroid tapering is mandatory. A recommended corticosteroid 
tapering schedule is specified in the protocol. Corticosteroid tapering can be initiated from Week 8 in 
subjects already demonstrating response (CDAI-70) to ustekinumab treatment.
For all subjects, final safety follow-up assessments will be performed 16 weeks after the last 
administration of ustekinumab within the study. For subjects completing the 104-week study and moving 
to commercially-available ustekinumab, final safety follow-up assessments should be performed before 
the first dose of commercially-available drug.
The study will be considered completed with the last visit for the last subject participating in the study.
A steering committee will provide consulting oversight during the study, to ensure the scientific validity 
of the clinical study, to identify any scientifically relevant trends, and to provide recommendations to the 
sponsor.
An exploratory substudy to assess changes in ultrasound parameters indicating transmural response to 
treatment with ustekinumab will be performed at selected study centers. Participation in the ultrasound 
substudy will be optional for subjects participating in the main study. The ultrasound substudy will be 
described in a separate substudy protocol.
SUBJECT POPULATION
Subjects enrolled will be male or female, ≥18 years of age, with active, moderate to severe, ileal and/or 
colonic Crohn’s disease, demonstrated by a baseline CDAI score of ≥220 and ≤450, and endoscopic 
evidence of active Crohn’s disease (with a SES-CD score ≥3, excluding the contribution of the narrowing 
component score). The subjects will previously have had an inadequate response with, lost response to, 
have been intolerant to, or have medical contraindications to either conventional therapy, or one previous 
biologic therapy approved for the treatment of Crohn’s disease in the countries in which the study is 
conducted. Study subjects will not have received more than one prior biologic for the treatment of 
Crohn’s disease. Those subjects previously treated with an anti-tumor necrosis factor (TNF) biologic 


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must have discontinued this at least 8 weeks prior to baseline; those treated with vedolizumab must have 
discontinued this at least 12 weeks prior to baseline.
DOSAGE AND ADMINISTRATION
All eligible subjects will receive induction treatment in accordance with the EU SmPC for ustekinumab. 
At Week 0, IV ustekinumab will be administered on a weight-tiered basis at a dose of approximately
6 mg/kg.
At Week 8, all subjects will receive a 90 mg SC injection of ustekinumab. Thereafter, subjects (CDAI-70 
responders) continuing to randomization at Week 16 will receive 90 mg ustekinumab SC at designated 
injection times up to Week 48, enabling 12-weekly or 8-weekly treatment intervals (as per EU SmPC) 
and, in the treat to target arm only, the eventual opportunity to dose adjust to a 4-weekly dosing regimen
(as described above; see Overview of Study Design).
After Week 8, subjects who have been trained how to self-inject may self-administer (in compliance with 
the EU SmPC) SC study drug at the times instructed by the investigator.
During the extension period, subjects will receive ustekinumab at 12-weekly, 8-weekly or 4-weekly 
intervals. The dosing frequency will depend on the previous dosing frequency, Week 48 ileocolonoscopy 
and CDAI findings, and subsequent CDAI and biomarker findings (see Overview of Study Design).
EFFICACY EVALUATIONS
Video ileocolonoscopy will be used to assess SES-CD at the times indicated in the Time and Events 
Schedules. Centrally-read SES-CD scores will be used to evaluate endoscopic response (reduction from 
baseline in SES-CD score ≥50%) and endoscopic remission (SES-CD score ≤2) at Week 48 and 
Week 104 or at early termination of ustekinumab treatment. Additionally, mucosal healing will be 
assessed during ileocolonoscopy to determine the presence or absence of mucosal inflammation and 
ulceration. For subjects with fistulizing disease, fistula closure will also be assessed.
The CDAI will be used to assess disease activity. Serum CRP concentrations will be measured as a 
marker of the degree of inflammation. Stool samples will be collected and analyzed to evaluate changes 
in FC. 
The wellbeing of subjects will be assessed using the IBDQ. Quality of life, fatigue, anxiety and 
depression will be evaluated using the EQ-5D-5L, FACIT-F, and HADS, questionnaires.
PHARMACOKINETIC EVALUATIONS
Serum samples will be analyzed to explore the PK and PD of ustekinumab.
IMMUNOGENICITY EVALUATIONS
Serum samples will be analyzed to detect and characterize anti-ustekinumab antibodies.


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SAFETY EVALUATIONS
Safety evaluations will include the assessment of adverse events, targeted events (including assessment 
for tuberculosis (TB) and other infection), clinical laboratory tests (hematology and serum chemistry), 
vital signs, physical examination, observations for infusion and/or allergic reactions, and concomitant 
medication review. Final safety follow-up assessments will be performed 16 weeks after the last 
administration of ustekinumab within the study (or before the first dose of commercially-available 
ustekinumab after the study, if earlier).
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS
Medical resource utilization data, including Crohn's disease-related hospitalizations and Crohn’s 
disease-related surgeries will be collected in the study. Additionally, time lost from work will be collected 
and the potential impact of ustekinumab on subjects’ work limitations, and daily productivity will be
assessed through the Work Productivity and Activity Impairment Questionnaire (WPAI).
STATISTICAL METHODS
The primary endpoint of this study is endoscopic response at Week 48 of the study. Endoscopic response 
is defined as showing (yes or no) a reduction from baseline in the SES-CD score of ≥50%. This study is 
designed to show that the percentage of subjects with endoscopic response at Week 48 in the treat to 
target arm is 15% higher compared with the routine care arm, which is considered to be a clinically
meaningful difference. Based on the results of the Phase 3 IM-UNITI study, endoscopic response in the 
routine care arm is estimated at 30% of subjects. Endoscopic response in the treat to target arm is 
estimated at 45% of subjects. A Fisher's exact test with a 0.050 two-sided significance level will have 
80% power to detect the difference between the routine care arm proportion of 30% and the treat to target
arm proportion of 45% when the sample size in each group is 174. With an estimated CDAI-70 response 
at Week 16 between 65% and 70% and a dropout rate between 10% and 17.5%, a total of 650 subjects 
should be enrolled.
The number and percentage of responders, and other categorical variables, will be summarized by 
treatment group and compared using the Fisher exact test. Changes from baseline and observed values for 
continuous/ordinal efficacy variables will be summarized descriptively at each assessment time point and 
at the subject’s last efficacy evaluation (endpoint). The change from baseline at each visit and at endpoint 
will be analyzed using the Wilcoxon signed rank test. Between-group comparisons will be analyzed by 
means of the Wilcoxon 2-sample test.
An interim analysis will be performed as soon as all enrolled subjects have completed the first 16 weeks 
of the study or discontinued earlier. Subject characteristics and a selection of efficacy and safety 
endpoints will be included in this interim analysis. Endoscopic outcomes at Week 16 will be analyzed for 
subjects in the treat to target arm. The main analysis will be performed when all randomized subjects have 
completed 48 weeks of study treatment or discontinued earlier. The final analysis will be performed when 
all subjects have completed the last study-related visit including the follow up.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
19
Approved, Date: 23 November 2017
TIME AND EVENTS SCHEDULE -ROUTINE CARE ARM
Period
Screena
Induction
Maintenance (Weeks 16 to 48):
ETe
Safety 
FUf
Week
0
Week 
8
Week
16
Assess
Visitsc
Disease 
Flare
Visitd
Week
48
Study Procedureb
Screening/Administrative
Informed consent (ICF)g
X
Demographics
X
Height
X
Medical history requirements 
X
Inclusion/exclusion criteriah
X
X
Chest radiographi
X
QuantiFERON-TB Gold In-Tube testj
X
Stool studies to evaluate for enteric pathogensk
X
Training on diary card completion
X
Serum pregnancy test
X
Study Drug Administration
Administer IV ustekinumab (induction)l
X
Randomizationm
X
Administer SC ustekinumabn
X
Xo
X
Xo
Dosing frequency decisionp
X
X
Safety Assessments
Detailed physical examination
X
X
X
Weight
X
X
X
X
X
X
X
Vital signsq
X
Xq
X
X
X
X
X
X
12-lead ECG
X
Urine pregnancy testr
X
X
Xo
X
Xo
X
TB evaluations/other infection assessment
X
X
X
X
X
X
X
X
Collect and review diary cards
X
X
X
X
X
X
X
Hematology, chemistryt
X
X
X
X
X
X
Study drug injection-site evaluation
X
X
Xo
X
X
Xo
X
Efficacy Assessments
CDAI assessmentsu
Xv
X
X
X
X
Stool sample (FC)w
X
X
X
X
X
X
C-reactive protein (CRP)w
X
X
X
X
X
X
Video ileocolonoscopyu
X
X
X
Fistula assessment
X
X
X


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
20
Approved, Date: 23 November 2017
Period
Screena
Induction
Maintenance (Weeks 16 to 48):
ETe
Safety 
FUf
Week
0
Week 
8
Week
16
Assess
Visitsc
Disease 
Flare
Visitd
Week
48
Study Procedureb
IBDQ
X
X
X
X
EQ-5D-5L
X
X
X
X
FACIT-F
X
X
X
X
HADS
X
X
X
X
Health Economics
Time lost from work
X
X
X
X
WPAI
X
X
X
X
Pharmacokinetics and Immunogenicity
Serum ustekinumab concentrationx
Xy
X
X
X
X
X
X
Antibodies to ustekinumabx
X
X
X
X
X
X
X
Ongoing Subject Review
Concomitant therapy
X
X
X
Xz
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Crohn’s disease-related hospitalizations 
X
X
X
X
X
X
X
X
Crohn’s disease-related surgeries
X
X
X
X
X
X
X
X
Footnotes: 
a.
The Screening period will be up to 5 weeks. A prior endoscopy may be used only if obtained within 3 months prior to baseline (Week 0), in which case the prior 
endoscopy must be centrally read again and SES-CD calculated based on this second, centralized read-out.
b.
The visit windows will be ±10 days for all visits. At study drug injection/assessment visits, all assessments are to be completed prior to study drug administration, 
unless otherwise specified. It is recommended that patient-reported outcome (PRO) assessments be completed first. 
c.
Assessment visits: the week of each visit will depend on initial maintenance dosing frequency regimen and subsequent dosing adjustments during the study.
d.
Disease flare assessments can be performed at any time between Week 16 and Week 48 in case of clinical worsening reported by the subject, consistent with 
disease flare in the investigator’s judgment. Clinical assessments in case of disease flare will be at the investigator’s discretion. Information on assessments of 
disease flare and on the reasons for dosing frequency changes will be documented in the CRF.
e.
Subjects who discontinue ustekinumab treatment before Week 104 will have Early Termination (ET) assessments as close as possible to the time of 
discontinuation, unless consent is withdrawn. ET assessments should include ileocolonoscopy.
f.
All subjects will have a final safety follow-up visit 16 weeks after the last administration of ustekinumab within the study (or before the first dose of 
commercially-available ustekinumab after the study, if earlier).
g.
Must be signed before first study-related activity.
h.
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation. Check clinical status
again before first dose of study medication.
i.
The screening chest radiograph may have been performed within 3 months before the Week 0 visit. Subjects who experience close contact with an individual with 
active TB during the conduct of the study must have a repeat chest radiograph (see Section 9.1.3).


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
21
Approved, Date: 23 November 2017
j.
To be performed at a central laboratory. In countries in which the QuantiFERON-TB Gold test is not considered approved/registered, a tuberculin skin test is 
additionally required. The QuantiFERON-TB Gold In-Tube test is not required at screening for subjects with a history of latent TB and appropriate treatment as 
described in the Inclusion Criteria (Section 4.1).
k.
Stool studies for enteric pathogens will be performed at the local laboratory and must include a stool culture and Clostridium difficile toxin assay.
l.
Induction treatment at Week 0: ustekinumab IV (weight-based dosing approximately 6 mg/kg) to be administered over a period of not less than 1 hour (see 
Section 6).
m.
Subjects with CDAI-70 at Week 16 will be randomized to either the treat to target arm or the routine care arm. Subjects who do not achieve CDAI-70 at Week 16 
will discontinue from the study.
n.
Ustekinumab SC (90 mg prefilled syringe). After Week 8, subjects who have been trained how to self-inject may self-administer. Information documented in the 
CRF will include date of administration, self-administration (yes/no) and whether administration was complete based on the returned syringe.
o.
Only subjects initially assigned to 8-weekly maintenance treatment will receive ustekinumab at Week 16 (subjects initially assigned to 12-weekly treatment will 
have the next ustekinumab injection at Week 20). Whether dosing is required at or after Week 48 will depend on the previous dosing frequency and Week 48 
ileocolonoscopy and CDAI findings, which will dictate subsequent dosing frequency during the extension period (see Section 3.1). During the maintenance period,
urinary pregnancy testing and injection site evaluation will only be performed at the times scheduled for ustekinumab injection.
p.
From Week 16, subjects’ ustekinumab maintenance treatment will be according to the EU SmPC for ustekinumab. After Week 16, subjects who lose response 
during 12-weekly SC dosing may benefit from an adjustment to 8-weekly maintenance treatment in compliance with the EU SmPC. Subjects may subsequently be 
dosed every 8 weeks or every 12 weeks according to clinical judgment. Subjects on an 8-weekly regimen at the time of disease flare, will not be able to dose adjust 
further and will leave the study if they would not benefit from continuing study treatment in the investigator’s judgment.
q.
Temperature, pulse/heart rate, blood pressure. At Week 0, vital signs assessed prior to infusion, approximately every 30 minutes during infusion, and twice 
(approximately 30-minute intervals) after the completion of infusion.
r.
Must be performed prior to each study drug administration in females of childbearing potential. Additional pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation.
s.
If TB is suspected at any time during the study, a chest radiograph, QuantiFERON-TB Gold In-Tube test, and a tuberculin skin test (in countries in which the 
QuantiFERON-TB Gold test is not considered approved/registered) should be performed (see Section 9.1.3).
t.
Hematocrit to be tested at all visits indicated (for CDAI assessment). Hematology and serum chemistry panels to be tested at screening, Week 0, and Week 48/ET 
(Section 9.6). Hematology and clinical chemistry tests do not need to be repeated at Week 0 if the screening tests were done ≤2 weeks previously.
u.
Ileocolonoscopic examinations and CDAI assessment will be scheduled to avoid an impact on CDAI data. For example, if ileocolonoscopy is performed on the day 
of the visit, the 7 days prior to the initiation of the colonoscopy preparation should be used to calculate the CDAI score for the visit. Ileocolonoscopies will be 
assessed at a central facility.
v.
For calculation of CDAI at Week 0, the hematocrit value obtained during screening will be used. 
w.
Analyzed at a central laboratory. During the maintenance treatment period up to Week 48, centrally-analyzed serum CRP levels and fecal calprotectin (FC) data 
will not be communicated to the investigator. The data will be analyzed at the end of the study. For FC testing, study site personnel will remind subjects of the 
need to provide stool samples.
x.
Analyzed at a central laboratory. Results available at the end of the study.
y.
For IV infusion at Week 0, a sample should be drawn before infusion and approximately 60 minutes after completion of the infusion. At all other study drug
injection/assessment visits blood samples should be collected prior to study drug injection.
z.
For subjects receiving oral corticosteroids who are randomized at Week 16 (CDAI-70 Responders) corticosteroid tapering is mandatory. Corticosteroid tapering 
can be initiated from Week 8 in subjects already demonstrating response to ustekinumab treatment (see recommended tapering schedule in Section 8).


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
22
Approved, Date: 23 November 2017
TIME AND EVENTS SCHEDULE -TREAT TO TARGET ARM
Period
Screen
aa
Induction
Maintenance (Weeks 16 to 48):
ETee
Safety 
FUff
Week
0
Week 
8
Week
16
Assess
Visitscc
Disease 
Flare 
Visitdd
Week
48
Study Procedurebb
Screening/Administrative
Informed consent (ICF)gg
X
Demographics
X
Height
X
Medical history requirements 
X
Inclusion/exclusion criteriahh
X
X
Chest radiographii
X
QuantiFERON-TB Gold In-Tube testjj
X
Stool studies to evaluate for enteric pathogenskk
X
Training on diary card completion
X
Serum pregnancy test
X
Study Drug Administration
Administer IV ustekinumab (induction)ll
X
Randomizationmm
X
Administer SC ustekinumabnn
X
Xoo
X
Xoo
Dosing frequency decisionpp
X
X
X
Safety Assessments
Detailed physical examination
X
X
X
Weight
X
X
X
X
X
X
X
X
Vital signsqq
X
Xqq
X
X
X
X
X
X
12-lead ECG
X
Urine pregnancy testrr
X
X
Xoo
X
Xoo
X
TB evaluationss/other infection assessment
X
X
X
X
X
X
X
X
Collect and review diary cards
X
X
X
X
X
X
X
Hematology, chemistrytt
X
X
X
X
X
X
X
X
Study drug injection-site evaluation
X
X
Xoo
X
X
Xoo
X
Efficacy Assessments
CDAI assessmentsuu
Xvv
X
X
X
X
X
X
Stool sample (FC)ww
X
X
X
X
X
X
X
C-reactive protein (CRP)ww
X
X
X
X
X
X
X
Video ileocolonoscopyuu
X
X
X
X
Fistula assessment
X
X
X


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
23
Approved, Date: 23 November 2017
Period
Screen
aa
Induction
Maintenance (Weeks 16 to 48):
ETee
Safety 
FUff
Week
0
Week 
8
Week
16
Assess
Visitscc
Disease 
Flare 
Visitdd
Week
48
Study Procedurebb
IBDQ
X
X
X
X
EQ-5D-5L
X
X
X
X
FACIT-F
X
X
X
X
HADS
X
X
X
X
Health Economics
Time lost from work
X
X
X
X
WPAI
X
X
X
X
Pharmacokinetics and Immunogenicity
Serum ustekinumab concentrationxx
Xyy
X
X
X
X
X
X
Antibodies to ustekinumabxx
X
X
X
X
X
X
X
Ongoing Subject Review
Concomitant therapy
X
X
X
Xzz
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Crohn’s disease-related hospitalizations 
X
X
X
X
X
X
X
X
Crohn’s disease-related surgeries
X
X
X
X
X
X
X
X
Footnotes: 
aa.
The Screening period will be up to 5 weeks. A prior endoscopy may be used only if obtained within 3 months prior to baseline (Week 0), in which case the prior 
endoscopy must be centrally read again and SES-CD calculated based on this second, centralized read-out.
bb.
The visit windows will be ±10 days for all visits. At study drug injection/assessment visits, all assessments are to be completed prior to study drug administration, 
unless otherwise specified. It is recommended that patient-reported outcome (PRO) assessments be completed first.
cc.
Assessment visits: the week of the visit will depend on initial maintenance dosing frequency regimen and subsequent treat to target dosing adjustments during the 
study.
dd.
For subjects with evidence of disease flare between dosing visits, CDAI, CRP, and FC will be assessed at the time of disease flare.
ee.
Subjects who discontinue from the study before Week 104 will have Early Termination (ET) assessments as close as possible to the time of discontinuation, unless 
consent is withdrawn. ET assessments should include ileocolonoscopy.
ff.
All subjects will have a final safety follow-up visit 16 weeks after the last administration of ustekinumab within the study (or before the first dose of 
commercially-available ustekinumab after the study, if earlier).
gg.
Must be signed before first study-related activity.
hh.
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation. Check clinical status
again before first dose of study medication.
ii.
The screening chest radiograph may have been performed within 3 months before the Week 0 visit. Subjects who experience close contact with an individual with 
active TB during the conduct of the study must have a repeat chest radiograph (see Section 9.1.3).


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
24
Approved, Date: 23 November 2017
jj.
To be performed at a central laboratory. In countries in which the QuantiFERON-TB Gold test is not considered approved/registered, a tuberculin skin test is 
additionally required. The QuantiFERON-TB Gold In-Tube test is not required at screening for subjects with a history of latent TB and appropriate treatment as 
described in the Inclusion Criteria (Section 4.1)
kk.
Stool studies for enteric pathogens will be performed at local laboratory and must include a stool culture and Clostridium difficile toxin assay.
ll.
Induction treatment at Week 0: ustekinumab IV (weight-based dosing approximately 6 mg/kg) to be administered over a period of not less than 1 hour (see 
Section 6).
mm. Subjects with CDAI-70 at Week 16 will be randomized to either the treat to target arm or the routine care arm. Subjects who do not achieve CDAI-70 at Week 16 
will discontinue from the study.
nn.
Ustekinumab SC (90 mg prefilled syringe). After Week 8, subjects who have been trained how to self-inject may self-administer. Information documented in the 
CRF will include date of administration, self-administration (yes/no) and whether administration was complete based on the returned syringe.
oo.
Only subjects initially assigned to 8-weekly maintenance treatment will receive ustekinumab at Week 16 (subjects initially assigned to 12-weekly treatment will 
have the next ustekinumab injection at Week 20). Whether dosing is required at or after Week 48 will depend on the previous dosing frequency and Week 48 
ileocolonoscopy and CDAI findings, which will dictate subsequent dosing frequency during the extension period (see Section 3.1). During the maintenance period,
urinary pregnancy testing and injection site evaluation will only be performed at the times scheduled for ustekinumab injection.
pp.
Initial dosing frequency assignment will be based on SES-CD at Week 16. From Week 20 (12-weekly dosing), or Week 24 (8-weekly dosing) onwards, the 
decision whether to continue on the same dosing frequency or to adjust the dosing frequency (eg, to increase to 8-weekly or 4-weekly dosing) will be based on 
treat to target assessments (CDAI, and CRP or FC assessed at the assessment visit). For subjects with evidence of disease flare between dosing visits, CDAI, CRP, 
and FC will be assessed prior to dosing adjustment decisions. 
qq.
Temperature, pulse/heart rate, blood pressure. At Week 0, vital signs obtained prior to infusion, approximately every 30 minutes during infusion, and twice 
(approximately 30-minute intervals) after the completion of infusion.
rr.
Must be performed prior to each study drug administration in females of childbearing potential. Additional pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation.
ss.
If TB is suspected at any time during the study, a chest radiograph, QuantiFERON-TB Gold In-Tube test, and a tuberculin skin test (in countries in which the 
QuantiFERON-TB Gold test is not considered approved/registered) should be performed (see Section 9.1.3).
tt.
Hematocrit to be tested at all visits indicated (for CDAI assessment). Hematology and serum chemistry panels to be tested at screening, Week 0 and Week 48/ET 
(Section 9.6). Hematology and clinical chemistry tests do not need to be repeated at Week 0 if the screening tests were done ≤2 weeks previously.
uu.
Ileocolonoscopic examinations and CDAI assessment will be scheduled to avoid an impact on CDAI data. For example, if ileocolonoscopy is performed on the day 
of the visit, the 7 days prior to the initiation of the colonoscopy preparation should be used to calculate the CDAI score for the visit. Ileocolonoscopies will be 
assessed at a central facility.
vv.
For calculation of CDAI at Week 0, the hematocrit value obtained during screening will be used.
ww. Analyzed at a central laboratory. For FC testing, study site personnel will remind subjects of the need to provide stool samples.
xx.
Analyzed at a central laboratory. Results available at the end of the study.
yy.
For IV infusion at Week 0, a sample should be drawn before infusion and approximately 60 minutes after completion of the infusion. At all other study drug 
injection/assessment visits blood samples should be collected prior to study drug injection.
zz.
For subjects receiving oral corticosteroids who are randomized at Week 16 (CDAI-70 Responders) corticosteroid tapering is mandatory. Corticosteroid tapering 
can be initiated from Week 8 in subjects already demonstrating response to ustekinumab treatment (see recommended tapering schedule in Section 8).


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
25
Approved, Date: 23 November 2017
TIME AND EVENTS SCHEDULE -EXTENSION PERIOD
Extension Period (Weeks 48 to 104)
ETddd
Safety FUeee
Assess Visitsbbb
Disease Flare 
Visitccc
Week
104
Study Procedureaaa
Study Drug Administration
Administer SC ustekinumabfff
X
Dosing frequency decisionggg
X
X
Safety Assessments
Detailed physical examination
X
X
Weight
X
X
X
X
Vital signshhh
X
X
X
X
Urine pregnancy testiii
X
X
TB evaluationjjj/other infection assessment
X
X
X
X
X
Collect and review diary cards
X
X
X
X
Hematology, chemistrykkk
X
X
X
X
Study drug injection-site evaluation
X
X
X
Efficacy Assessments
CDAI assessmentslll
X
X
X
X
Stool sample (FC)mmm
X
X
X
X
C-reactive protein (CRP)mmm
X
X
X
X
Video ileocolonoscopylll
X
X
Fistula assessment
X
X
IBDQ
Xnnn
X
X
EQ-5D-5L
Xnnn
X
X
FACIT-F
Xnnn
X
X
HADS
Xnnn
X
X
Health Economics
Time lost from work
Xnnn
X
X
WPAI
Xnnn
X
X
Pharmacokinetics and Immunogenicity
Serum ustekinumab concentrationooo
X
X
X
X
Antibodies to ustekinumabooo
X
X
X
X
Ongoing Subject Review
Concomitant therapy
X
X
X
X
X
Adverse events
X
X
X
X
X
Crohn’s disease-related hospitalizations 
X
X
X
X
X
Crohn’s disease-related surgeries
X
X
X
X
X


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
26
Approved, Date: 23 November 2017
Footnotes: 
aaa. The visit windows will be ±10 days for all visits. At study drug injection/assessment visits, all assessments are to be completed prior to study drug administration, 
unless otherwise specified. It is recommended that patient-reported outcome (PRO) assessments be completed first.
bbb. Assessment visits: the week of the visit will depend on initial maintenance dosing frequency regimen and subsequent treat to target dosing adjustments during the 
study. During the extension period, the dosing/visit frequency will depend on the previous dosing frequency, Week 48 ileocolonoscopy and CDAI findings, and 
subsequent CDAI and biomarker findings (see Section 3.1).
ccc. For subjects with evidence of disease flare between dosing visits, CDAI, CRP, and FC will be assessed at the time of disease flare.
ddd. Subjects who discontinue from the study before Week 104, or who discontinue ustekinumab treatment before the end of the study will have Early Termination 
(ET) assessments as close as possible to the time of discontinuation, unless consent is withdrawn. ET assessments should include ileocolonoscopy.
eee. All subjects will have a final safety follow-up visit 16 weeks after the last administration of ustekinumab within the study (or before the first dose of 
commercially-available ustekinumab after the study, if earlier).
fff.
Ustekinumab SC (90 mg prefilled syringe). Subjects who have been trained how to self-inject may self-administer. Information documented in the CRF will 
include date of administration, self-administration (yes/no) and whether administration was complete based on the returned syringe.
ggg. From Week 48, the frequency of dosing will depend on the previous dosing frequency, Week 48 ileocolonoscopy and CDAI findings, and subsequent CDAI and 
biomarker findings (see Section 3.1).
hhh. Temperature, pulse/heart rate, blood pressure. 
iii.
Must be performed prior to each study drug administration in females of childbearing potential. Additional pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation.
jjj.
If TB is suspected at any time during the study, a chest radiograph, QuantiFERON-TB Gold In-Tube test, and a tuberculin skin test (in countries in which the 
QuantiFERON-TB Gold test is not considered approved/registered) should be performed (see Section 9.1.3).
kkk. Hematocrit to be tested at all visits indicated (for CDAI assessment). Hematology and serum chemistry panels to be tested at Weeks 48/104/ET (Section 9.6). 
lll.
Ileocolonoscopic examinations and CDAI assessment will be scheduled to avoid an impact on CDAI data. For example, if ileocolonoscopy is performed on the day 
of the visit, the 7 days prior to the initiation of the colonoscopy preparation should be used to calculate the CDAI score for the visit. Ileocolonoscopies will be 
assessed at a central facility.
mmm.
Analyzed at a central laboratory. For FC testing, study site personnel will remind subjects of the need to provide stool samples.
nnn. During the extension period, PRO assessments will be performed at Week 80 and Week 104 only.
ooo. Blood samples should be collected prior to study drug injection. Analyzed at a central laboratory. Results available at the end of the study.


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
27
Approved, Date: 23 November 2017
ABBREVIATIONS
5-ASA
5-aminosalicylic acid
AZA
azathioprine
BCG
Bacille Calmette-Guérin
CDAI
Crohn’s Disease Activity Index
CDAI-70
≥70-point improvement versus baseline in Crohn’s Disease Activity Index
CI
confidence interval
CRF
case report form(s)
CRP
C-reactive protein
ECCO
European Crohn’s and Colitis Organisation
ECG
electrocardiogram
eDC
electronic data capture
EMA
European Medicines Agency
EQ-5D-5L
EuroQoL-5D Health Questionnaire (European quality of life-5 dimensions) 5 level
EU
European Union
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FC
fecal calprotectin
GCP
Good Clinical Practice
HADS
Hospital Anxiety and Depression Scale
HIV
human immunodeficiency virus
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL-
interleukin-
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
IWRS
interactive web response system
LOCF
last observation carried forward
6-MP
6-mercaptopurine
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent to treat
m2ITT
Modified intent to treat population who enter the extension phase
MTX
methotrexate
PD
pharmacodynamic(s)
PFS
prefilled syringe
PK
pharmacokinetic(s)
PQC
product quality complaint
PRO
patient-reported outcome(s)
QoL
quality of life
SC
subcutaneous
SES-CD
simple endoscopic score for Crohn’s disease
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
Th
T helper
TNF
tumor necrosis factor
WPAI
Work Productivity and Activity Impairment


STELARA (ustekinumab)
Clinical Protocol CNTO1275CRD3005 Amendment 3
28
Approved, Date: 23 November 2017
DEFINITIONS OF TERMS
Biologic treatments:
Biological treatments including tumor necrosis factor (TNF) antagonists or 
vedolizumab.
Biologic-naïve
With no prior treatment with a biologic approved for the treatment of Crohn’s disease in 
the countries in which the study is conducted.
EU SmPC:
The European Union (EU) Summary of Product Characteristics [SmPC]
for 
ustekinumab for the treatment of Crohn’s disease, which at the time of protocol writing
has received positive opinion from the Committee for Medicinal Products for Human 
Use (CHMP) at the European Medicines Agency (EMA).
Routine care:
For the purposes of this protocol, ‘routine care’ refers to a pragmatic ustekinumab 
maintenance treatment strategy in subjects with Crohn’s disease, in compliance with the 
EU SmPC for ustekinumab.
Treat to target:
Following initial treatment assignment based on early endoscopy, the treat to target 
ustekinumab maintenance strategy for this study will involve regular assessment of 
disease activity (CDAI and biomarkers) with subsequent adjustment of treatment in case 
of persistent inflammatory disease activity.


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1.
INTRODUCTION
Ustekinumab is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal antibody to 
human IL-12/23p40 that binds with high affinity to the p40 subunit of human IL-12 and IL-23. 
By inhibiting interaction with the cell surface IL-12Rβ1 receptor protein, ustekinumab 
effectively neutralizes 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 Crohn’s disease. 
There is a significant medical need for new safe and effective therapies for moderate to severe, 
active Crohn’s disease. Inhibition of IL-12 and IL-23 and associated inflammatory pathways 
constitutes a novel mechanism of action for the treatment of Crohn’s disease. The therapeutic 
potential of this approach is evident from nonclinical and clinical data, including the findings of 
recent Phase 3, double-blind, placebo-controlled studies.
For the most comprehensive nonclinical and clinical information regarding the efficacy and
safety of ustekinumab, refer to the latest version of the Investigator's Brochure for ustekinumab.8
A risk/benefit assessment for this study is provided in Section 2 of the Investigational Medicinal 
Product Dossier (Attachment 11).
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
Ustekinumab (STELARA®) has been approved by the European Medicines Agency (EMA) and 
the United States Food and Drug Administration for the treatment of moderate to severe plaque 
psoriasis in adults or adolescent patients, and for the treatment of active psoriatic arthritis. More 
recently, ustekinumab has been approved for the treatment of adult patients with moderately to 
severely active Crohn’s disease who have had an inadequate response with, lost response to, 
were intolerant to, or have medical contraindications to either: conventional therapy, or TNFα 
antagonist therapy.
Clinical Studies
Efficacy/Safety Studies
The efficacy and safety of ustekinumab for subjects with moderate to severely active Crohn’s 
disease was demonstrated in 3 Phase 3, randomized, double-blind, placebo-controlled, parallel 
group studies. Two studies (UNITI-1 and UNITI-2) evaluated response up to Week 8 after 
intravenous (IV) induction of ustekinumab (130 mg or approximately 6 mg/kg by tiered, 
weight-based dosing). The UNITI-1 study evaluated subjects with prior failure or intolerance to 
at least 1 TNF antagonist, whereas the UNITI-2 study evaluated subjects who had failed 
conventional therapy. In both studies, a significantly greater proportion of subjects were in 
clinical response and remission in the ustekinumab treatment group, compared with the placebo 
group. The number of ustekinumab-treated subjects with a 70-point reduction from baseline in 


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Crohn’s Disease Activity Index [CDAI] was significant compared with the placebo group as 
early as Week 3 and continued to improve through Week 8.8
In the IM-UNITI Phase 3 study, ustekinumab maintenance therapy up to Week 44 was evaluated 
in subjects who had participated in the UNITI-1 or UNITI-2 induction studies. Subjects who had 
a clinical response to induction therapy were randomized to subcutaneous (SC) treatment with 
either ustekinumab 90 mg every 12 weeks (n=129), or ustekinumab 90 mg every 8 weeks
(n=128), or placebo (n=131). For both 12-weekly and 8-weekly maintenance dosing regimens, 
statistically significant maintenance of clinical remission (CDAI score <150 points) and clinical 
response (defined as reduction from Week 0 of the induction study in CDAI of ≥100 points) was 
demonstrated at Week 44 compared with placebo. Subjects who did not maintain response to 
ustekinumab when treated every 12 weeks were allowed to increase the frequency of dosing to 
every 8 weeks. In these cases, clinical remission was achieved in 41% of subjects 16 weeks after 
dosing frequency adjustment. 5
Nonresponders to ustekinumab induction treatment received ustekinumab 90 mg SC at Week 0 
of the IM-UNITI study. If clinical response was achieved after 8 weeks, ustekinumab treatment 
was continued at 8-weekly intervals to Week 40. More than half of the nonresponders to 
induction treatment attained response 8 weeks after an additional SC dose of ustekinumab; a 
substantial number of these subjects (68%) were in clinical response and were in clinical 
remission (50%) at Week 44 after continuing to receive ustekinumab 90 mg SC every 8 weeks.
Subcutaneous (SC) ustekinumab at doses of 90 mg every 8 weeks or every 12 weeks up to 
Week 44 was well tolerated during the IM-UNITI study, with a safety profile generally
comparable with placebo. The proportions of subjects with adverse events were comparable 
across treatment groups with no evidence of a dose effect. Serious adverse events reported in 
more than 1 ustekinumab-treated subject were predominantly events of Crohn’s disease, or 
related symptoms and complications. In addition, the proportions of subjects who discontinued 
due to adverse events were comparable across treatment groups with no evidence of a dose 
effect.
No events of anaphylaxis or other serious infusion reactions were reported during ustekinumab 
IV induction studies in subjects with Crohn’s disease. Additionally, <3% of subjects treated with
ustekinumab developed antibodies to ustekinumab. No apparent association between the
development of antibodies to ustekinumab and the development of injection site reactions was
observed. Subjects positive for antibodies to ustekinumab tended to have lower efficacy,
however, antibody positivity did not preclude a clinical response. The majority of subjects who
were positive for antibodies to ustekinumab had neutralizing antibodies.8
1.2.
Overall Rationale for the Study
Inflammatory bowel diseases (IBD) are chronic, progressive, and disabling conditions. Most 
current strategies, which target control of symptoms, do not appear to significantly alter the 
natural course of the disease. Recent studies in Crohn’s disease underscore the need to look 
beyond symptoms and to treat endoscopic/macroscopic lesions, ultimately with the aim of 
preventing structural damage and disability. Due to the invasive nature and/or cost of


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endoscopies or cross-sectional imaging, frequent repetition of these procedures is not feasible; 
therefore, surrogate biomarkers of inflammation, including C-reactive protein (CRP) and fecal 
calprotectin (FC) have been increasingly studied in IBD.6,20,21
A ‘treat to target’ strategy has been advocated as an optimized management approach for various 
diseases, by which strictly defined treatment targets facilitate decision making in clinical 
practice. Key to the success of this treatment strategy is the definition of appropriate treatment 
targets and adoption of algorithms that drive therapeutic changes within distinct time frames.
This approach has been shown to be successful in chronic, immune-mediated inflammatory 
disorders such as rheumatoid arthritis and psoriatic arthritis. Recently, the value of such an 
approach in patients’ management has been suggested for IBD.2,16
The goal of this study of adult Crohn’s disease subjects treated with ustekinumab is to 
demonstrate that a maintenance strategy based on early endoscopy followed by regular 
assessment of biomarkers (FC and CRP) and clinical symptoms (CDAI) with subsequent 
adjustment of treatment in case of persistent inflammatory disease activity (failure to achieve the 
target) is more successful in achieving endoscopic improvement than a pragmatic maintenance 
strategy based on guidance provided in the EU SmPC for the use of ustekinumab in Crohn’s 
disease.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
The endpoints listed below will be observed values at all visits assessed and at endpoint (last 
observation carried forward [LOCF]) and changes from baseline for continuous/ordinal variables 
unless otherwise specified.
Objectives
Endpoints
Primary

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving endoscopic response.

Endoscopic response at Week 48, 
defined as showing (yes or no) a 
reduction from baseline in simple 
endoscopic score for Crohn’s disease
(SES-CD)
of 
≥50%. 
Randomized 
subjects who
stop treatment before 
reaching Week 48 due to any reason, or 
subjects without endoscopic data at 
Week 
48 
will 
be 
analyzed 
as 
nonresponders.


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Objectives
Endpoints
Secondary

To examine the robustness of the primary 
endpoint analysis, sensitivity analyses of the 
primary endpoint will be conducted.

Endoscopic response at Week 48, 
defined as showing (yes or no) a 
reduction from baseline in SES-CD 
score of ≥50%. Randomized subjects 
who stop treatment before reaching 
Week 48 due to reasons other than 
lack/loss of efficacy will be excluded 
from the analysis.

Endoscopic response defined as a 
reduction from baseline in SES-CD 
score of ≥50% at endpoint (LOCF).

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) 
approach 
in 
achieving 
endoscopic 
remission.

Endoscopic remission defined as a SES-
CD score ≤2 at Week 48 and endpoint 
(LOCF).

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving mucosal healing.

Mucosal healing defined as the complete 
absence of mucosal ulcerations in any 
ileocolonic segment at Week 48 and 
endpoint (LOCF).

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving clinical remission.

Clinical remission defined as a CDAI 
score of <150 points.

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in achieving clinical response.

Clinical 
response 
defined 
as 
a 
≥100-point reduction from the baseline 
CDAI score, or a CDAI score <150.

To evaluate the efficacy of a treat to target 
strategy 
coupled 
with 
early 
endoscopic 
assessment versus a clinically driven (routine 
care) approach in eliminating the need for 
corticosteroids while maintaining disease control.

Corticosteroid-free clinical remission.

Corticosteroid-free endoscopic response 
(endoscopic response defined as a 
reduction from baseline in SES-CD 
score of ≥50%).

To evaluate the effect of a treat to target strategy 
coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach on 
serum CRP and FC levels.

Serum CRP.

FC.


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Objectives
Endpoints

To evaluate the effect of a treat to target strategy 
coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach on 
health-related quality of life (QoL), patient-
reported 
outcomes 
(PROs)
and 
pharmacoeconomics.

Percentage of subjects with a 16-point 
change from baseline for Inflammatory 
bowel disease questionnaire (IBDQ).

Percentage of subjects with a 7-point 
change 
from 
baseline 
in 
work 
productivity and activity impairment 
(WPAI) scores for each domain.
Changes from baseline for:

IBDQ,

European quality of life 5 dimensions 5 
level (EQ-5D-5L),

Functional 
Assessment 
of 
Chronic 
Illness Therapy-Fatigue (FACIT-F),

Hospital anxiety and depression scale 
(HADS),

WPAI,

Time lost from work.

To describe the safety of two SC ustekinumab 
maintenance 
regimens 
in 
a 
randomized 
population.

Adverse events.

Clinical laboratory data.

Vital signs.

Physical examination findings.
Exploratory

To explore the effect of a treat to target strategy 
coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach on 
fistula response.
For subjects with fistulas at baseline:

≥50% reduction from baseline in the 
number of draining fistulas at Week 48, 
Week 104, and endpoint (LOCF).

To explore
the pharmacokinetics (PK), and 
immunogenicity of ustekinumab therapy.

To explore the pharmacodynamics (PD) of 
ustekinumab therapy, correlating the PK with 
clinical outcomes, including CDAI measures, 
changes in CRP and FC, and endoscopic 
outcomes.

Serum ustekinumab concentrations.

Antibodies to ustekinumab.

To explore the benefit of a treat to target strategy 
coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach on 
Crohn's 
disease-related 
hospitalizations 
and 
surgeries.

Crohn’s disease-related hospitalizations.

Crohn’s disease-related surgery.


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Objectives
Endpoints

To explore the effectiveness of maintenance of 
ustekinumab treatment up to Week 104.

Endoscopic response at Week 104 and 
endpoint (LOCF), defined as showing 
(yes or no) a reduction from baseline in 
SES-CD of ≥50%. Randomized subjects 
who
stop treatment before reaching 
Week 104 due to any reason, or subjects 
without endoscopic data at Week 104, 
will be analyzed as nonresponders.

Endoscopic 
response 
at 
Week 104, 
defined as showing (yes or no) a 
reduction from baseline in SES-CD 
score of ≥50%. Randomized subjects 
who
stop treatment before reaching 
Week 104 due to reasons other than 
lack/loss of efficacy will be excluded 
from the analysis.

Endoscopic remission defined as SES-
CD score ≤2 at Week 104 and endpoint 
(LOCF).

Mucosal healing defined as the complete 
absence of mucosal ulcerations in any 
ileocolonic segment at Week 104 and 
endpoint (LOCF).

Clinical remission defined as a CDAI 
score of <150 points.

Clinical response defined as a 
≥100-point reduction from the baseline 
CDAI score, or a CDAI score of
<150 points.

Corticosteroid-free clinical remission.

Corticosteroid-free endoscopic response 
(endoscopic response defined as a 
reduction from baseline in SES-CD 
score of ≥50%).

Serum CRP.

FC.

PROs and pharmacoeconomics (IBDQ, 
EQ-5D-5L, FACIT-F, HADS, time lost 
from work, WPAI).

Clinical and biomarker remission (CDAI 
score of <150 points, CRP ≤10 mg/L, 
and FC ≤250 µg/g) at Week 104 and 
endpoint (LOCF).


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Objectives
Endpoints

To explore the effectiveness of de-escalated 
ustekinumab dosing after Week 48.

Durations of corticosteroid-free clinical 
remission and biomarker remission,

Durations of corticosteroid-free clinical 
remission and biomarker remission after 
dose de-escalation,

Duration of de-escalated doses.
Refer to Section 9 (Study Evaluations) for evaluations related to endpoints.
2.2.
Hypothesis
Initial treatment assignment for the treat to target ustekinumab maintenance treatment strategy
will be based on early endoscopy, followed by regular assessment of disease activity (CDAI, FC,
and CRP) with subsequent adjustment of treatment in case of persistent inflammatory disease 
activity. The routine care maintenance treatment strategy will be based on the guidance on 
posology in the EU SmPC.
The hypothesis is that a ‘treat to target’ ustekinumab maintenance treatment strategy coupled 
with early endoscopic assessment will result in a higher endoscopic response rate (defined as the 
percentage of subjects achieving ≥50% reduction in SES-CD versus baseline) after 48 weeks of 
treatment, compared with a pragmatic (per EU SmPC) maintenance treatment strategy in 
subjects with Crohn’s disease.
This study is designed to show that the percentage of subjects with endoscopic response at 
Week 48 in the treat to target arm is 15% higher compared with the routine care arm. Based on 
the results of the Phase 3 IM-UNITI study, endoscopic response in the routine care arm is 
estimated at 30% of subjects. Endoscopic response in the treat to target arm is estimated at 45% 
of subjects.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized,
open-label, parallel-group, multicenter, multinational, Phase 3b
interventional study of ustekinumab in adult subjects with active, moderate to severe, ileal and/or 
colonic Crohn’s disease. The benefit of a treat to target maintenance treatment strategy versus 
routine care will be investigated. For the treat to target strategy, ustekinumab treatment will be 
adjusted based on the regular assessment of disease activity by objective clinical and biological 
outcome measures and clinical symptoms. Routine care will be pragmatic, in accordance with
the EU SmPC for ustekinumab in Crohn’s disease.
A target of 650 adult male and female subjects with endoscopic evidence of active disease will 
be enrolled. Subjects enrolled will have previously had an inadequate response with, lost 
response to, been intolerant to, or had medical contraindications to either conventional therapy, 
or one previous biologic therapy approved for the treatment of Crohn’s disease in the countries 


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in which the study is conducted. Study subjects may be biologic-naïve or biologic-experienced, 
having received no more than one prior biologic for the treatment of Crohn’s disease. 
During a screening period of up to 5 weeks, eligibility of subjects will be evaluated, and 
centrally-read endoscopic assessments at screening will be used for baseline evaluation. At 
Week 0, all eligible subjects will initiate IV induction treatment with ustekinumab, in line with 
the EU SmPC, on a weight-tiered basis at a dose of approximately 6 mg/kg IV (see Section 6). 
At Week 8, all subjects will receive a 90 mg SC injection of ustekinumab.
At Week 16, subjects who do not achieve a CDAI improvement of ≥70 points versus Week 0 
(CDAI-70) will leave the study. Subjects who remain in the study will be randomized in a 1:1 
ratio to either one of two arms for open-label maintenance treatment up to Week 48: the treat to 
target arm or the routine care arm. Randomized subjects will be stratified according to whether 
biologic-naïve at baseline versus prior exposure to 1 biologic for treatment of Crohn’s disease, 
and according to baseline SES-CD score ≤16 or SES-CD >16.
Routine care arm up to Week 48
In the routine care arm, assessment visits will be scheduled according to the timing of 
maintenance treatment injections, which will be in compliance with the EU SmPC for
ustekinumab for the treatment of Crohn’s disease, in which dosing every 12 weeks is 
recommended. At Week 16, (ie, 8 weeks after the first SC dose) subjects continuing in the study 
will have demonstrated a CDAI-70 response. Nonetheless, subjects who have not shown 
adequate response based on the investigator’s judgment may receive a second SC dose at 
Week 16.
Blood and stool samples will be taken at each assessment visit for central analysis but the results 
of CRP and FC assessments during the maintenance period up to Week 48 will not be 
communicated to the investigator. Overall analysis of CRP and FC data will be performed at the 
end of the study. 
During the routine care maintenance treatment period up to Week 48, in case of clinical 
worsening reported by the subject, consistent with disease flare in the investigator’s judgment, 
clinical assessments of disease flare will be performed at the investigator’s discretion. In 
accordance with the EU SmPC for ustekinumab, subjects who lose response during 12-weekly 
dosing may benefit from an adjustment to 8-weekly maintenance treatment. Subjects may 
subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment.
Information on assessments of disease flare and on the reasons for dosing frequency changes will 
be documented in the case report form (CRF). In contrast, subjects already receiving 8-weekly 
treatment will not be able to adjust the ustekinumab dose following disease flare and will leave 
the study if they would not benefit from continuing study treatment in the investigator’s 
judgment.


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Treat to target arm up to Week 48
In the treat to target arm, initial ustekinumab maintenance treatment assignment will be based on 
centrally-read ileocolonoscopy (performed at Week 16 in this arm only). Subjects with <25% 
improvement in SES-CD score at Week 16 versus baseline will be assigned to 8-weekly 
maintenance treatment and will receive ustekinumab 90 mg SC at Week 16. Only subjects 
assigned to 8-weekly treatment will receive ustekinumab at Week 16. In contrast, subjects with 
≥25% improvement in SES-CD score at Week 16 versus baseline will be assigned to 12-weekly 
treatment and will receive the next ustekinumab maintenance dose (90 mg SC) at Week 20.
Subsequently, at assessment visits (from Week 24 for subjects assigned to the 8-weekly regimen 
or from Week 20 for the 12-weekly group) ustekinumab maintenance treatment up to Week 48 
will be directed by treat to target assessments. Among the subgroup of subjects with elevated 
CRP at baseline (ie, CRP >2.87 mg/L at Week 0), the treatment target will be the achievement 
of:

CDAI <220 and ≥70-point improvement in CDAI score from baseline (Week 0)
AND

CRP ≤10 mg/L or FC ≤250 µg/g
For subjects who do not have elevated CRP at baseline (ie, CRP ≤2.87 mg/L at Week 0) in the 
presence of active disease, CRP would not be considered a biomarker target for dose adjustment, 
therefore the treatment target for these subjects will be the achievement of:

CDAI <220 and ≥70-point improvement in CDAI score from baseline (Week 0) 
AND

FC ≤250 µg/g.
Subjects meeting the treatment target will continue with the same ustekinumab dosing frequency. 
However, maintenance dosing frequency will be optimized for all subjects failing to meet the 
treatment target at the assessment visit. Those subjects previously on 12-weekly regimens will be 
adjusted to 8-weekly dosing; those previously on 8-weekly regimens will be adjusted to 
4-weekly dosing. Among those, subjects subsequently failing to meet the treatment target at the 
next assessment visit 4 weeks after dosing will not be able to adjust dosing further and will leave 
the study.
In case of disease flare between scheduled assessment visits, subjects will undergo CDAI and 
biomarker (CRP and FC) assessments at the time of disease flare. Dosing frequency will be 
adjusted as described above for subjects failing to meet the treatment target.
Extension period: dosing adjustments from Week 48
From Week 48, subjects will continue ustekinumab treatment in the study extension period, up to 
Week 104. The frequency of dosing will be based on endoscopic and/or clinical remission at 
Week 48, and subsequently on clinical remission and biomarker findings as summarized below 
in Table 1. 


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From Week 48, ustekinumab dose de-escalation will be implemented for subjects with both 
endoscopic remission (SES-CD score ≤2) at Week 48 and corticosteroid-free clinical remission 
(CDAI score of <150 points) of at least 16 weeks’ duration. Among such subjects, those 
receiving 8-weekly ustekinumab will adjust to 12-weekly dosing, whereas those receiving 
4-weekly ustekinumab will adjust to 8-weekly dosing. In the latter case, further dose de-
escalation to 12-weekly ustekinumab dosing will be applied for subjects with corticosteroid-free 
clinical remission (CDAI score of <150 points) and biomarker remission (CRP ≤10 mg/L and FC 
≤250 µg/g) at 2 subsequent, consecutive visits 8 weeks apart. Subjects receiving 12-weekly 
ustekinumab with endoscopic remission at Week 48 will maintain this 12-weekly dosing 
frequency.
Subjects with either clinical remission or endoscopic remission, but not both, at Week 48 will 
continue with the same dosing frequency. For those with only clinical remission, subsequent 
dosing de-escalation will be dependent on maintenance of corticosteroid-free clinical remission 
and demonstration of biomarker remission at 2 consecutive visits. For subjects with only 
endoscopic remission, subsequent dose de-escalation will
be dependent on being in
corticosteroid-free clinical remission and demonstrating biomarker remission at 2 consecutive 
visits (Table 1).
Conversely, subjects with neither corticosteroid-free clinical remission nor endoscopic remission 
having received 12-weekly or 8-weekly ustekinumab up to Week 48 will undergo dose 
escalation to 8-weekly or 4-weekly dosing, respectively. After dose escalation, if neither clinical 
remission nor biomarker remission is evident at the next visit, subjects will leave the study. Later 
in the extension period, only those who achieve corticosteroid-free clinical remission of 
≥16 weeks’ duration and demonstrate biomarker remission over 2 consecutive visits will 
undergo dose de-escalation (Table 1). Subjects with neither corticosteroid-free clinical remission 
nor endoscopic remission who have received ustekinumab at 4-weekly intervals up to Week 48 
will not be able to adjust dosing further and will leave the study.


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Table 1:
Extension Period Ustekinumab Dosing From Week 48
Clinical remission 
(CDAI score of <150 
points) at Week 48
Endoscopic remission 
(SES-CD score ≤2) at 
Week 48
Ustekinumab Dosing Strategy
Yes
Yes
From Week 48, for subjects with corticosteroid-free clinical 
remission of ≥16 weeks’ duration, dosing will be de-escalated
from 4-weekly to 8-weekly, or from 8-weekly to 12-weekly 
dosing (subjects on a 12-weekly regimen at Week 48 will 
continue with this frequency).
For subjects de-escalated to 8-weekly dosing and subsequently 
maintaining corticosteroid-free clinical remission, and 
demonstrating biomarker remission* over 2 consecutive visits, 
there will be a second de-escalation to 12-weekly dosing.
No
Yes
At Week 48, subjects will continue with the same dosing 
frequency. After Week 48, for corticosteroid-free subjects in 
clinical remission and demonstrating biomarker remission* over 
2 consecutive visits, dosing will be de-escalated from 4-weekly 
to 8-weekly, or from 8-weekly to 12-weekly dosing (subjects on 
a 12-weekly regimen will continue with this frequency).
Yes
No
At Week 48, subjects will continue with the same dosing 
frequency. After Week 48, for subjects maintaining 
corticosteroid-free clinical remission for ≥16 weeks and 
demonstrating biomarker remission* over 2 consecutive visits, 
dosing will be de-escalated from 4-weekly to 8-weekly, or from 
8-weekly to 12-weekly dosing (subjects on a 12-weekly 
regimen will continue with this frequency).
No
No
From Week 48, dosing will be escalated, from 12-weekly to 
8-weekly, or from 8-weekly to 4-weekly dosing. Subjects on a 
4-weekly regimen will not be able to dose adjust further and 
will leave the study. 
After dose escalation, if neither clinical remission nor 
biomarker remission is evident at the next visit, subjects will 
leave the study.
For subjects continuing in the extension period who 
subsequently achieve corticosteroid-free clinical remission of 
≥16 weeks’ duration and demonstrate biomarker remission* 
over 2 consecutive visits, dosing will be de-escalated (eg, from 
4-weekly to 8-weekly, or from 8-weekly to 12-weekly dosing).
*Biomarker remission: CRP ≤10 mg/L and FC ≤250 µg/g at 2 consecutive visits.
Extension period: dosing in case of disease flare


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In case of disease flare at any time during the extension period,
dosing will be 
escalated/re-escalated (12-weekly to 8-weekly, or 8-weekly to 4-weekly). Among the subgroup 
of subjects with elevated CRP at baseline (ie, CRP >2.87 mg/L at Week 0), disease flare during 
the extension period will be defined as:

CDAI ≥220 and <70-point improvement in CDAI score from baseline (Week 0)
AND

CRP >10 mg/L or FC >250 µg/g
Among subjects who do not have elevated CRP at baseline (ie, CRP ≤2.87 mg/L at Week 0) 
disease flare during the extension period will be defined as:

CDAI ≥220 and <70-point improvement in CDAI score from baseline (Week 0) 
AND

FC >250 µg/g.
For those subjects escalated to 8-weekly dosing, further escalation to 4-weekly dosing will be 
implemented in case of persistent or recurring disease flare. Subjects receiving 4-weekly 
ustekinumab during the extension period who experience disease flare will not be able to adjust 
dosing further and will leave the study.
Study visits
All subjects will be evaluated at Weeks 0, 8, and 16, at each assessment visit at the times 
scheduled for study drug administration, and at Week 48 and Week 104. In cases of disease flare 
arising between scheduled study visits, subjects will also be assessed at the time of disease flare. 
Assessments of CDAI, CRP, and FC will be performed throughout the study at the times 
indicated in the Time and Events Schedules for each study arm and for the extension period. For 
subjects with fistulizing disease, fistula closure will also be assessed.
Blood samples for PK and immunogenicity assessments will be collected at Weeks 0, 8, and 16, 
at all assessment visits, and at Week 48, Week 104, or early termination. Patient-reported 
outcomes will include assessments of QoL and pharmacoeconomics at Weeks 0, 16, 48, 80 and 
104, or upon early termination. Adverse event data and information on concomitant therapies 
will be collected throughout the study.
Ileocolonoscopic assessment will be performed at the Week 48 study visit for subjects in both
arms, and at Week 104. A subject discontinuing treatment before Week 104 will have an early 
termination visit at the time of discontinuation, unless the subject withdraws consent. Early 
termination assessments should include an ileocolonoscopic assessment.
For subjects receiving corticosteroids, randomized at Week 16 (CDAI-70 responders) 
corticosteroid tapering is mandatory from Week 16. Corticosteroid tapering can be initiated from 


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Week 8 in subjects already demonstrating response (CDAI-70) to ustekinumab treatment (see 
recommended tapering schedule in Section 8).
For all subjects, final safety follow-up assessments will be performed 16 weeks after the last 
administration of ustekinumab within the study. For subjects completing the 104-week study and 
moving to commercially-available ustekinumab, final safety follow-up assessments should be 
performed before the first dose of commercially-available drug. For detailed information on the 
timing of safety and efficacy assessments throughout the study refer to the Time and Events 
Schedule for each study arm.
An interim analysis of efficacy and safety data will be performed when all subjects have 
completed the first 16 weeks of the study or discontinued earlier (Section 11.6).
A steering committee will provide consulting oversight during the study, to ensure the scientific 
validity of the clinical study, to identify any scientifically relevant trends, and to provide 
recommendations to the sponsor (Section 11.7).
A diagram of the study design is provided below in Figure 1. A diagram of the potential 
ustekinumab maintenance dosing frequency adjustments between Weeks 16 and 48 for the treat 
to target arm is shown in Figure 2.
Figure 1:
Schematic Overview of the Study Design
EXTENSION
PERIOD
TO WEEK 104
Week
0
IV 
INDUCTION PERIOD
Week
8
SC 
CDAI-70 
non-responders: 
leave the study
Week 16
assessments
Maintenance
Routine care 
arm
MAINTENANCE 
TREATMENT PERIOD
WEEK 16 TO WEEK 48
CDAI-70 
responders: 
randomized 
at Week 16
Maintenance
Treat to 
target arm
Week 48 to 
Week 104 
Extension 
Period


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Figure 2:
Ustekinumab Maintenance Dosing in the Treat to Target Arm (Week 16 to Week 48)
SES-CD ≥25%: Subjects with ≥25% improvement in SES-CD at Week 16 versus baseline
SES-CD <25%: Subjects with <25% improvement in SES-CD at Week 16 versus baseline
12-weekly ustekinumab maintenance dosing
8-weekly ustekinumab maintenance dosing
4-weekly ustekinumab maintenance dosing
T2T: Y
Subjects meeting treatment targets
T2T: N
Subjects failing to meet treatment targets at assessment visit [or evaluated between scheduled 
assessment visits in case of disease flare]
*
Subjects meeting treatment targets following adjustment to 4-weekly dosing will continue on
4-weekly dosing. Subjects failing to meet treatment targets at the next assessment visit 4 weeks 
after dosing will leave the study.


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An exploratory substudy to assess changes in ultrasound parameters indicating transmural 
response to treatment with ustekinumab will be performed at selected study centers. Participation 
in the ultrasound substudy will be optional for subjects participating in the main study. The 
ultrasound substudy will be described in a separate substudy protocol.
3.2.
Study Design Rationale
Randomization
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups.
Study Population 
Subjects enrolled in this study may be biologic-naïve or biologic-experienced, having received 
no more than one prior biologic approved for the treatment of Crohn’s disease in the countries in 
which the study is conducted. It is anticipated that approximately one third of the subjects 
enrolled will be biologic naïve. The UNITI-1 and UNITI-2 studies demonstrated the efficacy and 
safety of ustekinumab induction treatment in subjects with Crohn’s disease who were 
respectively either previous anti-TNFα therapy failures, or conventional therapy failures (either 
anti-TNFα naïve [68.6%] or had previously received but not failed anti-TNFα therapy [31.4%]). 
Following this, the IM-UNITI study demonstrated similar maintenance treatment effects 
regardless of prior treatment history (ie, both in conventional therapy failures, including those
naïve to prior TNF antagonists, and also in TNF antagonist-refractory subjects).5 To ensure 
balanced distribution between treatment arms in the present study, randomized subjects will be 
stratified according to whether biologic naïve at baseline versus prior exposure to 1 biologic for 
the treatment of Crohn’s disease. 
With the aim of balancing the distribution of baseline disease severity between treatment arms, 
randomized subjects will also be stratified according to baseline SES-CD. For the purposes of 
this study, SES-CD >16 will define subjects with severe Crohn’s disease.11 Thus, stratification 
will be according to baseline SES-CD score ≤16 or SES-CD >16.
Primary Endpoint
In line with the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)
consensus, an objective assessment of disease activity, endoscopic response, will be used for the 
primary endpoint of this study.16 An objective assessment is also considered an appropriate 
approach for an open-label study. The SES-CD is a standard, validated measure of endoscopic 
disease activity, which is simple and reproducible.7
Randomization at Week 16
At Week 16, CDAI-70 will be used to distinguish responding subjects who will be randomized 
into the maintenance treatment period. The CDAI has been widely used in clinical trials and 
CDAI-70 is an accepted measure of clinical response.16 Subjects will be selected on the basis of 


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response at Week 16 since this is considered an adequate treatment interval to demonstrate 
response to induction treatment. The IM-UNITI study demonstrated that more than half of the 
nonresponders to an IV induction dose subsequently responded 8 weeks after an additional SC 
dose of ustekinumab.8
Target Assessments in the Treat to Target Maintenance arm
For the treat to target arm, both clinical assessments (CDAI) and measures of inflammation will 
guide ustekinumab maintenance treatment. Although inducing and maintaining clinical remission 
of symptoms is an important therapeutic goal in Crohn’s disease, management based on 
symptoms alone may be insufficient to reduce or prevent long-term bowel damage. Even 
asymptomatic patients may have endoscopic evidence of active bowel inflammation. Due to the 
inconsistent correlation between symptoms and mucosal disease activity, symptom-based 
treatment might lead to suboptimal therapy in a substantial proportion of patients. Inadequate 
control of inflammation may result in structural bowel damage, with a resultant need for surgery 
in many patients. Therefore, objective measures of bowel inflammation should also be 
considered. For this reason, early ileocolonoscopic assessment at Week 16 has been incorporated 
into the treat to target strategy for this study to direct initial maintenance dosing frequency.
Biomarkers such as CRP and FC are objective measures of inflammation, which are less invasive
and more cost-effective than ileocolonoscopy, and can be repeated often within a predefined 
timeframe. Elevated CRP and FC concentrations correlate well with endoscopic and histologic 
evidence of inflammation, and normalization of concentrations has been associated with positive 
treatment outcomes.2,1,13,22 Therefore, for the treat to target arm, biomarkers (CRP or FC) will be 
used as target assessments, monitored regularly and used to guide ustekinumab maintenance 
treatment.
Other Endpoints
The endoscopic and clinical outcomes evaluated as secondary endpoints for this study are 
accepted measures of response in Crohn’s disease. Endoscopic endpoints will include mucosal 
healing, defined as the complete absence of mucosal ulcerations in any ileocolonic segment, 
which is associated with better outcomes in clinical trials.16
A further goal of maintenance therapy for subjects with Crohn’s disease is the ability to reduce 
or eliminate corticosteroid use. To assess the efficacy of ustekinumab in eliminating the need for 
corticosteroids while maintaining disease control, corticosteroid-free clinical remission, and 
corticosteroid-free endoscopic response will be evaluated at Week 48 and Week 104. To enable
evaluation, subjects receiving corticosteroids with a CDAI-70 response at Week 16 will undergo 
mandatory steroid tapering. Tapering of corticosteroids was undertaken in the IM-UNITI study, 
which demonstrated greater proportions of ustekinumab subjects in remission and corticosteroid 
free compared with the placebo group after 44 weeks of maintenance treatment. It is also 
consistent with clinical practice for patients on effective treatment.
Reliable assessment of symptoms, QoL, mood, and fatigue from a patient’s perspective is of 
recognized value, and PROs evaluating these elements are included in this study. During the 


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IM-UNITI study, clinically-meaningful improvements in health-related QoL (including IBDQ) 
were maintained over 44 weeks in ustekinumab-treated subjects.
It is of interest to determine whether ustekinumab serum levels correlate with endoscopic 
outcomes, CDAI measures, and changes in CRP or FC. Therefore, exploratory analyses of PK, 
immunogenicity and PD will be performed.
Medical Resource Utilization and Health Economics Data Collection
Medical resource utilization data including Crohn’s disease-related hospitalizations and Crohn’s 
disease-related surgeries will be collected from Week 0 to the safety follow-up visit to enable
evaluation of the health economics of ustekinumab treatment. Additionally, the impact of 
ustekinumab treatment on work productivity will be assessed using the WPAI and time lost from 
work.
Dosing
Consistent with the EU SmPC for ustekinumab in Crohn’s disease, all subjects will receive tiered, 
weight-based IV induction dosing, which was demonstrated to be well tolerated and effective in 
the UNITI-1 and UNITI-2 induction studies. Subsequently, subjects randomized to the routine 
care arm will receive an ustekinumab maintenance dosing regimen consistent with the EU SmPC, 
based on either 12-weekly or 8-weekly 90 mg SC dosing, the positive benefit/risk profile of 
which was demonstrated by the 44-week IM-UNITI study.
Maintenance treatment in the treat to target arm will also involve initial assignment to 12-weekly 
or 8-weekly 90 mg SC treatment, which in this arm will be based on endoscopic results at 
Week 16. However, within the treat to target approach, there is the potential for more intensive 
management, with optimization to 4-weekly dosing for subjects failing to meet treatment targets 
following 8-weekly dosing. Real-world experience of more intensive maintenance dosing 
regimens than those assessed in the IM-UNITI study has been reported for Crohn’s disease 
patients.10,23 Additionally, ustekinumab 90 mg SC every 4 weeks was reported to be well 
tolerated in a Phase 2 study of subjects with multiple sclerosis.19
Study Period
The initial study treatment period is 48 weeks, of which 32 weeks will be the randomized 
maintenance treatment period. Subjects receiving study treatment up to Week 48 will receive 
between 3 and 7 maintenance treatment doses of study drug, depending on the treatment arm and 
adjustments to dosing frequency. Based on the findings of the IM-UNITI study, this treatment 
period is considered sufficient to evaluate the efficacy of ustekinumab maintenance treatment 
strategies.
Extension Period
Following Week 48 assessments, study treatment will be extended up to Week 104. This will 
identify subjects with sustained remission during longer-term maintenance of ustekinumab 
treatment. Furthermore, there is a lack of data on the impact of continuing treatment in subjects 
with clinical remission but not endoscopic remission, who may have persistent moderate lesions. 


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Previously, endoscopic evaluation of patients with sustained remission following azathioprine 
treatment revealed persistent lesions in a significant proportion.12 The extension period of the 
present study may provide valuable information on continuation of ustekinumab treatment in 
subjects with persisting lesions.
Extension of ustekinumab treatment to Week 104 will also enable examination of the 
effectiveness of de-escalated dosing. There is interest in de-escalation strategies for biological 
treatment of patients with IBD, an approach that has been proposed for patients in deep 
remission.14 For this study, ustekinumab dosing frequency will be de-escalated from Week 48 in 
subjects with endoscopic remission and corticosteroid-free clinical remission of at least 
16-weeks’ duration, ie
demonstrating
stable clinical remission. Additionally, subjects 
de-escalated from 4-weekly to 8-weekly dosing will undergo a second de-escalation to 
12-weekly ustekinumab if clinical and biomarker remission at 2 consecutive visits is confirmed, 
which will avoid serial, repeat endoscopies. 
After Week 48, dose de-escalation will be possible for subjects with sustained corticosteroid-free
clinical remission in the absence of Week 48 endoscopic remission, only if biomarker remission 
indicates the absence of active inflammation at 2 consecutive visits. De-escalation of dosing will 
also be implemented after Week 48 in subjects with endoscopic remission but not clinical 
remission, if they are corticosteroid-free
and demonstrate biomarker remission over 
2 consecutive visits. Provision for this type of subject has been made because a previous study
identified a subset of Crohn’s disease patients with persistent symptoms (CDAI >150) but no 
endoscopic lesions following treatment.15
A final ileocolonoscopy at Week 104 will allow assessment of endoscopic response, remission 
and mucosal healing after extended treatment, both for subjects maintaining the same dose 
frequency, or needing escalated doses, and for those for whom dose de-escalation is 
implemented.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 5 weeks before administration of the 
study drug.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female ≥18 years of age


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2.
Criterion modified per Amendment 2
2.1
Have active, moderate to severe, ileal and/or colonic Crohn’s disease, demonstrated by:

Baseline CDAI score of ≥220 and ≤450.
and

Endoscopy with evidence of active Crohn’s disease (defined as SES-CD score 
≥3 excluding the contribution of the narrowing component score) obtained 
within the 5-week screening period. A prior endoscopy may be used only if 
obtained within 3 months prior to baseline (Week 0), in which case the prior 
endoscopy must be centrally read again and SES-CD calculated based on this 
second, centralized read-out.
3.
Has had an inadequate response with, lost response to, was intolerant to, or had medical 
contraindications to either:

conventional therapy, or 

one previous biologic therapy approved for the treatment of Crohn’s disease in the 
countries in which the study is conducted.
4.
Adhere to the following requirements for concomitant medication for the treatment of 
Crohn’s disease. The following medications are permitted provided doses meeting the 
requirements below are stable for or have been discontinued at least 3 weeks prior to 
baseline (Week 0), unless otherwise specified:
a. Oral 5-aminosalicylic acid (5-ASA) compounds.
b. Oral corticosteroids (eg, prednisone, budesonide) at a prednisone-equivalent dose of 
≤40 mg/day or ≤9 mg/day of budesonide.
c. Antibiotics being used as a primary treatment of Crohn’s disease.
d. Subjects receiving conventional immunomodulators (ie, azathioprine [AZA], 
6-mercaptopurine [6-MP], or methotrexate [MTX]) must have been taking them for 
≥12 weeks, and on a stable dose for a least 4 weeks prior to baseline.


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5.
Are eligible according to tuberculosis (TB) infection screening criteria:
a. Have no history of latent or active TB prior to screening. Exceptions are made for
subjects currently receiving treatment for latent TB, if there is no evidence of active TB, 
or who have a history of latent TB and documentation of having completed adequate 
treatment for latent TB within 3 years prior to the first administration of study drug. It is 
the responsibility of the investigator to verify the adequacy of previous TB treatment 
and provide appropriate documentation.
Note: The exceptions outlined above exclude subjects in countries with high multi-drug 
resistant TB burden (eg, South Africa, Bulgaria, and the Russian Federation), due to 
potential concerns for multidrug resistant TB.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or 
physical examination.
c. Have had no recent close contact with a person with active TB or, if there has been 
such contact, will be referred to a physician specializing in TB to undergo additional
evaluation and, if warranted, receive appropriate treatment for latent TB before the first 
administration of study drug.
d. Within 2 months prior to the first administration of study drug, either have a negative
QuantiFERON-TB Gold test (Attachment 1), or have a newly identified positive
QuantiFERON-TB Gold test in which active TB has been ruled out, and for which
appropriate treatment for latent TB has been initiated before the first administration of 
study drug (except in countries with high multidrug resistant TB burden [eg, South 
Africa, Bulgaria, and the Russian Federation], where subjects with a newly identified 
positive QuantiFERON-TB Gold test result are excluded). Indeterminate results should 
be handled as outlined in Section 9.1.2. A negative tuberculin skin test (see 
Attachment 2), 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 
before the first administration of study drug, is additionally required if the
QuantiFERON-TB gold test is not approved/registered in that country or the tuberculin 
skin test is mandated by local health authorities. The QuantiFERON-TB Gold In-Tube 
test or the tuberculin skin test are not required at screening for subjects with a history of 
latent TB and appropriate treatment as described above.
e. Have a chest radiograph (at least a posterior-anterior view), taken within 3 months 
prior to the first administration of study drug and read by a qualified radiologist, with no
evidence of current active TB or old inactive TB.
6.
Must sign an informed consent form (ICF) (or their legally acceptable representative if 
applicable must sign) indicating that he or she understands the purpose of, and 
procedures required for, the study and is willing to participate in the study.


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7.
A woman 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 Week 0.
8.
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies.
Before randomization, a woman must be either:
a.
Not of childbearing potential defined as: 
o
Premenarchal
o
Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL) in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy, however in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.
o
Permanently sterile
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy.
b.
Of childbearing potential and
o
practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly) 
Examples of highly effective contraceptives include
- user-independent methods:
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the subject.)
- user-dependent methods:
combined (estrogen- and progestogen-containing ) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, and transdermal; progestogen-only hormone 
contraception associated with inhibition of ovulation: oral and 
injectable
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies.


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Hormonal contraception may be susceptible to interaction with the study 
drug, which may reduce the efficacy of the contraceptive method.
o
agrees to remain on a highly effective method throughout the study and for
at least 15 weeks after the last dose of study drug.
Note: If the childbearing potential changes after the start of the study or the risk of 
pregnancy changes (eg, a woman who is not heterosexually active becomes active,) a 
woman must begin a highly effective method of contraception, as described throughout 
the inclusion criteria.
9.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 15 weeks after the last study drug administration.
10.
During the study and for 15 weeks after receiving the last dose of study drug, in addition 
to a highly effective method of contraception, a man 

who is sexually active with a woman of childbearing potential must agree to use a 
barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository)

must agree not to donate sperm.
11.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Has complications of Crohn’s disease such as symptomatic strictures or stenoses, short 
gut syndrome, or any other manifestation that might be anticipated to require surgery, 
could preclude the use of the CDAI to assess response to therapy, or would possibly 
confound the ability to assess the effect of treatment with 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 prior to 
baseline, or 8 weeks prior to baseline for intra-abdominal abscesses, provided there is no 
anticipated need for any further surgery. Subjects with active fistulas may be included if 
there is no anticipation of a need for surgery and there are currently no abscesses 
identified.
3.
Has had any kind of bowel resection within 6 months prior to baseline.
4.
Has a draining (ie, functioning) stoma or ostomy.


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5.
Has received more than one previous biologic therapy approved for the treatment of 
Crohn’s disease in the countries in which the study is conducted.
6.
Has previously received a biologic agent targeting IL-12 and/or IL-23, including but not 
limited to ustekinumab (CNTO 1275).
7.
Has received any of the following prescribed medications or therapies within the 
specified period:
a. IV corticosteroids <3 weeks prior to baseline.
b. Other oral immunomodulatory agents (eg, 6-thioguanine [6-TG], cyclosporine,
tacrolimus, sirolimus, or mycophenolate mofetil) <6 weeks prior to baseline.
c. Non-autologous stem cell therapy or biologic agents that deplete B or T cells
<12 months prior to baseline.
d. Vedolizumab <12 weeks prior to baseline.
e. Anti-TNF biologic agents or other agents intended to suppress or eliminate TNF 
<8 weeks prior to baseline.
f. Any investigational drug within 4 weeks before first administration of study drug or 
within 5 half-lives of the investigational drug, whichever is longer.
g. Treatment with apheresis or total parenteral nutrition (TPN) as a treatment for 
Crohn’s disease <3 weeks prior to baseline.
8.
Has received a Bacille Calmette-Guérin (BCG) vaccination within 12 months or any 
other live bacterial or live viral vaccination within 12 weeks of baseline.
9.
Have a stool culture or other examination positive for an enteric pathogen, including 
Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative 
and there are no signs of ongoing infection with that pathogen.
10.
Has a history of, or ongoing, chronic or recurrent infectious disease, including but not 
limited to, chronic renal infection, chronic chest infection, recurrent urinary tract 
infection (eg, recurrent pyelonephritis or chronic nonremitting cystitis), or open, 
draining, or infected skin wounds or ulcers.
11.
Has current signs or symptoms of infection. Established nonserious infections (eg, acute 
upper respiratory tract infection, simple urinary tract infection) need not be considered 
exclusionary at the discretion of the investigator.
12.
Has a history of serious infection (eg, sepsis, pneumonia, or pyelonephritis), including 
any infection requiring hospitalization or IV antibiotics, for 8 weeks prior to baseline.


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13.
Has evidence of a herpes zoster infection ≤8 weeks prior to baseline.
14.
Has a history of latent or active granulomatous infection, including histoplasmosis or 
coccidioidomycosis, prior to screening. Refer to inclusion criteria for information 
regarding eligibility with a history of latent TB.
15.
Has evidence of current active infection, including TB, or a nodule suspicious for lung 
malignancy on screening or any other available chest radiograph, unless definitively 
resolved surgically or by additional imaging and with source document confirmation.
16.
Has or ever has had a nontuberculous mycobacterial infection or serious opportunistic
infection (eg, cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
17.
Is known to be infected with HIV, hepatitis B, or hepatitis C.
18.
Has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms 
thereof.
19.
Has a transplanted organ (with exception of a corneal transplant >12 weeks prior to 
screening).
20.
Has a known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy 
and/or splenomegaly.
21.
Has any known malignancy or has a history of malignancy (with the exception of basal 
cell carcinoma; squamous cell carcinoma in situ of the skin; or cervical carcinoma in 
situ that has been treated with no evidence of recurrence; or squamous cell carcinoma of 
the skin that has been treated with no evidence of recurrence within 5 years prior to 
screening).
22.
Has previously undergone allergy immunotherapy (administration of an antigen) for 
prevention of anaphylactic reactions.
23.
Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients, or 
an allergy to latex (refer to Investigator's Brochure).8
24.
is a woman who is pregnant, or breast-feeding, or planning to become pregnant while 
enrolled in this study or within 15 weeks after the last dose of study drug
25.
is a man who plans to father a child while enrolled in this study or within 15 weeks after 
the last dose of study drug.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 


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that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 8 PRESTUDY AND CONCOMITANT THERAPY for details 
regarding prohibited and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Subjects must agree not to receive a live virus or live bacterial vaccination, including a 
BCG vaccination, during the study or for 15 weeks after receiving study drug.
4.
Subjects must not receive ustekinumab outside the protocol or participate in any other
clinical study with an investigational agent while in this study, and must terminate study
participation if they do. If they intend to receive ustekinumab or participate in any other
clinical study with an investigational agent, this should be preceded by an early 
termination visit.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Up to Week 16, all enrolled subjects will receive ustekinumab induction therapy. At Week 16,
subjects achieving CDAI improvement of ≥70 points versus baseline (Week 0), will be 
randomized in a 1:1 ratio to one of two ustekinumab maintenance treatment arms: the treat to 
target arm or the routine care arm.
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
one of two treatment groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be balanced 
by using randomly permuted blocks and will be stratified by whether the subject was 
biologic-naïve at baseline/had prior exposure to 1 biologic for treatment of Crohn’s disease, and 
according to baseline SES-CD score ≤16 or SES-CD >16. The interactive web response system 
(IWRS) will assign a unique treatment code, which will dictate the treatment assignment and 
matching study drug kit for the subject. The requestor must use his or her own user identification 
and personal identification number when contacting the IWRS, and will then give the relevant 
subject details to uniquely identify the subject.


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Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
All eligible subjects will receive induction treatment in accordance with the EU SmPC for 
ustekinumab. At Week 0, IV ustekinumab will be administered on a weight-tiered basis at a dose 
of approximately 6 mg/kg. Subjects with body weight ≤55 kg at Week 0 will receive 260 mg IV 
ustekinumab. Those subjects with body weight >55 kg and ≤85 kg will receive 390 mg IV 
ustekinumab. Subjects with body weight >85 kg at Week 0 will receive 520 mg IV ustekinumab.
For IV administration, the study drug will be administered to each subject over a period of not 
less than 1 hour. The infusion should be completed within 5 hours of preparation. 
At Week 8, all subjects will receive a 90 mg SC injection of ustekinumab. Subsequently, subjects 
continuing to randomization at Week 16 (CDAI-70 responders) will receive 90 mg ustekinumab 
SC at designated injection times, enabling 12-weekly, 8-weekly or 4-weekly treatment intervals 
depending on the study arm and response (see Section 3.1).
After Week 8, subjects who have been trained how to self-inject may self-administer (in 
compliance with the EU SmPC) SC study drug at the times instructed by the investigator. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol. For each administration of study drug, the date of injection will be 
recorded in the CRF, whether study drug was self-administered, and if so, whether SC 
administration was complete (based on the returned syringe). Detailed instructions on the 
administration of study drug are provided in the Site Investigational Product Procedures Manual.
Routine care arm up to Week 48
In the routine care arm, the timing of maintenance injections up to Week 48 will be in 
compliance with the EU SmPC for ustekinumab for the treatment of Crohn’s disease, in which 
dosing every 12 weeks is recommended. At Week 16, (ie, 8 weeks after the first SC dose), 
subjects who have not shown adequate response based on the investigator’s judgment may 
receive a second SC dose at that time. During the routine care maintenance treatment period, 
clinical assessments in case of disease flare will be at the investigator’s discretion. Consistent 
with the EU SmPC for ustekinumab, subjects who lose response during 12-weekly dosing may 
benefit from an adjustment to 8-weekly maintenance treatment. Subjects may subsequently be 
dosed every 8 weeks or every 12 weeks according to clinical judgment. Information on 
assessments of disease flare and on the reasons for dosing frequency changes will be documented 
in the CRF. Those subjects previously receiving 8-weekly treatment will not be able to adjust the 
ustekinumab dose following disease flare and will leave the study if they would not benefit from 
continuing study treatment in the investigator’s judgment.
Treat to target arm up to Week 48
In the treat to target arm, initial ustekinumab maintenance treatment assignment will be based on 
centrally-read endoscopy findings. Subjects with <25% improvement in SES-CD score at 


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Week 16 versus baseline will be assigned to 8-weekly maintenance treatment and will receive 
the next ustekinumab 90 mg SC injection at Week 16. Subjects with ≥25% improvement in SES-
CD score at Week 16 versus baseline will be assigned to 12-weekly treatment and will receive 
the next ustekinumab maintenance dose (90 mg SC) at Week 20.
Subsequently, at assessment visits for the treat to target arm (from Week 24 for subjects assigned 
to the 8-weekly regimen or from Week 20 for the 12-weekly group) ustekinumab maintenance 
treatment up to Week 48 will be directed by treat to target assessments (CDAI, and CRP or FC). 
Subjects meeting the treatment target will continue on the same ustekinumab dosing frequency. 
Maintenance dosing frequency will be optimized for subjects failing to meet the treatment target: 
those subjects previously on 12-weekly regimens will be adjusted to 8-weekly dosing; those 
previously on 8-weekly regimens will be adjusted to 4-weekly dosing. Among those, subjects 
subsequently failing to meet the treatment target at the next assessment visit 4 weeks after dosing
will not be able to optimize dosing further and will leave the study.
In case of disease flare between scheduled assessment visits for the treat to target arm, subjects 
will undergo CDAI, CRP and FC assessments. Dosing frequency will be adjusted as described 
above for subjects failing to meet the treatment target.
Extension period: dosing adjustments from Week 48
From Week 48, subjects will continue ustekinumab treatment in the study extension period, up to 
Week 104. The frequency of dosing will be based on endoscopic and/or clinical remission at 
Week 48, and subsequently on clinical remission and biomarker findings (refer to Section 3.1, 
Table 1).
From Week 48, ustekinumab dose de-escalation will be implemented for subjects with both 
endoscopic remission (SES-CD score ≤2) at Week 48 and corticosteroid-free clinical remission 
(CDAI score of <150 points) of at least 16 weeks’ duration. Among such subjects, those 
receiving 8-weekly ustekinumab will adjust to 12-weekly dosing, whereas those receiving 
4-weekly ustekinumab will adjust to 8-weekly dosing. In the latter case, further dose de-
escalation to 12-weekly ustekinumab will be applied for subjects with corticosteroid-free clinical 
remission (CDAI score of <150 points) and biomarker remission (CRP ≤10 mg/L and FC 
≤250 µg/g) at 2 subsequent, consecutive visits 8 weeks apart. Subjects receiving 12-weekly 
ustekinumab with endoscopic remission at Week 48 will maintain this 12-weekly dosing 
frequency.
Subjects with either clinical remission or endoscopic remission, but not both, at Week 48 will 
continue with the same dosing frequency. For those with only clinical remission, subsequent 
dosing de-escalation will be dependent on maintenance of corticosteroid-free clinical remission 
and demonstration of biomarker remission at 2 consecutive visits. For subjects with only 
endoscopic remission, subsequent dose de-escalation will be dependent
on being in 
corticosteroid-free clinical remission and demonstrating biomarker remission at 2 consecutive 
visits (Section 3.1, Table 1).


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Conversely, subjects with neither corticosteroid-free clinical remission nor endoscopic remission 
having received 12-weekly or 8-weekly ustekinumab up to Week 48 will undergo dose 
escalation to 8-weekly or 4-weekly dosing, respectively. After dose escalation, if neither clinical 
remission nor biomarker remission is evident at the next visit, subjects will leave the study. Later 
in the extension period, only those who achieve corticosteroid-free clinical remission of 
≥16 weeks’ duration and demonstrate biomarker remission over 2 consecutive visits will 
undergo dose de-escalation (Table 1). Subjects with neither corticosteroid-free clinical remission 
nor endoscopic remission who have received ustekinumab at 4-weekly intervals up to Week 48 
will not be able to adjust dosing further and will leave the study.
Disease flare during the extension period will be defined according to the CDAI, CRP and FC 
criteria provided in Section 3.1. In case of disease flare at any time during the extension period, 
dosing will be escalated/re-escalated (12-weekly to 8-weekly, or 8-weekly to 4-weekly). For 
those subjects escalated to 8-weekly dosing, further escalation to 4-weekly dosing will be 
implemented in case of persistent or recurring disease flare. Subjects receiving 4-weekly 
ustekinumab during the extension period who experience disease flare will not be able to adjust 
dosing further and will leave the study.
7.
TREATMENT COMPLIANCE
Study drug will be administered as a single IV infusion (Week 0) by qualified staff followed by 
SC injections (Week 8 onwards). Details of each administration will be recorded in the CRF, 
including date, time of injection, and start and stop times and volume infused (for the IV 
infusion).
After Week 8, subjects may self-administer (in compliance with the EU SmPC) SC injections of 
study drug at the times instructed by the investigator. When study drug is self-administered by 
subjects the amount of study drug dispensed will be recorded and compared with the amount 
returned, whether as empty syringes or syringes containing study drug.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy Therapies
Disallowed prestudy therapies, with specified intervals before baseline (Week 0) are listed in the 
study exclusion criteria (Section 4.2). Prestudy therapies documented at screening will include 
any previous biologic therapies, therapies for Crohn’s disease (including those for extraintestinal 
manifestations), or therapies for other immune-mediated conditions. For previous biologic 
therapies approved for the treatment of Crohn’s disease in the countries in which the study is 
conducted, the reason for stopping treatment (eg, inadequate response or loss of response, 
intolerance, contraindications, or other reasons) will be documented in the CRF.
Concomitant Therapies
Concomitant medication will be reviewed at each visit. Concomitant therapies must be recorded 
throughout the study from signing of consent to last study visit. Recorded information will 


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include a description of the type of the drug, treatment period, dosing regimen, route of 
administration, and its indication.
Subjects 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 during the
study provided the subject was on a stable dose for a specified period prior to baseline (as
defined in the inclusion criteria in Section 4.1). Subjects receiving these medications at baseline 
should maintain a stable dose throughout this study, with the exception of oral corticosteroids for 
subjects with CDAI-70 response (see tapering schedule for oral corticosteroids below).
Enrolled subjects 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.

Antibiotics as a treatment of Crohn’s disease.

Total parenteral nutrition as a treatment of Crohn’s disease.
If the above medications are initiated or doses/regimens modified, subjects should continue to 
attend all study visits and have all assessments. If, due to medical necessity in the opinion of the 
investigator, the above medications are initiated or increased, this does not represent a deviation 
from the study protocol.
Subjects may transiently use (ie, for <4 weeks) increased doses of corticosteroids for reasons 
other than loss of response to treatment for Crohn’s disease (eg, stress doses of corticosteroids 
for surgery, asthma, adrenocortical insufficiency, etc).
Oral Corticosteroids
Subjects will be allowed to enter the study on oral corticosteroids at a prednisone-equivalent 
dose of ≤40 mg/day or ≤9 mg/day of budesonide. For subjects receiving corticosteroids, 
randomized at Week 16 (CDAI-70
Responders) corticosteroid tapering is mandatory. 
Corticosteroid tapering can be initiated from Week 8 in subjects already demonstrating response
(CDAI-70) to ustekinumab treatment.
If subjects experience a worsening in their disease activity while tapering corticosteroids, further 
dose decreases may be suspended, and/or their oral corticosteroid dose may be temporarily 
increased if deemed necessary by the investigator. The oral corticosteroid dose, however, may 
not be increased above the baseline dose unless due to medical necessity. For subjects whose 
corticosteroid taper is interrupted on this basis, investigators are encouraged to resume tapering 
within 4 weeks.


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Recommended tapering schedule for oral corticosteroids (other than budesonide):

Dose >15 mg/day prednisone or equivalent: taper daily dose by 5 mg/week until receiving 
10 mg/day, then continue tapering at 2.5 mg/week until 0 mg/day.

Dose 11 to 15 mg/day prednisone or equivalent: taper daily dose to 10 mg/day for 1 week, 
then continue tapering at 2.5 mg/week until 0 mg/day.

Dose ≤10 mg/day prednisone or equivalent: taper daily dose by 2.5 mg/week until 0 mg/day.
Recommended tapering schedule for oral budesonide:

Subjects receiving budesonide should have their daily dose tapered by 3 mg every 3 weeks 
until 0 mg/day.
Prohibited Medications
Enrolled subjects must not initiate any of the following Prohibited Medications during the study. 
If prohibited medications are initiated at any time during the study, treatment with study drug
will be discontinued and subjects will complete early termination assessments and the final 
safety follow-up visit.

Immunomodulatory agents other than 6-MP/AZA or MTX.

Immunomodulatory biologic agents.

Experimental Crohn’s disease medications.
Note: Subjects must not receive ustekinumab outside of the protocol or participate in any other 
clinical study with an investigational agent while in this study, and must terminate study 
participation if they do. 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.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedules summarize the frequency and timing of efficacy, PK,
immunogenicity, health economic, and safety measurements applicable to this study.
All study-specific PRO assessments should be conducted/completed before any tests, procedures, 
or other consultations for that visit to prevent influencing subject perceptions. The PRO 
instruments will be provided in the local language in accordance with local guidelines.
Study site personnel will remind subjects of the need to provide stool samples at the visits 
indicated in the Time and Events Schedules.


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Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
Medical resource utilization and health economics data will be collected. Refer to Section 9.5, 
Medical Resource Utilization and Health Economics for details.
The total blood volume to be collected from each subject during this study will be approximately
348 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.2.
Screening Phase
The eligibility of subjects will be assessed during a 5-week screening period. At screening, 
written informed consent must be obtained from the subject for this study by the investigator or 
designee prior to conducting any protocol-specific procedure.
Procedures to be performed at screening are outlined in the Time and Events Schedules. The 
requirements regarding prestudy therapies are detailed in Section 4.
During the screening period subjects will receive training in diary card completion for CDAI and 
for recording information on adverse events. Subjects’ height and weight will be recorded. For 
calculation of CDAI by the investigator or appropriate site personnel at Week 0, the hematocrit 
value obtained during screening will be used.
A baseline, centrally-read, ileocolonoscopic evaluation will be performed during screening. A 
previous video ileocolonoscopy may be used, provided this has been obtained within 3 months 
prior to baseline (Week 0), in which case the prior ileocolonoscopy must be read again at a 
central facility and SES-CD calculated based on this second, centralized read-out.
Women of childbearing potential must have a negative serum β-hCG pregnancy test at screening.
Subjects are to be reminded that they are required to use an acceptable method of contraception
during the study and must continue taking such precautions for 15 weeks after receiving the
study drug (Sections 4.1 and 4.3). The method(s) of contraception used by each subject must be 
documented.
Subjects must have a chest radiograph during screening or have had a chest radiograph within 
3 months prior to Week 0, with no evidence of current active TB or old inactive TB (see 
Section 4.1). Additionally, subjects must undergo testing for TB (Attachment 1
and 
Attachment 2) and their medical history assessment must include specific questions about a 
history of TB or known occupational or other personal exposure to individuals with active TB. 
The subject should be asked about past testing for TB, including chest radiograph results and 
responses to tuberculin skin or other TB testing.


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Subjects with a negative QuantiFERON-TB Gold test result (and a negative tuberculin skin test
result in countries in which the QuantiFERON-TB Gold test is not approved/registered or the 
tuberculin skin test is mandated by local health authorities) are eligible to continue with 
screening procedures. Subjects with a newly identified positive QuantiFERON-TB Gold (or 
tuberculin skin) test result must undergo an evaluation to rule out active TB and initiate 
appropriate treatment for latent TB. Appropriate treatment for latent TB is defined according to 
local country guidelines for immunocompromised patients. If no local country guidelines for 
immunocompromised patients exist, the ECCO guidelines must be followed, or the subject will 
be excluded from the study.17
Note: Subjects in countries with high multidrug-resistant TB burden (eg, South Africa, Bulgaria, 
and the Russian Federation) identified with latent TB at screening will be excluded from 
participating in the study.
A subject whose first QuantiFERON-TB Gold test result is indeterminate should have the test
repeated. In the event that the second QuantiFERON-TB Gold test result is also indeterminate,
the subject may be enrolled without treatment for latent TB if active TB is ruled out, his/her 
chest radiograph shows no abnormality suggestive of TB (active or old, inactive TB) and the 
subject has no additional risk factors for TB as determined by the investigator. This 
determination must be promptly reported to the sponsor’s medical monitor and recorded in the 
subject's source documents and initialed by the investigator. Note: Subjects in countries with 
high multidrug-resistant TB burden (eg, South Africa, Bulgaria, and the Russian Federation) 
with a repeat indeterminate QuantiFERON-TB Gold test result will be excluded from 
participating in the study, unless their chest radiograph shows no abnormality suggestive of TB 
(active or old, inactive TB), they have no additional risk factors for TB as determined by the 
investigator and medical monitor, and they have a negative tuberculin skin test result within the 
2 months prior to baseline, in which case they may be enrolled without treatment for latent TB.
An assessment of all screening laboratory test results, clinical data, and concomitant medication
data will be made by the principal investigator or designee to confirm that the subject satisfies all
inclusion criteria and does not violate any exclusion criteria.
9.1.3.
Open-Label Treatment Phase
Subjects will visit the study sites for efficacy and safety evaluations at the times scheduled for 
study drug administration. Procedures to be performed at those assessment visits are outlined in 
the Time and Events Schedules. All procedures are to be conducted prior to administration of 
study drug, unless otherwise specified.
Each study visit will have a window of ±10 days. 
Subjects will be instructed to complete diary cards for CDAI or adverse event information daily 
up to Week 104.
Ileocolonoscopic examinations and CDAI assessments will be scheduled to avoid an impact on 
CDAI data. For example, if ileocolonoscopy is performed on the day of the visit, the 7 days prior 


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to the initiation of the ileocolonoscopy preparation should be used to calculate the CDAI score 
for the visit.
After Week 8, subjects who have been trained how to self-inject may self-administer (in 
compliance with the EU SmPC) SC study drug at the times instructed by the investigator. 
Information documented in the CRF will include date of administration, self-administration 
(yes/no) and whether administration was complete based on the returned syringe.
Throughout the study, women of childbearing potential must have a negative urine pregnancy 
test, tested at assessment visits, prior to study drug administration.
Study drug should not be administered to a subject with a clinically important, active infection.
Investigators are required to evaluate subjects for any signs or symptoms of infection, and also 
review subjects’ diary cards for signs of infection, at scheduled visits (refer to the Time and 
Events Schedules). If a subject 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 subject without history of 
chickenpox, study treatment should be interrupted until the symptoms have resolved and no 
active infection is present.
If a subject has a clinically important, active infection at the time of a scheduled injection, which
cannot be controlled within 10 days, the subjects should be discontinued from the study 
(Section 10.2). 
Early Detection of Active Tuberculosis
To aid in the early detection of TB reactivation or new TB infection during study participation, 
subjects must be evaluated for signs and symptoms of active TB at scheduled visits (refer to 
Time and Events Schedules). The following series of questions is suggested for use during the 
evaluation:

“Have you had a new cough of >14 days’ duration or a change in a chronic cough?”

“Have you had any of the following symptoms:

Persistent fever?

Unintentional weight loss?

Night sweats?”

“Have you had close contact with an individual with active TB?” (If there is uncertainty as 
to whether a contact should be considered “close,” a physician specializing in TB should be 
consulted.)
If the evaluation raises suspicion that a subject may have TB reactivation or new TB infection, 
study drug administration should be interrupted and an immediate and thorough investigation 
should be undertaken, including, where possible, consultation with a physician specializing in 
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Investigators should be aware that TB reactivation in immunocompromised subjects may present 
as disseminated disease or with extrapulmonary features. Subjects with evidence of active TB 
must immediately discontinue study drug and should be referred for appropriate treatment.
Subjects who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QuantiFERON TB Gold test, a repeat 
tuberculin skin test
in countries in which the QuantiFERON-TB Gold test is not 
approved/registered or the tuberculin skin test is mandated by local health authorities, and, if 
possible, referral to a physician specializing in TB to determine the subject’s risk of developing 
active TB and whether treatment for latent TB is warranted. Study drug administration should be 
interrupted during the investigation. A positive QuantiFERON TB Gold (or tuberculin skin) test 
result should be considered detection of latent TB. If the QuantiFERON TB Gold Test is 
indeterminate, the test should be repeated as outlined in Section 9.1.2. If recommended, 
treatment for latent TB must be initiated before the administration of further study drug. Subjects 
who discontinue treatment for latent TB prematurely or who are noncompliant with therapy must 
immediately discontinue further administration of study drug and undergo early termination 
assessments (Section 10). Refer to Attachment 1 and Attachment 2 for details regarding 
QuantiFERON-TB Gold and tuberculin skin testing during the study.
Weeks 0 to 8
At Week 0, the investigator will review the inclusion/exclusion criteria to confirm subjects’ 
continuing eligibility for study. Following the assessments indicated in the Time and Events 
Schedules, all eligible subjects will receive ustekinumab IV induction treatment at Week 0 and 
then ustekinumab 90 mg SC at Week 8.
Week 16 Randomization
At Week 16, subjects who do not achieve CDAI-70 versus baseline (Week 0) will leave the 
study. Subjects who remain in the study will be randomized in a 1:1 ratio to either one of two
arms for open-label maintenance treatment up to Week 48: the routine care arm or the treat to 
target arm. 
Routine Care Arm: Weeks 16 to 48
In the routine care arm, the timing of maintenance treatment injections will be in compliance 
with the EU SmPC for ustekinumab for the treatment of Crohn’s disease, in which dosing every 
12 weeks is recommended. At Week 16, (ie, 8 weeks after the first SC dose), subjects who have 
not shown adequate response based on the investigator’s judgment may receive a second SC
dose at that time.
Blood and stool samples will be taken at each maintenance assessment visit. Biomarkers will be 
assessed in a centralized manner at the end of the study.
During the routine care maintenance treatment period, in case of clinical worsening reported by 
the subject, consistent with disease flare in the investigator’s judgment, clinical assessments of 
disease flare will be performed at the investigator’s discretion. In accordance with the EU SmPC 


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for ustekinumab, subjects who lose response during 12-weekly dosing may benefit from an 
adjustment to 8-weekly maintenance treatment. Subjects may subsequently be dosed every 
8 weeks or every 12 weeks according to clinical judgment. Information on assessments of 
disease flare and on the reasons for dosing frequency changes will be documented in the CRF. In 
contrast, those subjects previously receiving 8-weekly treatment will not be able to adjust the 
ustekinumab dose following disease flare and will leave the study if they would not benefit from 
continuing study treatment in the investigator’s judgment.
Assessments including video ileocolonoscopy at Week 48 will be performed for all subjects as 
indicated in the Time and Events Schedules.
Treat to Target Arm: Weeks 16 to 48
In the treat to target arm, all subjects will undergo ileocolonoscopic evaluation at Week 16. 
Subsequent study assessments will be scheduled according to injection timing, which will be 
determined by the dosing frequency assigned to subjects. Initial ustekinumab maintenance 
treatment assignment will be based on centrally-read ileocolonoscopy findings. Subjects with 
<25% improvement in SES-CD score at Week 16 versus baseline will be assigned to 8-weekly 
maintenance treatment and will receive ustekinumab 90 mg SC at Week 16. Subjects with ≥25% 
improvement in SES-CD score at Week 16 versus baseline will be assigned to 12-weekly 
treatment and will receive the next ustekinumab maintenance dose (90 mg SC) at Week 20.
At subsequent assessment visits (ie, from Week 24 for the 8-weekly regimen or from Week 20 
for the 12-weekly regimen) ustekinumab maintenance treatment will be directed by treat to target 
assessments. Among the subgroup of subjects with elevated CRP at baseline (ie, CRP 
>2.87 mg/L at Week 0) the treatment target will be the achievement of:

CDAI <220 and ≥70-point improvement in CDAI score from baseline (Week 0) 
AND:

CRP ≤10 mg/L or FC ≤250 µg/g.
For subjects who do not have elevated CRP at baseline (ie, CRP ≤2.87 mg/L at Week 0) in the 
presence of active disease, CRP would not be considered a biomarker target for dose adjustment, 
therefore the treatment target for these subjects will be the achievement of:

CDAI <220 and ≥70-point improvement in CDAI score from baseline (Week 0) 
AND

FC ≤250 µg/g.
Subjects meeting the treatment target will continue with the same ustekinumab dosing frequency. 
However, maintenance dosing frequency will be optimized for all subjects failing to meet the 
treatment target at the assessment visit. Those subjects previously on 12-weekly regimens will be 
adjusted to 8-weekly dosing; those previously on 8-weekly regimens will be adjusted to 
4-weekly dosing. Among those, subjects subsequently failing to meet the treatment target at the 


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next assessment visit 4 weeks after dosing will not be able to optimize dosing further and will 
leave the study.
In case of disease flare between scheduled assessment visits for the treat to target arm, subjects 
will undergo CDAI and biomarker (CRP and FC) assessments. Dosing frequency will be 
adjusted as described above for subjects failing to meet the treatment target.
Assessments including video ileocolonoscopy at Week 48 will be performed for all subjects as 
indicated in the Time and Events Schedules.
Extension Period: Weeks 48 to 104
From Week 48, the frequency of dosing and associated assessment visits will depend on the 
previous dosing frequency, Week 48 ileocolonoscopy and CDAI findings, and subsequent CDAI 
and biomarker findings (see Section 3.1, Table 1). In case of disease flare, dosing frequency may 
be escalated (Section 3.1). Subjects will undergo the assessments indicated in the Time and 
Events Schedule for the extension period. 
Completion of Treatment
For all subjects, Week 104 visit assessments including video ileocolonoscopy will be performed 
as indicated in the Time and Events Schedule for the extension period.
End of Treatment/Early Withdrawal
In both arms, subjects discontinuing from the study before Week 104 will have the early 
termination assessments indicated in the Time and Events Schedules, to be performed as close as 
possible to the time of discontinuation, unless consent is withdrawn. Early termination 
assessments should include video ileocolonoscopy.
9.1.4.
Posttreatment Phase (Follow Up)
All subjects should complete a final safety follow-up visit 16 weeks after their last study drug
administration within the study, as outlined in the Time and Events Schedules. Subjects 
discontinuing from the study will be instructed that study drug will not be made available to 
them after they have discontinued study drug and that they should return to their primary 
physician to determine standard of care. For subjects completing the 104-week study and 
continuing to respond to ustekinumab, it is anticipated that ustekinumab will be commercially 
available for the treatment of Crohn’s disease at the time of study completion. In this case, final 
safety 
follow-up 
assessments 
should 
be 
performed 
before 
the 
first 
dose 
of 
commercially-available ustekinumab. In the event of ustekinumab not being available for some 
subjects, alternative options will be discussed based on country-specific requirements and 
regulations (Section 16.1).
Information on subsequent therapies for Crohn’s disease, including commercially-available 
ustekinumab if applicable, will be documented at the final safety follow-up visit. 


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9.2.
Efficacy Evaluations
9.2.1.
Crohn’s Disease Activity Index
The CDAI will be assessed at the visits indicated in the Time and Events Schedules by collecting 
information on 8 different Crohn’s disease-related variables (Attachment 3 and Attachment 4).
These 8 variables are: 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 wellbeing.3 The last 4 variables are scored over 7 days by the subject on a diary card.
9.2.2.
C-reactive Protein
Serum CRP has been demonstrated to be useful as a marker of inflammation in patients with 
IBD. In Crohn’s disease, elevated CRP concentrations have been associated with severe clinical 
activity, elevated sedimentation rate, and active disease as detected by colonoscopy.20,21 Blood 
samples for the measurement of CRP will be collected from all subjects at the visits indicated in 
the Time and Events Schedules. The serum CRP will be assayed using a validated, high 
sensitivity CRP assay at a central laboratory. 
In the routine care arm, the results of CRP testing during the maintenance period up to Week 48 
will not be communicated to the investigator during the study; these data will be analyzed at the 
end of the study.
In the treat to target arm, CRP will be assessed at every assessment visit to be used by 
investigators as part of treat to target assessments for the adjustment of maintenance dosing 
frequency up to Week 48, and in cases of disease flare between assessment visits.
During the extension period, regardless of the original treatment arm, CRP data may be used to 
guide ustekinumab dosing (eg, for demonstration of biomarker remission in cases requiring a 
dosing de-escalation, see Section 3.1, or in case of disease flare requiring dose escalation).
9.2.3.
Fecal Calprotectin
Fecal calprotectin (FC) has been demonstrated to be a sensitive and specific marker in 
identifying intestinal inflammation and response to treatment in patients with IBD.6 Stool 
samples for FC concentrations will be collected from all subjects at the visits indicated in the 
Time and Events Schedules. The assay for FC concentration will be performed using a validated 
method at a central laboratory.
In the routine care arm, the results of FC testing during the maintenance period up to Week 48 
will not be communicated to the investigator during the study; these data will be analyzed at the 
end of the study.
In the treat to target arm, FC will be tested at every assessment visit to be used by investigators 
as part of treat to target assessments for the adjustment of maintenance dosing frequency up to 
Week 48, and in cases of disease flare between assessment visits.


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During the extension period, regardless of the original treatment arm, FC data may be used to 
guide ustekinumab dosing (eg, for demonstration of biomarker remission in cases requiring a 
dosing de-escalation, see Section 3.1, or in case of disease flare requiring dose escalation).
9.2.4.
Video Ileocolonoscopy
Ileocolonoscopy will be used to assess SES-CD at the times indicated in the Time and Events 
Schedules. The SES-CD is a simple, reproducible, and easy-to-use endoscopic scoring system 
for Crohn's disease, by which endoscopic parameters (ulcer size, ulcerated and affected surfaces, 
stenosis) are scored from 0 to 3.7 In the treat to target arm, initial ustekinumab maintenance 
treatment assignment will be based on centrally-read ileocolonoscopy findings at Week 16 
(Section 3.1). For all subjects, centrally-read SES-CD scores will be used to evaluate endoscopic 
response (reduction from baseline in SES-CD score ≥50%) and endoscopic remission (SES-CD 
score ≤2) at Week 48, at Week 104, or at early termination of ustekinumab treatment.
Mucosal healing will be assessed during ileocolonoscopy to determine the presence or absence 
of mucosal inflammation and ulceration. Video ileocolonoscopies will be assessed by a central 
facility.
9.2.5.
Fistula Assessment
All subjects will be assessed for fistulas at the times indicated in the Time and Events Schedules. 
For subjects with fistulizing disease, fistula closure will be assessed. Enterocutaneous fistulas 
(eg, perianal and abdominal) will be considered no longer draining (ie, closed) when there is 
absence of drainage despite gentle compression. Rectovaginal fistulas will be considered closed 
based on either physical examination or absence of relevant symptoms (eg, passage of rectal 
material or flatus from the vagina).
9.2.6.
Inflammatory Bowel Disease Questionnaire
The IBDQ (Attachment 5) is a 32-item self-report questionnaire for subjects with IBD to 
evaluate the PROs across 4 dimensions: bowel symptoms (loose stools, abdominal pain), 
systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to 
cancel social events), and emotional function (anger, depression, irritability). Scores range from 
32 to 224 with higher scores indicating better outcomes.9 The IBDQ questionnaires will be 
completed at the times indicated in the Time and Events Schedules.
9.2.7.
EQ-5D-5L
The EuroQoL-5D-5L Health Questionnaire (EQ-5D-5L; Attachment 6) is a validated quality-of-
life instrument to be completed by the subject. The EQ-5D-5L provides a visual analogue scale 
to integrate many aspects of the subject’s disease process into a single assessment along with 
targeted quality-of-life questions. It is a non-disease-specific measure of health status that 
provides a simple descriptive profile and a single index value that can be used in the clinical and 
economic evaluation of health care and in population health surveys. The EQ-5D-5L
questionnaires will be completed at the times indicated in the Time and Events Schedules.


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9.2.8.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
The FACIT-F scale (Attachment 7) is a 13-item fatigue scale with a 7-day recall period. It 
measures the level of fatigue during the usual daily activities. The level of fatigue is measured on 
a 4-point Likert scale (0=very much fatigued to 4=not at all fatigued). It has been validated in 
studies of patients with IBD in correlating severity of fatigue with overall health-related QoL as 
well as disease-specific QoL.16 The FACIT-F data will be collected at the times indicated in the 
Time and Events Schedules.
9.2.9.
Hospital Anxiety and Depression Scale (HADS)
The HADS (Attachment 8) is a validated 14-item scale with 7 of the items relating to anxiety and 
7 relating to depression. Each item is scored from 0 to 3, with higher scores indicating greater 
likelihood of depression or anxiety. Cases of anxiety or depression are each defined by subscale 
scores of 8 or greater, and categorized as normal (score of 0 to 7), mild (score of 8 to 10), 
moderate (score of 11 to 14), and severe (score of 15 to 21). The recall period is the past week. 
The HADS takes approximately 2 to 5 minutes to complete.4,24 The HADS data will be collected 
at the times indicated in the Time and Events Schedules.
9.3.
Pharmacokinetics and Immunogenicity
Serum samples will be used to evaluate the PK of ustekinumab, as well as the detection and 
characterization of anti-ustekinumab antibodies. Serum collected for PK and immunogenicity 
analyses may additionally be used to evaluate safety or efficacy aspects that address concerns 
arising during or after the study period, for further characterization of immunogenicity or for the 
evaluation of relevant biomarkers. Genetic analyses will not be performed on these serum 
samples. Subject confidentiality will be maintained.
For IV infusion at Week 0, a sample should be drawn before infusion and approximately 
60 minutes after completion of the infusion. At all other assessment visits, blood samples should 
be collected prior to study drug injection. At visits where serum concentration and antibodies to 
ustekinumab will be evaluated, 1 blood draw of sufficient volume can be used. Venous blood 
samples will be collected and each serum sample will be divided into 3 aliquots (1 each for PK, 
antibodies to study drug, and a backup). Additional information about the collection, handling, 
and shipment of biological samples can be found in the Laboratory Manual.
9.4.
Additional Biomarkers
Additional tests may be performed on the stool samples taken for FC assessments, to test for 
additional markers related to intestinal inflammation and treatment response such as the 
microbiome. Genetic analyses will not be performed on biological samples obtained for this 
study.
9.4.1.
Analytical Procedures
Pharmacokinetics
Serum samples will be analyzed to determine concentrations of ustekinumab using a validated, 
specific, and sensitive method by or under the supervision of the sponsor. 


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Immunogenicity
The detection and characterization of anti-ustekinumab antibodies will be performed using a 
validated assay method by or under the supervision of the sponsor. All samples collected for 
detection of anti-ustekinumab antibodies will also be evaluated for ustekinumab serum 
concentration to enable interpretation of the antibody data.
9.4.2.
Pharmacokinetic Parameters 
Serum samples will be used to evaluate various PK parameters.
9.4.3.
Immunogenicity Assessments (Anti-ustekinumab antibodies)
Anti-ustekinumab antibodies will be evaluated in serum samples collected from all subjects 
according to the Time and Events Schedules. Additionally, serum samples should be collected at 
the final visit from subjects who are discontinued from treatment or withdrawn from the study. 
These samples will be tested by the sponsor or sponsor's designee.
Serum samples will be screened for antibodies binding to ustekinumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of ustekinumab. 
9.5.
Medical Resource Utilization and Health Economics
Medical resource utilization, including Crohn's disease-related hospitalizations and Crohn’s 
disease-related surgeries will be collected. Additionally, time lost from work will be collected 
and the potential impact of ustekinumab on subjects’ work and activities, and on daily 
productivity will be assessed through the Work Productivity and Activity Impairment
Questionnaire (WPAI).
9.5.1.
Work Productivity and Activity Impairment (WPAI)
The Work Productivity and Activity Impairment (WPAI) questionnaire is a well-validated 
instrument to measure impairments in work and activities (Attachment 9).18 It is a 6-item 
questionnaire with a 7-day recall period. The WPAI produces 4 types of scores: absenteeism 
(work time missed), presenteesism (impairment at work/reduced on-the-job effectiveness), work 
productivity loss (overall work impairment/absenteeism plus presenteeism), and activity 
impairment. The WPAI outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, ie, worse outcomes. 
9.5.2.
Time Lost From Work
Time lost from work will be collected by asking the subjects a single question, “How many days 
did you miss from work due to your Crohn’s disease in the last 4 weeks?”
9.6.
Safety Evaluations
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.


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Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedules:
Adverse Events
Subjects will complete diary cards during the study to record information on adverse events.
Diary cards will be collected and reviewed by the investigator at the times indicated in the Time 
and Events Schedules. Adverse events will be reported by the subject (or, when appropriate, by a 
caregiver, surrogate, or the subject's legally acceptable representative) for the duration of the 
study. Adverse events will be followed by the investigator as specified in Section 12, Adverse 
Event Reporting.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. The laboratory reports must 
be filed with the source documents.
Hematocrit will be tested by the local laboratory at the times indicated in the Time and Events 
Schedules to enable CDAI evaluations.
At screening, Week 0, Week 48, and Week 104 (or for early termination assessments, if 
applicable) the following tests will be performed by the local laboratory:

Hematology Panel
-hemoglobin
-hematocrit
-white blood cell (WBC) count with differential
-platelet count

Serum Chemistry Panel
-sodium
- phosphate
-potassium
-albumin
-chloride
-total protein
-blood urea nitrogen (BUN)/urea
-creatinine
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-total and direct bilirubin
-alkaline phosphatase
-calcium
Hematology and clinical chemistry tests do not need to be repeated at Week 0 if the screening 
tests were done ≤2 weeks previously.


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For women of childbearing potential, serum pregnancy testing will be performed at screening 
and urine pregnancy testing will be performed before each dose of study drug and at the safety 
follow-up visit.
Electrocardiogram (ECG)
A 12-lead ECG will be performed at screening.
Vital Signs 
Vital signs (temperature, pulse/heart rate, blood pressure [systolic and diastolic]) will be assessed 
at screening and at the times indicated in the Time and Events Schedules. At Week 0, vital signs 
will be assessed prior to infusion, approximately every 30 minutes during infusion, and twice (at 
approximately 30-minute intervals) after the completion of infusion.
Physical Examination
While assessment of the subjects’ for safety and efficacy requires some physical examination by 
an investigator at all visits, a more complete, detailed physical exam will be performed at the 
visits specified in the Time and Events Schedules. Body weight will be assessed at the visits 
indicated in the Time and Events Schedules.
Concomitant Medication Review
Concomitant medication will be reviewed at each visit.
Infusion Reactions
An infusion reaction is defined as an adverse event that occurs during or within 1 hour following 
the infusion of study drug, 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 drug 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 (see Section 12.1.1), the 
infusion may be restarted with caution.
Injection Site Reaction
A study drug injection-site reaction is any adverse reaction at a study drug 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 
remaining duration of the infusion, and for 1 hour after the end of the infusion in the event that 
emergency resuscitation is required. All subjects must be observed carefully for symptoms of an 


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allergic reaction (eg, urticaria, itching, hives). 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.
Subjects who experience serious adverse reactions related to either an injection or infusion 
should be discontinued from further study injections. For severe reactions related to the injection 
or infusion, the subject may be permanently discontinued from further study injections at the 
discretion of the investigator (refer to Section 10.2).
Subjects who experience reactions following an injection or infusion that result in bronchospasm
with wheezing and/or dyspnea that requires ventilatory support, or symptomatic hypotension 
with a decrease in systolic blood pressure greater than 40 mmHg, will not be permitted to receive
additional injections.
Infections
Study drug should not be administered to a subject with a clinically important, active infection.
Investigators are required to evaluate subjects for any signs or symptoms of infection, and also 
review subjects’ diary cards for signs of infection, at scheduled visits (refer to the Time and 
Events Schedules).
If a subject 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 subject without history of chickenpox, 
study treatment should be interrupted until the symptoms have resolved and no active infection is 
present.
Additional Assessments
Assessments for TB and infection will be performed at the visits specified in the Time and 
Events Schedules. Refer to Attachment 1
and Attachment 2
for details regarding 
QuantiFERON-TB Gold In-Tube and tuberculin skin testing and to Section 9.1.2 and 
Section 9.1.3 for additional details regarding TB testing and infections during the study.
9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Time and Events Schedules for the timing and frequency of all 
sample collections. Instructions for the collection, handling, and shipment of samples are found 
in the laboratory manual.


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10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed assessments 
at Week 104.
Subjects who discontinue study treatment for any reason before Week 104 will not be considered 
to have completed the study.
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before Week 104, the subject should not 
terminate their study participation. Instead, subjects should return for a final safety visit 
16 weeks after the last study drug administration.
A subject's study treatment must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study treatment

The subject fails to meet the protocol-specified response criteria for continuation of study 
treatment as described in Section 3.1:

A subject fails to demonstrate CDAI improvement of 70 points versus baseline 
(Week 0) at Week 16

Up to Week 48: a subject in the routine care arm, receiving 8-weekly ustekinumab 
maintenance treatment, experiences disease flare and would not benefit from continuing 
study treatment in the investigator’s judgment

Up to Week 48: a subject in the treat to target arm, scheduled to receive 4-weekly 
ustekinumab maintenance treatment, fails to meet the treatment target (CDAI, and CRP
or FC) at the next assessment visit 4 weeks after dosing.

At Week 48, a subject receiving 4-weekly ustekinumab treatment demonstrates neither 
clinical remission nor endoscopic remission.

A subject whose dosing was escalated from Week 48 demonstrates neither clinical 
remission nor endoscopic remission at the next visit.

During the extension period, a subject receiving 4-weekly ustekinumab treatment 
experiences disease flare. 

The subject becomes pregnant or plans a pregnancy within the study period or within 
15 weeks after the last study drug administration.

The subject is deemed ineligible according to the following TB screening criteria:

A diagnosis of active TB is made


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
A subject has symptoms suggestive of active TB based on follow-up assessment 
questions and/or physical examination, or has had recent close contact with a person 
with active TB, and cannot or will not continue to undergo additional evaluation.

A subject undergoing continued evaluation has a chest radiograph with evidence of 
current active TB and/or a positive QuantiFERON-TB Gold test result (and/or a positive 
tuberculin skin test result in countries in which the QuantiFERON-TB Gold 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 drug and continued to completion.
Indeterminate QuantiFERON TB Gold test results should be handled as described in 
Section 9.1.2. Subjects with persistently indeterminate QuantiFERON-TB Gold test 
results may continue 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 subject has no additional risk factors for TB as determined by the investigator. 
This determination must be promptly reported to the sponsor’s medical monitor and 
recorded in the subject's source documents and initialed by the investigator.

A subject receiving treatment for latent TB discontinues this treatment prematurely or is 
noncompliant with the therapy.

The subject has an injection site or infusion reaction resulting in bronchospasm with 
wheezing and/or dyspnea requiring ventilatory support, or symptomatic hypotension with a 
>40 mmHg decrease in systolic blood pressure.

The subject has a malignancy including squamous cell skin cancer. Consideration may be 
given to allow subjects who develop ≤2 basal cell skin cancers that are adequately treated 
with no evidence of residual disease to continue to receive study drug.

The subject initiates the following prohibited medications during the study:

Immunomodulatory agents other than 6-MP/AZA or MTX

Immunomodulatory biologic agents

Experimental Crohn’s disease medications

The subject receives ustekinumab outside of the protocol or participates in any other clinical 
study with an investigational agent.

The subject has a clinically important active infection at the time of a scheduled injection, 
which cannot be controlled within 10 days.

The subject withdraws consent for administration of study drug.

The subject has Crohn’s disease-related surgery (with the exception of drainage of an 
abscess or seton placement).
If a subject discontinues study treatment for any reason before Week 48, the early termination
assessments indicated in the Time and Events Schedules should be performed as close as 
possible to the time of discontinuation.


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Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow up

Withdrawal of consent

Death

Sponsor decision.
Subjects who terminate study participation will not be required to return for any follow-up 
assessments; however, these subjects should complete the Early Termination assessments 
specified in the Time and Events Schedules at the time they terminate study participation. 
If a subject is lost to follow up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
10.3.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. 
All statistical tests will be 2-sided at a significance level of 0.05 unless otherwise specified.
Baseline for all analyses will be the day of the start of study treatment unless otherwise specified.
An interim analysis will be performed as soon as all enrolled subjects have completed the first 
16 weeks of the study or discontinued earlier. Further details of the interim analyses are provided 
in Section 11.6.
The main analysis will be performed when all randomized subjects have completed 48 weeks of 
study treatment or discontinued earlier.
The final analysis will be performed when all subjects have completed the last study-related visit 
including the follow up.


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11.1.
Subject Information
The intent-to-treat (ITT) population will be defined as all subjects who sign informed consent 
and who are not screening failures. The interim analysis will be based on this ITT population.
The main analysis population will be the modified intent-to-treat (mITT) population defined as 
all subjects in the ITT population randomized to one of the 2 maintenance treatment arms. 
Efficacy analysis for the 48-week treatment phase will be performed for this mITT population.
Safety analysis for the 48-week treatment phase will be based on subjects in the mITT who 
receive at least one dose of study treatment in the maintenance period.
The final analysis population will be based on all subjects in the mITT population who enter the 
extension phase (m2ITT). Efficacy analysis for the 104-week treatment phase will be based on 
this m2ITT population. Safety analysis for the 104-week treatment phase will also be based on 
subjects in the m2ITT population who receive at least one dose of study treatment in the 
extension period.
If there are a substantial number of protocol violators that affect efficacy outcomes (eg, >10%), 
an additional per protocol analysis may be performed and will be pre-specified in the Statistical 
Analysis Plan.
11.2.
Sample Size Determination
The primary endpoint of this study is endoscopic response at Week 48 of the study. Endoscopic 
response is defined as showing (yes or no) a reduction from baseline in the SES-CD score of 
≥50%. 
This study is designed to show that the percentage of subjects with endoscopic response at 
Week 48 in the treat to target arm is 15% higher compared with the routine care arm, which is 
considered to be a clinically meaningful difference. Based on the results of the Phase 3 
IM-UNITI study, endoscopic response in the routine care arm is estimated at 30% of subjects. 
Endoscopic response in the treat to target arm is estimated at 45% of subjects.
A Fisher's exact test with a 0.050 two-sided significance level will have 80% power to detect the 
difference between the routine care arm proportion of 30% and the treat to target arm proportion 
of 45% when the sample size in each group is 174. With an estimated CDAI-70 response at 
Week 16 between 65% and 70%, and a dropout rate between 10% and 17.5%, a total of 
650 subjects should be enrolled.
11.3.
Efficacy Analyses 
11.3.1.
Primary Endpoint
The primary efficacy endpoint is endoscopic response at Week 48, defined as showing (yes or 
no) a reduction from baseline in SES-CD score of ≥50%. Randomized subjects who stop 
treatment before reaching Week 48 due to any reason, or subjects without endoscopic data at 
Week 48 will be analyzed as nonresponders. The number and percentage of responders will be 
summarized by treatment group and compared using the Fisher exact test.


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11.3.2.
Secondary Endpoints
The endpoints listed below will be observed values at all visits assessed and at endpoint (last 
observation carried forward [LOCF]) and changes from baseline for continuous/ordinal variables 
unless otherwise specified.
The following secondary efficacy endpoints will be analyzed within each arm and compared 
between the 2 arms:

Endoscopic response at Week 48, defined as showing (yes or no) a reduction from baseline 
in SES-CD score of ≥50%. Randomized subjects who stop treatment before reaching 
Week 48 due to reasons other than lack/loss of efficacy will be excluded from the analysis.

Endoscopic response defined as a reduction from baseline in SES-CD score of ≥50% at 
endpoint (LOCF).

Endoscopic remission defined as SES-CD score ≤2 at Week 48 and endpoint (LOCF).

Mucosal healing defined as the complete absence of mucosal ulcerations in any ileocolonic 
segment at Week 48 and endpoint (LOCF).

Clinical remission defined as CDAI score of <150 points.

Clinical response defined as ≥100-point reduction from the baseline CDAI score, or a CDAI 
score <150.

The following will be analyzed both for the whole mITT population, and for those subjects 
who were receiving corticosteroids at baseline:

Corticosteroid-free clinical remission.

Corticosteroid-free endoscopic response (endoscopic response defined as a reduction 
from baseline in SES-CD score of ≥50%).

Serum CRP.

FC.
In addition, changes from baseline for the following health-related QoL, PROs and 
pharmacoeconomic endpoints will be analyzed:

IBDQ (also the percentage of subjects with a 16-point change from baseline).

EQ-5D-5L.

FACIT-F.

HADS.

Time lost from work.

WPAI (also the % subjects with a 7-point change from baseline for each domain).
For subjects with fistulas at baseline, exploratory analyses will include fistula response (defined 
as ≥50% reduction from baseline in the number of draining fistulas) at Week 48, Week 104, and 
endpoint (LOCF).


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Exploratory analyses of Crohn's disease-related hospitalizations and Crohn's disease-related 
surgery will be performed.
Exploratory analyses for subjects treated beyond Week 48 in the extension period will include:

Endoscopic response at Week 104 and endpoint (LOCF), defined as showing (yes or no) a 
reduction from baseline in SES-CD score of ≥50%. Randomized subjects who stop 
treatment for any reason before reaching Week 104, or subjects without endoscopic data at 
Week 104, will be analyzed as nonresponders. A separate analysis will exclude subjects who 
stop treatment before reaching Week 104 due to reasons other than lack/loss of efficacy.

Endoscopic remission defined as SES-CD score ≤2 at Week 104 and endpoint (LOCF).

Mucosal healing defined as the complete absence of mucosal ulcerations in any ileocolonic 
segment at Week 104 and endpoint (LOCF).

Clinical remission defined as a CDAI score of <150 points.

Clinical response defined as a ≥100-point reduction from the baseline CDAI score, or a 
CDAI score of <150 points.

Corticosteroid-free clinical remission.

Corticosteroid-free endoscopic response (endoscopic response defined as a reduction from 
baseline in SES-CD score of ≥50%).

Serum CRP.

FC.

Changes from baseline for health-related QoL and pharmacoeconomic endpoints (IBDQ, 
EQ-5D-5L, FACIT-F, HADS, time lost from work, WPAI).

Clinical and biomarker remission (CDAI score of <150 points, CRP ≤10 mg/L, and FC 
≤250 µg/g) at Week 104 and endpoint (LOCF).

Durations of corticosteroid-free clinical remission and biomarker remission, durations of 
remission after dose de-escalation, and time from first de-escalation to first re-escalation.
The exploratory analyses for subjects treated in the extension period will be based on the total 
group. If the two arms (treat to target and routine care) contain substantial numbers of subjects,
an additional descriptive analysis per arm (without between-group comparison) might be 
considered. Subsequently, results from the extension period might also be explored per dosing 
regimen at the start of the extension period.
Changes from baseline throughout the study and observed values for continuous/ordinal efficacy 
variables (eg, PRO data) will be summarized descriptively at each assessment time point and at 
the subject’s last efficacy evaluation (endpoint). The change from baseline at each visit and at 
endpoint will be analyzed using the Wilcoxon signed rank test. When applicable, between-group 
comparisons will be analyzed by means of the Wilcoxon 2-sample test. Summary tabulations 
will display the number of observations, mean, standard deviation, median, minimum, maximum 
and 95% confidence interval (CI) overall and, if applicable by treatment group.


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For categorical variables (eg, response rates), the number and percentage per category will be 
summarized overall, and if applicable by treatment group including between-group comparison
using the Fisher exact test.
11.4.
Pharmacokinetic/Immunogenicity/Pharmacodynamic Analyses
Exploratory analyses of the PK, immunogenicity, and PD of study treatment will include: 

Characterization of the PK and immunogenicity of ustekinumab in subjects with Crohn’s 
disease

Assessment of the relationship between systemic ustekinumab exposure and:

clinical outcomes, including CDAI measures.

changes in CRP and FC.

endoscopic outcomes.
11.5.
Safety Analyses
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 adverse 
events are adverse events with onset during the treatment phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. In addition, 
comparisons between treatment groups will be provided if appropriate.
Analyses of adverse events in this study will include:

Frequency and type of adverse events.

Frequency and type of serious adverse events.

Frequency and type of reasonably related adverse events.

Frequency and type of adverse events leading to discontinuation of study drug.

Frequency of infusion reactions

Frequency of injection-site reactions. 

Frequency and type of infections, including infections requiring oral or parenteral 
antimicrobial treatment.

Frequency and type of serious infections.
Information evaluated for the above events of interest will include: time of onset, duration of 
events, time to resolution, concomitant therapies, and relationship to ustekinumab.


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Listings of subjects with serious adverse events and adverse events leading to discontinuation of 
study drug will also be provided. Any deaths, malignancies, or major cardiovascular events will 
either be presented in a listing or described in the clinical study report.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled time point. Changes from 
baseline results will be presented in pre- versus post-treatment cross-tabulations (with classes for 
below, within, and above normal ranges). A listing of subjects with any laboratory results outside
the reference ranges will be provided.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, and blood pressure (systolic and diastolic) 
values and changes from baseline will be summarized at each scheduled time point. The 
percentage of subjects with values beyond clinically important limits will be summarized.
Physical Examination
Frequency tabulations of the abnormalities will be made at each scheduled time point.
11.6.
Interim Analysis 
When all subjects have completed the first 16 weeks of the study or discontinued earlier an 
interim analysis will be performed for publication purposes. This analysis will provide relevant 
information on the benefit:risk of ustekinumab in subjects who have received their first 
ustekinumab IV injection (approximately 6 mg/kg) at the start of the study (Week 0) and the 
second ustekinumab SC injection (90 mg) at Week 8. In addition, a subgroup of subjects (those 
randomized to the treat to target arm) will undergo endoscopy at Week 16 per protocol. These 
data will also be analyzed, further expanding the knowledge of the effect of ustekinumab on 
endoscopic outcomes.
The Interim population will consist of all subjects enrolled in the study who receive at least one
study treatment. Results will be presented for the entire population. Subject characteristics and a 
selection of efficacy and safety endpoints will be included in this interim analysis. Endoscopic 
outcomes at Week 16 will be analyzed for subjects in the treat to target arm.
11.7.
Steering Committee
A steering committee provided consulting oversight during protocol development and will do so 
during the course of the study to ensure the scientific validity of the clinical study, to identify any 
scientifically relevant trends, and to provide recommendations to the sponsor. The steering 
committee serves as an expert advisory group. Any final strategic decision will belong to the 
sponsor.


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


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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For 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 Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:


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Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Unexpected therapeutic or clinical benefit from use of a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug from breastfeeding
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.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow up of safety. Serious adverse 
events, including those spontaneously reported to the investigator within 16 weeks after the last 
dose of study drug, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
Anticipated events will be recorded and reported as described in Attachment 10.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 


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(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available


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
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons)

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.
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.3.3.
Events of Special Interest
Any newly identified malignancy or case of active TB occurring after the first administration of 
study drug(s) in subjects participating in this clinical study must be reported by the investigator 
according to the procedures in Section 12.3.2. Investigators are also advised that active TB is 
considered a reportable disease in most countries. These events are to be considered serious only if 
they meet the definition of a serious adverse event.
12.3.4.
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to 
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the 
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must discontinue further study treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.


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12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Solution for Intravenous Infusion
Ustekinumab for IV injection is supplied as a sterile solution in a single-use glass vial. Each vial
contains 130 mg ustekinumab in 26 mL. The solution is clear, colorless to light yellow. The 
aqueous medium contains L-histidine, L-histidine hydrochloride
monohydrate, sucrose, 
polysorbate 80, L-methionine and EDTA disodium salt dihydrate at a pH of 6.0. No preservatives 
are present.
Ustekinumab for IV injection should only be used for the IV induction dose at Week 0 of the study 
(Section 6).


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Solution for Injection for Subcutaneous Administration
The ustekinumab for SC injection supplied for this study is a sterile solution in a single-use 
prefilled syringe (PFS). Each PFS contains 90 mg ustekinumab in 1.0 mL of liquid. The solution is 
clear to slightly opalescent, colorless to light yellow. The aqueous medium contains L-histidine, 
L-histidine hydrochloride, sucrose, and polysorbate 80 at a pH of 6.0. No preservatives are present.
The needle cover on the PFS contains dry natural rubber.
Details regarding the study drug are provided in the Pharmacy Manual/Site Investigational
Product and Procedures Manual.
14.2.
Packaging
The study drug will be uniquely packaged to ensure that it is appropriately managed throughout 
the supply chain process.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage 
All study drug must be stored at controlled temperatures ranging from 2°C to 8°C, not frozen, 
and protected from light. The solution in the vial or PFS should not be shaken. Prior to 
administration, the solution should be inspected visually for particulate matter and discoloration. 
The solution should not be used if it is discolored or cloudy, or if foreign particulate matter is 
present.
Study drug in glass vials and PFS will be ready to use. The pharmacist (or designated personnel) 
will prepare the required volume of study drug using the appropriate vials or PFS.
Aseptic procedures must be used during the preparation and administration of the ustekinumab 
solution for IV injection. 
After Week 8, following proper training in SC injection technique, subjects may self-administer 
ustekinumab for SC injection at the times instructed by the investigator. Study site personnel will 
instruct subjects on how to store study drug for at-home use as indicated for this protocol.
Refer to the Pharmacy Manual/Site Investigational Product and Procedures Manual for 
additional guidance on study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject, or dispensed
to the subject, and the return of study drug from the subject (if applicable), must be documented 
on the drug accountability form. Subjects must be instructed to return all original containers, 
whether empty or containing study drug. All study drug will be stored and disposed of according 


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to the sponsor's instructions. Study-site personnel must not combine contents of the study drug 
containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. If applicable, the return to the sponsor of 
unused study drug, will be documented on the drug return form. When the study site is an 
authorized destruction unit and study drug supplies are destroyed on-site, this must also be 
documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure 

EU SmPC for ustekinumab for the treatment of Crohn’s disease

Pharmacy Manual/Site Investigational Product and Procedures Manual

Laboratory Manual

IWRS Manual 

Manual for electronic data capture (eDC)

Sample ICF

Paper PRO questionnaires

Contact information page

Subject diaries

Subject study card
Samples of the following assessments are included as attachments to the protocol:

CDAI

IBDQ


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
EQ-5D-5L

FACIT-F

HADS

WPAI
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of the
World Health Organisation (450 mL once every 2 months, up to a maximum of 3 L over 
12 consecutive months for blood donation).
This study will be conducted only in those countries where ustekinumab has been submitted for 
registration for the treatment of Crohn’s disease and where the intent is to make ustekinumab
available in the market. It is anticipated that ustekinumab will be commercially available for the 
treatment of Crohn’s disease in subjects continuing to respond to ustekinumab at the time of 
study completion. Nevertheless, ustekinumab may not be available for some subjects completing 
the 104-week study, depending on regulatory approval and reimbursement timelines. In this 
event, alternative options will be discussed based on country-specific requirements and 
regulations.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.


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16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation.
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study


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


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should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-
related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker, PK, and immunogenicity research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand 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.


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Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:


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


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The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. These data are electronically 
extracted for use by the sponsor. If an electronic source is utilized, references made to the CRF 
in the protocol include the electronic source system but information collected through the 
electronic source may not be limited to that found in the CRF. Data in this system may be 
considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All 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 an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
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:


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
Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, 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.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
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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17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the 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.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development


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17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding 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 generated as a result of this study, are considered confidential 
and remain the sole property of the sponsor. The investigator agrees to maintain this information 
in confidence and use this information only to accomplish this study, and will not use it for other 
purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ustekinumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory analyses 
performed after the Clinical Study Report has been issued will be reported in a separate report 
and will not require a revision of the Clinical Study Report. Study subject identifiers will not be 
used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 


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information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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Attachment 1: QuantiFERON-TB Gold Testing
The QuantiFERON-TB Gold test is one of the interferon-(IFN-) based blood assays for TB screening (Cellestis, 
2016). It utilizes the recently identified M. tuberculosis-specific antigens ESAT-6 and CFP-10 in the standard 
format, as well as TB7.7 (p4) in the In-Tube format, to detect in vitro cell-mediated immune responses in infected 
individuals. The QuantiFERON-TB Gold assay measures the amount of IFN-produced by sensitized T-cells when 
stimulated with the synthetic M. tuberculosis-specific antigens. In M. tuberculosis-infected persons, sensitized 
T lymphocytes will secrete IFN-in response to stimulation with the M. tuberculosis-specific antigens and, thus, the 
QuantiFERON-TB Gold test should be positive. Because the antigens used in the test are specific to M. tuberculosis
and not found in BCG, the test is not confounded by BCG vaccination, unlike the tuberculin skin test. However, 
there is some cross-reactivity with the 3 Mycobacterium species, M. kansasii, M. marinum, and M. szulgai. Thus, a 
positive test could be the result of infection with one of these 3 species of Mycobacterium, in the absence of M. 
tuberculosis infection.
In a study of the QuantiFERON-TB Gold test (standard format) in subjects with active TB, sensitivity was shown to 
be approximately 89% (Mori et al, 2004). Specificity of the test in healthy BCG-vaccinated individuals has been 
demonstrated to be more than 98%. In contrast, the sensitivity and specificity of the tuberculin skin test was noted to 
be only about 66% and 35% in a study of Japanese patients with active TB and healthy BCG-vaccinated young 
adults, respectively. However, sensitivity and specificity of the tuberculin skin test depend on the population being 
studied, and the tuberculin skin test performs best in healthy young adults who have not been BCG-vaccinated.
Data from a limited number of published studies examining the performance of the QuantiFERON-TB Gold assay in 
immunosuppressed populations suggest that the sensitivity of the QuantiFERON-TB Gold test is better than the 
tuberculin skin test even in immunosuppressed patients (Ferrara et al, 2005; Kobashi et al, 2007; Matulis et al, 
2008). The ability of IFN--based tests to detect latent infection has been more difficult to study due to the lack of a
gold standard diagnostic test; however, several TB outbreak studies have demonstrated that the tests correlated 
better than the tuberculin skin test with the degree of exposure that contacts had to the index TB case (Brock et al, 
2004; Ewer et al, 2003). In addition, TB contact tracing studies have shown that patients who had a positive 
QuantiFERON-TB Gold test result and were not treated for latent TB infection were much more likely to develop 
active TB during longitudinal follow up than those who had a positive tuberculin skin test and a negative 
QuantiFERON-TB Gold test result (Higuchi et al, 2007; Diel et al, 2008).
Although the performance of the new IFN--based blood tests for active or latent M. tuberculosis infection have not 
been well validated in the immunosuppressed population, experts believe these new tests will be at least as, if not 
more, sensitive, and definitely more specific, than the tuberculin skin test (Barnes, 2004; personal communication, 
April, 2008 TB Advisory Board).
Performing the QuantiFERON-TB Gold Test
The QuantiFERON-TB Gold test In-Tube format will be provided for this study. The In-Tube format contains 
1 additional M. tuberculosis-specific antigen, TB7.7 (p4), which is thought to increase the specificity of the test. 
To perform the test using the In-Tube format, blood is drawn through standard venipuncture into supplied tubes that 
already contain the M. tuberculosis-specific antigens. Approximately 3 tubes will be needed per subject, each 
requiring 1 mL of blood. One tube contains the M. tuberculosis-specific antigens, while the remaining tubes contain 
positive and negative control reagents. Thorough mixing of the blood with the antigens is necessary prior to 
incubation. The blood is then incubated for 16 to 24 hours at 37C, after which tubes are centrifuged for 
approximately 15 minutes at 2000 to 3000 g. Following centrifugation, plasma is harvested from each tube, frozen, 
and shipped on dry ice to the laboratory. The laboratory will perform an ELISA to quantify the amount of IFN-
present in the plasma using spectrophotometry and computer software analysis.
The laboratory will analyze and report results for each subject, and sites will be informed of the results. Subjects 
who have an indeterminate result should have the test repeated.
Adherence to Local Guidelines
Local country guidelines for immunocompromised patients should be consulted for acceptable antituberculous 
treatment regimens for latent TB. If no local country guidelines for immunocompromised patients exist, ECCO 
guidelines must be followed.


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In countries in which the QuantiFERON-TB Gold test is not considered approved/registered, a tuberculin skin test is 
recommended but not additionally required if tuberculin is not available.
References
Barnes PF. Diagnosing latent tuberculosis infection: Turning glitter to gold [editorial]. Amer J Respir Crit Care 
Med. 2004;170:5-6.
Brock I, Weldingh K, Lillebaek T, et al. Comparison of tuberculin skin test and new specific blood test in 
tuberculosis contacts. Am J Respir Crit Care Med. 2004;170:65-69.
Cellestis. QuantiFERON-TB Gold clinicians guide and QuantiFERON-TB Gold In-Tube Method package insert. 
Downloaded from www.cellestis.com, February 2009.
Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. Predictive value of a whole blood IFN-
assay for the development of active tuberculosis disease after recent infection with mycobacterium tuberculosis. Am 
J Respir Crit Care Med. 2008;177:1164-1170.
Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of 
Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet. 2003;361:1168-1173.
Ferrara G, Losi M, Meacci M, et al. Routine hospital use of a new commercial whole blood interferon-assay for 
the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2005; 172:631-635.
Higuchi K, Nobuyuki H, Mori T, Sekiya Y. Use of QuantiFERON-TB Gold to investigate tuberculosis contacts in a 
high school. Respirology. 2007;12:88-92.
Kobashi Y, Mouri K, Obase Y, et al. Clinical evaluation of QuantiFERON TB-2G test for immunocompromised 
patients. Eur Respir J. 2007; 30:945-950.
Matulis G, Jüni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with 
autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon assay. Ann Rheum 
Dis. 2008;67:84-90
Mori T, Sakatani M, Yamagishi F, et al. Specific detection of tuberculosis infection: An interferon--based assay 
using new antigens. Am J Respir Crit Care Med. 2004;170:59-64.
Rahier JF, Magro F, Abreu C et al. Second European evidence-based consensus on the prevention, diagnosis and 
management of opportunistic infections in inflammatory bowel disease. Journal of Crohn's and Colitis 2014;8:443-
468.


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Attachment 2: Tuberculin Skin Testing
Administering the Mantoux Tuberculin Skin Test
The Mantoux tuberculin skin test (CDC, 2000) is the standard method of identifying persons infected with 
Mycobacterium tuberculosis. Multiple puncture tests (Tine and Heaf) should not be used to determine whether a 
person is infected because the amount of tuberculin injected intradermally cannot be precisely controlled. Tuberculin 
skin testing is both safe and reliable throughout the course of pregnancy. The Mantoux tuberculin test is performed 
by placing an intradermal injection of 0.1 mL of tuberculin into the inner surface of the forearm. The test must be 
performed with tuberculin that has at least the same strength as either 5 tuberculin units (TU) of standard purified 
protein derivative (PPD)-S or 2 TU of PPD-RT 23, Statens Seruminstitut, as recommended by the World Health 
Organization. PPD strengths of 1 TU or 250 TU are not acceptable (Menzies, 2000). Using a disposable tuberculin 
syringe with the needle bevel facing upward, the injection should be made just beneath the surface of the skin. This 
should produce a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter. To prevent needle-stick 
injuries, needles should not be recapped, purposely bent or broken, removed from disposable syringes, or otherwise 
manipulated by hand. After they are used, disposable needles and syringes should be placed in puncture-resistant 
containers for disposal. Institutional guidelines regarding universal precautions for infection control (eg, the use of 
gloves) should be followed. A trained health care worker, preferably the investigator, should read the reaction to the 
Mantoux test 48 to 72 hours after the injection. Subjects should never be allowed to read their own tuberculin skin 
test results. If a subject fails to show up for the scheduled reading, a positive reaction may still be measurable up to 
1 week after testing. However, if a subject who fails to return within 72 hours has a negative test, tuberculin testing 
should be repeated. The area of induration (palpable raised hardened area) around the site of injection is the reaction 
to tuberculin. For standardization, the diameter of the induration should be measured transversely (perpendicular) to 
the long axis of the forearm. Erythema (redness) should not be measured. All reactions should be recorded in 
millimeters, even those classified as negative.
Interpreting the Tuberculin Skin Test Results
In many countries, the most conservative definition of positivity for the tuberculin skin test is reserved for 
immunocompromised patients, and this definition is to be applied in this study to maximize the likelihood of 
detecting latent TB, even though the subjects may not be immunocompromised at baseline.
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.
Country-specific guidelines for immunocompromised patients should be consulted for the interpretation of 
tuberculin skin test results. If no local country guidelines for immunocompromised patients exist, the ECCO
guidelines must be followed. 
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable antituberculous 
treatment regimens for latent TB. If no local country guidelines for immunocompromised patients exist, ECCO
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.
Rahier JF, Magro F, Abreu C et al. Second European evidence-based consensus on the prevention, diagnosis and 
management of opportunistic infections in inflammatory bowel disease. Journal of Crohn's and Colitis 2014;8:443-
468.


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


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Attachment 4: Standard Weight Table (Sample)
Actual Height
Inches (cm)
Standard Weight in Pounds
Men (kg)
Standard Weight in Pounds
Women (kg)
58.0 (147.3)
115.0 (52.2)
58.5 (148.6)
116.0 (52.6)
59.0 (149.9)
117.0 (53.1)
59.5 (151.1)
118.3 (53.6)
60.0 (152.4)
119.5 (54.2)
60.5 (153.7)
120.8 (54.8)
61.0 (154.9)
122.0 (55.3)
61.5 (156.2)
123.5 (56.0)
62.0 (157.5)
136.0 (61.7)
125.0 (56.7)
62.5 (158.8)
137.0 (62.1)
126.5 (57.4)
63.0 (160.0)
138.0 (62.6)
128.0 (58.0)
63.5 (161.3)
139.0 (63.0)
129.5 (58.7)
64.0 (162.6)
140.0 (63.5)
131.0 (59.4)
64.5 (163.8)
141.3 (64.1)
132.5 (60.1)
65.0 (165.1)
142.5 (64.6)
134.0 (60.8)
65.5 (166.4)
143.8 (65.2)
135.5 (61.4)
66.0 (167.6)
145.0 (65.8)
137.0 (62.1)
66.5 (168.9)
146.5 (66.4)
138.5 (62.8)
67.0 (170.2)
148.0 (67.1)
140.0 (63.5)
67.5 (171.5)
149.5 (67.8)
141.5 (64.2)
68.0 (172.7)
151.0 (68.5)
143.0 (64.9)
68.5 (174.0)
152.5 (69.2)
144.5 (65.5)
69.0 (175.3)
154.0 (69.8)
146.0 (66.2)
69.5 (176.5)
155.5 (70.5)
147.5 (66.9)
70.0 (177.8)
157.0 (71.2)
149.0 (67.6)
70.5 (179.1)
158.5 (71.9)
150.5 (68.3)
71.0 (180.3)
160.0 (72.6)
152.0 (68.9)
71.5 (181.6)
161.8 (73.4)
153.5 (69.6)
72.0 (182.9)
163.5 (74.1)
155.0 (70.3)
72.5 (184.2)
165.3 (75.0)
73.0 (185.4)
167.0 (75.7)
73.5 (186.7)
169.0 (76.6)
74.0 (188.0)
171.0 (77.5)
*
Height in shoes with one-
inch heels 
74.5 (189.2)
172.8 (78.4)
*
Indoor clothing weighing 5 
pounds for men and 
3 pounds for women
75.0 (190.5)
174.5 (79.1)
75.5 (191.8)
176.8 (80.2)
*
Centimeters x 0.3937 = 
inches
76.0 (193.0)
179.0 (81.2)
*
Pounds x 0.4535 = kilograms


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Attachment 5: Inflammatory Bowel Disease Questionnaire (IBDQ)
PPD


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Attachment 6: EuroQoL-5D-5L Health Questionnaire (EQ-5D-5L) – Sample UK English Version


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Attachment 7: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) [Sample]
Source: http://www.facit.org/FACITOrg/Questionnaires


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Attachment 8: Hospital Anxiety and Depression Scale (HADS) [Sample]
Hospital Anxiety and Depression Scale (HADS)
Instructions: Doctors are aware that emotions play an important part in most illnesses. If your doctor knows about these feelings 
he or she will be able to help you more. This questionnaire is designed to help your doctor know how you feel. Read each item 
and circle the reply which comes closest to how you have been feeling in the past week. Don’t take too long over your replies: 
your immediate reaction to each item will probably be more accurate than a long thought out response.
I feel tense or ‘wound up’:
A
I feel as if I am slowed down:
D
Most of the time 
3 
Nearly all of the time 
3 
A lot of the time 
2 
Very often 
2 
Time to time, occasionally 
1 
Sometimes 
1 
Not at all 
0 
Not at all 
0 
I still enjoy the things I used to enjoy:
D
I get a sort of frightened feeling like 
‘butterflies in the stomach’:
A
Definitely as much 
0 
Not at all 
0 
Not quite so much 
1 
Occasionally 
1 
Only a little 
2 
Quite often 
2 
Not at all 
3 
Very often 
3 
I get a sort of frightened feeling like 
something awful is about to happen:
A
I have lost interest in my appearance:
D
Very definitely and quite badly 
3 
Definitely 
3 
Yes, but not too badly 
2 
I don’t take as much care as I should 
2 
A little, but it doesn’t worry me 
1 
I may not take quite as much care 
1 
Not at all 
0 
I take just as much care as ever 
0 
I can laugh and see the funny side of things:
D
I feel restless as if I have to be on the 
move:
A
As much as I always could 
0 
Very much indeed 
3 
Not quite so much now 
1 
Quite a lot 
2 
Definitely not so much now 
2 
Not very much 
1 
Not at all 
3 
Not at all 
0 
Worrying thoughts go through my mind:
A
I look forward with enjoyment to things:
D
A great deal of the time 
3 
A much as I ever did 
0 
A lot of the time 
2 
Rather less than I used to 
1 
From time to time but not too often 
1 
Definitely less than I used to 
3 
Only occasionally 
0 
Hardly at all 
2 
I feel cheerful:
D
I get sudden feelings of panic:
A
Not at all 
3 
Very often indeed 
3 
Not often 
2 
Quite often 
2 
Sometimes 
1 
Not very often 
1 
Most of the time 
0 
Not at all 
0 


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I can sit at ease and feel relaxed:
A
I can enjoy a good book or radio or TV 
programme:
D
Definitely 
0 
Often 
0 
Usually 
1 
Sometimes 
1 
Not often 
2 
Not often 
2 
Not at all 
3 
Very seldom 
3 
Questions relating to anxiety are indicated by an 'A' while those relating to depression are shown 
by a 'D'. Scores of 0-7 in respective subscales are considered normal, with 8-10 borderline and 
11 or over indicating clinical 'caseness'


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Attachment 9: Work Productivity and Activity Impairment (WPAI) [Sample]
Work Productivity and Activity Impairment Questionnaire: 
CROHN’S DISEASE (WPAI-CD)
The following questions ask about the effect of your Crohn’s disease on your ability to work and 
perform normal daily activities. Please fill in the blanks or circle a number, as indicated.
1. Are you currently in paid employment? ______NO
______YES
NO, tick “NO” and skip to question 6.
The next questions refer to the past seven days, not including today.
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your Crohn’s disease? Include hours you missed on sick days, times you went 
in late, left early, etc., because of your Crohn’s disease. Do not include time you missed to 
participate in this study.
______HOURS
3. During the past seven days, how many hours did you miss from work because of any other 
reason, such as annual leave, holidays, time off to participate in this study?
______HOURS
4. During the past seven days, how many hours did you actually work?
______HOURS (If “0”, skip to question 6)


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5. During the past seven days, how much did your Crohn’s disease affect your productivity 
while you were working? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual. If Crohn’s disease affected your work only a little, choose a low number. Choose a 
high number if Crohn’s disease affected your work a great deal. 
Crohn’s disease 
had no effect on 
my work
Crohn’s disease 
completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6. During the past seven days, how much did your Crohn’s disease affect your ability to 
perform your normal daily activities, excluding your job? 
By normal activities, we mean the usual activities you perform, such as working around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were limited in 
the amount or kind of activities you could perform and times you accomplished less than you 
would like. If Crohn’s disease affected your activities only a little, choose a low number.
Choose a high number if Crohn’s disease affected your activities a great deal. 
Crohn’s disease 
had no effect on 
my daily 
activities
Crohn’s disease 
completely 
prevented me from 
doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
WPAI-CD (UK English)


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Attachment 10:
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 in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor as described in 
Section 12.3.2, Serious Adverse Events. These anticipated events are exempt from expedited reporting as 
individual single cases to Health Authorities. However if based on an aggregate review, it is determined 
that an anticipated event is possibly related to study drug, the sponsor will report these events in an 
expedited manner.
Serious adverse events relating to lack of efficacy (eg, events attributed to Crohn’s disease or related 
symptoms such as abdominal pain, diarrhea, nausea, vomiting, fistula, and rectal bleeding) or progression 
of the disease under study (ie, stenosis, stricture, ileus, or bowel obstruction) will not be reported as 
15 day SUSARs (with the exception of fistula complications or fistula events that are indicated by the 
investigator to represent infections).
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of prespecified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).


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Attachment 11: 
Risk/Benefit Assessment of the Investigational Medicinal Product Dossier


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INVESTIGATOR AGREEMENT
PPD
PPD
PPD

SAP_001.pdf: 
1 
Final, Date: 30 June 2020  
 
Janssen EMEA * 
 
 
Statistical Analysis Plan  Main analysis Week 48 
 
Patients Treated with Ustekinumab 
 
STARDUST 
Protocol CNTO1275CRD3005; Phase 3b 
 
 CNTO1275  (ustekinumab)  
 
 
 
* Janssen EMEA is an organization in Europe, the Middle East, and Africa that operates through different legal 
entities in various countries. The legal entity acting as the sponsor for Janssen EMEA studies may vary, such as, 
but not limited to Janssen Pharmaceutica NV or Janssen-Cilag International.  
 
 
Status: 
Final 
Date: 
30 June 2020 
Prepared by: 
Janssen-Cilag BV, The Netherlands 
Document No.: EDMS-RIM-91304 
 
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.
NCT03107793


CNTO1275  (ustekinumab)  
 
Statistical Analysis Plan CNTO1275CRD3005
2 
Fi
l D t
30 J
2020
 
 
 
 
Study of Treat to Target Versus Routine Care Maintenance Strategies in 
PPD
PPD
PPD


CNTO1275  (ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275CRD3005 
3 
Fi
l D t
30 J
2020
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 3
AMENDMENT HISTORY .............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION ................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Visit Windows ................................................................................................................................... 8
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 9
2.3.
Analysis Sets .................................................................................................................................... 9
2.3.1.
All Enrolled Analysis Set ............................................................................................................... 9
2.3.2.
Full Analysis Set ........................................................................................................................... 9
2.3.3.
Full Randomized Analysis Set ...................................................................................................... 9
2.3.4.
Efficacy Analysis Set(s) ................................................................................................................ 9
2.3.5.
Per-Protocol Analysis Set(s) ......................................................................................................... 9
2.3.6.
Safety Analysis Set ....................................................................................................................... 9
2.3.7.
IUS All enrolled Analysis Set ........................................................................................................ 9
2.3.8.
IUS Efficacy Analysis Set ............................................................................................................. 9
2.3.9.
Pharmacokinetics Analysis Set .................................................................................................... 9
2.4.
Definition of Subgroups .................................................................................................................. 10
2.5.
Study Day and Relative Day .......................................................................................................... 10
2.6.
Baseline and Endpoint ................................................................................................................... 10
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 10
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 11
4.
SUBJECT INFORMATION ................................................................................................................ 11
4.1.
Demographics and Baseline Characteristics ................................................................................. 11
4.1.1.
Demographics ............................................................................................................................. 11
4.1.2.
Baseline Characteristics ............................................................................................................. 12
4.2.
Medical History ............................................................................................................................... 13
4.3.
Disposition Information .................................................................................................................. 13
4.4.
Treatment Compliance ................................................................................................................... 13
4.5.
Extent of Exposure ......................................................................................................................... 13
4.6.
Protocol Deviations ........................................................................................................................ 14
4.7.
Prior and Concomitant Medications ............................................................................................... 14
5.
EFFICACY ......................................................................................................................................... 14
5.1.
Analysis Specifications .................................................................................................................. 14
5.1.1.
Level of Significance ................................................................................................................... 15
5.1.2.
Data Handling Rules ................................................................................................................... 15
5.2.
Primary Efficacy Endpoint .............................................................................................................. 15
5.2.1.
Definition ..................................................................................................................................... 15
5.2.2.
Estimand ..................................................................................................................................... 15
5.2.3.
Analysis Methods ........................................................................................................................ 15
5.3.
Other Efficacy Endpoints ............................................................................................................... 16
5.3.1.
Secondary Efficacy Endpoints at (or through) Week 48 ............................................................. 16
5.3.2.
Secondary Efficacy Endpoints - PRO Endpoints ........................................................................ 19
5.3.3.
Healthcare resource utilization endpoints .................................................................................. 19
5.3.3.1.
Definition .................................................................................................................................. 20
5.3.3.1.1.
Video Ileocolonoscopy ......................................................................................................... 20
5.3.3.1.2.
 ................................................................................ 20
5.3.3.1.3.
C-reactive Protein and Fecal Calprotectin ........................................................................... 20
5.3.3.1.4.
Fistula Assessment .............................................................................................................. 20
5.3.3.1.5.
Inflammatory Bowel Disease Questionnaire (IBDQ) ............................................................ 21
5.3.3.1.6.
EuroQoL-5D-5L Health Questionnaire (EQ-5D-5L) ............................................................. 21


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5.3.3.1.7.
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) .............................. 21
5.3.3.1.8.
Hospital Anxiety and Depression Scale (HADS).................................................................. 21
5.3.3.1.9.
Work Productivity and Activity Impairment (WPAI) .............................................................. 21
5.3.3.1.10.
Time Lost From Work ........................................................................................................... 22
5.3.3.2.
Analysis Methods .................................................................................................................... 22
5.3.3.3.
Data Handling Rules ................................................................................................................ 22
5.3.3.3.1.
Video- Ileocolonoscopy ........................................................................................................ 22
5.3.3.3.2.
CDAI ..................................................................................................................................... 22
5.3.3.3.3.
IBDQ ..................................................................................................................................... 22
5.3.3.3.4.
EQ-5D-5L ............................................................................................................................. 23
5.3.3.3.5.
HADS ................................................................................................................................... 23
5.3.3.3.6.
FACIT-F ................................................................................................................................ 23
5.3.3.3.7.
WPAI .................................................................................................................................... 23
5.3.3.4.
Treatment failure rules ............................................................................................................. 24
5.3.3.5.
Missing Data Imputation .......................................................................................................... 24
6.
Exploratory IUS Variable(s) ........................................................................................................... 24
6.1.
Definition ..................................................................................................................................... 26
6.1.1.
Analysis Methods ........................................................................................................................ 27
7.
SAFETY ............................................................................................................................................. 28
7.1.
Adverse Events .............................................................................................................................. 29
7.2.
Vital Signs and Physical Examination Findings ............................................................................. 29
8.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 30
8.1.
Pharmacokinetics ........................................................................................................................... 30
8.2.
Immunogenicity .............................................................................................................................. 31
9.
HEALTH ECONOMICS ..................................................................................................................... 32
REFERENCES ............................................................................................................................................ 32
ATTACHMENTS ......................................................................................................................................... 32
1.
STATISTICAL ANALYSIS PLAN FOR INTERIM ANALYSIS .......................................................... 32
2.
VITY INDEX (SAMPLE).......................................................................... 33
3.
INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (IBDQ) ................................................... 34
4.
EUROQOL-5D-5L HEALTH QUESTIONNAIRE (EQ-5D-5L)  SAMPLE UK ENGLISH VERSION 41
5.
FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY-FATIGUE (FACIT-F)............. 45
6.
HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) [SAMPLE] ......................................... 46
7.
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT (WPAI) [SAMPLE] .................................. 48
 
 
 
 


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AMENDMENT HISTORY 
Not apllicable. 
ABBREVIATIONS 
 
Abbreviation Text 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
BWT 
bowel wall thickness 
CDAI 
 
CDAI-70 
70-point improvement versu
 
CI 
Confidence interval 
CRF 
Case report form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CT 
computed tomography 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECCO 
rganisation 
eCRF 
Electronic case report form 
ESGAR 
European Society of Gastrointestinal and Abdominal Radiology 
EU 
European Union 
EQ-5D-5L  
EuroQoL-5D-5L Health Questionnaire 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FC 
Fecal calprotectin 
FDA 
Food and Drug Administration 
HADS 
Hospital Anxiety and Depression Scale 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-Treat 
IUS 
high-frequency intestinal ultrasound 
IV 
Intravenous 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PD 
Pharmacodynamic 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PRO 
Patient-reported outcome(s)  
QoL 
Quality of life 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SES-CD 
 
SmPC 
Summary of Product Characteristics 
TB 
Tuberculosis 
TNF 
tumor necrosis factor 
WHO-DD 
World Health Organization Drug Dictionary 
WPAI 
Work Productivity and Activity Impairment 


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1. 
INTRODUCTION 
In this trial, after a screening period of up to 5 weeks, eligibility of subjects will be evaluated, and all 
eligible subjects will initiate intravenous (IV) induction treatment with ustekinumab followed by a 
90 mg SC injection of ustekinumab at week 8. At Week 16, subjects who do not achieve a CDAI 
improvement of 70 points versus Week 0 will leave the study. Subjects who remain in the study will be 
randomized in a 1:1 ratio to either one of two arms for open-label maintenance treatment up to Week 
48: the treat to target arm or the routine care arm.  
Within this study an exploratory ultrasound substudy is started with the aim to collect high-frequency 
intestinal ultrasound (IUS) parameters to assess changes in IUS parameters indicating transmural 
response to treatment with ustekinumab up to week 48. Participation in this substudy is optional for 
subjects participating in the main study.  
From Week 48, subjects will continue ustekinumab treatment in the study extension period, up to Week 
104. The frequency of dosing will be based on endoscopic and/or clinical remission at Week 48, and 
subsequently on clinical remission and biomarker findings. 
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the main analysis of the first 48 weeks. The main population will consist of all 
subjects enrolled in the study who receive at least one study treatment and who are randomized to T2T 
or RC arm. Results will be presented per treatment arm. Subject characteristics, efficacy and safety 
endpoints will be included in this main analysis.  
Subject characteristics, based on subjects who participated in substudy, and all IUS parameters assessed 
during the first 48 weeks of the study will also be included in this main analysis. 
1.1. 
Trial Objectives 
The primary objective is to evaluate the efficacy of a treat to target strategy coupled with early 
endoscopic assessment versus a clinically driven (routine care) approach in achieving endoscopic 
response. 
Secondary objectives are: 
 To examine the robustness of the primary endpoint analysis, sensitivity analyses of the primary 
endpoint will be conducted. 
 To evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach in achieving endoscopic remission, mucosal healing, 
clinical remission and clinical response. 
 To evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach in eliminating the need for corticosteroids while 
maintaining disease control. 
 To evaluate the effect of a treat to target strategy coupled with early endoscopic assessment versus 
a clinically driven (routine care) approach on serum CRP and FC levels and on health-related quality 
of life (QoL), patient-reported outcomes (PROs) and pharmacoeconomics. 
 To describe the safety of two SC ustekinumab maintenance regimens in a randomized population.
Exploratory objectives within the substudy are to explore: 
 the effectiveness of ustekinumab treatment in achieving IUS response. 


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 the effectiveness of ustekinumab treatment in achieving IUS remission. 
 the effect of ustekinumab treatment on BWT. 
 the effect of ustekinumab treatment on vascularization as determined by color Doppler signal. 
 the effect of ustekinumab treatment on loss of bowel wall stratification. 
 the effect of ustekinumab treatment on inflammatory mesenteric fat. 
1.2. 
Trial Design 
This is a randomized, open-label, parallel-group, multicenter, multinational, Phase 3b interventional 
A target of 650 
adult male and female subjects with endoscopic evidence of active disease will be enrolled. 
During a screening period of up to 5 weeks, eligibility of subjects will be evaluated, and centrally-read 
endoscopic assessments at screening will be used for baseline evaluation. At Week 0, all eligible subjects 
will initiate IV induction treatment with ustekinumab, in line with the EU SmPC, on a weight-tiered 
basis at a dose of approximately 6 mg/kg IV. At Week 8, all subjects will receive a 90 mg SC injection 
of ustekinumab. 
At Week 16, subjects who do not achieve a CDAI improvement of 70 points versus Week 0 will leave 
the study. Subjects who remain in the study will be randomized in a 1:1 ratio to either one of two arms 
for open-label maintenance treatment up to Week 48: the treat to target arm or the routine care arm. 
Subjects randomized to the routine care arm will receive an ustekinumab maintenance dosing regimen 
consistent with the EU SmPC. 
Maintenance treatment in the treat to target arm will also involve initial assignment to 12 weekly or 8 
weekly 90 mg SC treatment, which in this arm will be based on endoscopic results at Week 16. However, 
within the treat to target approach, there is the potential for more intensive management, with 
optimization to 4 weekly dosing for subjects failing to meet treatment targets following 8 weekly dosing. 
Treatment targets are based on CDAI and biomarkers (CRP and FC). 
The main study treatment period is 48 weeks, of which 32 weeks will be the randomized maintenance 
treatment period. Subjects completing the study will receive between 3 and 7 maintenance treatment 
doses of study drug, depending on the treatment arm and adjustments to dosing frequency.  
From Week 48, subjects will continue ustekinumab treatment in the study extension period, up to Week 
104. The frequency of dosing will be based on endoscopic and/or clinical remission at Week 48, and 
subsequently on clinical remission and biomarker findings.  
All subjects will have a final safety follow-up visit 16 weeks after the last administration of ustekinumab 
within the study. 
1.3. 
Statistical Hypotheses for Trial Objectives 
coupled with early 
endoscopic assessment will result in a higher endoscopic response rate (defined as the percentage of 
-CD versus baseline) after 48 weeks of treatment, compared 
study is designed to show that the percentage of subjects with endoscopic response at Week 48 in the 


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treat to target arm is 15% higher compared with the routine care arm: endoscopic response in the routine 
care arm is estimated at 30% of subjects, in the treat to target arm is estimated at 45% of subjects. 
The primary endpoint of this study is endoscopic response at Week 48 of the study. Endoscopic response 
is defined as showing (yes or no) a reduction from baseline in the SES-
The null 
hypothesis that is to be tested to address the primary objective of the trial is that there is no difference 
between the routine care and treat to target arm in the primary efficacy endpoint. 
1.4. 
Sample Size Justification 
A Fisher's exact test with a 0.050 two-sided significance level will have 80% power to detect the 
difference between the routine care arm proportion of 30% and the treat to target arm proportion of 45% 
when the sample size in each group is 174. With an estimated CDAI 70 response at Week 16 between 
65% and 70%, and a dropout rate between 10% and 17.5%, a total of 650 subjects should be enrolled. 
1.5. 
Randomization and Blinding 
As this is an open study, blinding procedures are not applicable. 
At Week 16, subjects achieving 
 0), will be 
randomized in a 1:1 ratio to one of two ustekinumab maintenance treatment arms: the treat to target arm 
or the routine care arm. Central randomization will be implemented in this study. Subjects will be 
randomly assigned to one of two treatment groups based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The randomization will 
be balanced by using randomly permuted blocks and will be stratified by whether the subject was 
biologic naïve at baseline or 
according to baseli
 
2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Visit Windows 
Unless otherwise specified, actual scheduled visits will be used for over time summaries and listings, 
with no visit windows applied. 
Only for endpoint: As subjects do not always adhere to the protocol visit schedule, the following rules 
are applied to assign the early termination visits to an analysis visit. Listed below are the visit windows 
and the target days for each visit. The reference day is Study Day 1. If a subject has 2 or more actual 
visits in 1 visit window, the visit closest to the target day will be used as the protocol visit for that visit 
window. The other additional visit(s) will not be used in the summaries or analyses, but they can be used 
for determination of clinically important endpoints. If 2 actual visits are equidistant from the target day 
within a visit window, the later visit is used. 
All assignments will be made in chronological order. Once a visit date is assigned to a visit window, it 
will no longer be used for a later time point except for the endpoint. Listed below (Table 1) are the visit 
windows and the target days for visit week 16 and week 48 that should be used to reschedule an early 
termination visit. 
Table 1  Visit Windows 
Scheduled 
Visit 
Number 
Time 
Interval 
(label on 
output) 
Time 
Interval 
(Day)* 
Target 
Time Point 
(Day) 
1 
Screening 
< 1
-14 to 1


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2 
Baselinea 
<=1
1
3 
Week 8 
44-85
57
4 
Week 16b 
86-141 
113 
5 
Week 48 
306-377c 
336 
* Relative to Study Day 1 
a First medication day is Day 1 (baseline  week 0). 
b Randomization is at Week 16 
c Window is based on actual week 48 visits  
 
2.2. 
Pooling Algorithm for Analysis Centers 
Not applicable. 
2.3. 
Analysis Sets 
2.3.1. 
All Enrolled Analysis Set 
The all enrolled analysis set includes all subjects who were not screen failures or did not drop out during 
screening. 
2.3.2. 
Full Analysis Set  
The full analysis set (FAS) includes all enrolled subjects who received at least 1 dose of study agent.
2.3.3. 
Full Randomized Analysis Set  
The all full analysis set (FRAS) includes all subjects from FAS that were randomized at week 16, 
regardless of study treatment being administered once randomized. Data of the first 16 weeks of 
induction for all subjects in FAS was analyzed as an interim analysis (see section 3). 
2.3.4. 
Efficacy Analysis Set(s) 
The Efficacy analysis set includes all subjects from FRAS. 
2.3.5. 
Per-Protocol Analysis Set(s) 
The per protocol analysis set (PP) includes the subjects in the full analysis set (FAS) who are in 
compliance with the protocol.  
2.3.6. 
Safety Analysis Set 
The safety analysis set includes all subjects from FRAS. 
2.3.7. 
IUS All enrolled Analysis Set 
The IUS all enrolled analysis set includes all subjects from the FAS that participated in the 
CNTO1275CRD3005 substudy. That is, signed ICF for substudy and at least one IUS assessment has 
been performed.  
2.3.8. 
IUS Efficacy Analysis Set 
The IUS efficacy analysis set (IUS FRAS) includes all subjects from FRAS that participated in the 
CNTO1275CRD3005 IUS substudy with most affected part of the bowel available at baseline.  
2.3.9. 
Pharmacokinetics Analysis Set 
The PK Analysis Set is defined as subjects from FAS that have at least 1 valid blood sample drawn for 
PK analysis. 


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2.4. 
Definition of Subgroups 
TBD 
2.5. 
Study Day and Relative Day 
Study Day 1 or Day 1 refers to the start of the first study agent administration. All efficacy and safety 
assessments at all visits will be assigned a day relative to this date. 
Study day or relative day for a visit is defined as: 
 
Visit date - 
 date of Day 1 
 
Visit date - date of Day 1, if visit date < date of Day 1 
There is no 'Day 0'. 
2.6. 
Baseline and Endpoint 
Baseline is defined as the last observation prior to the start of the first study agent administration. Date 
and time of baseline assessment can be the same as date and time of first study agent administration (for 
 
Endpoint is defined as the last available postbaseline result within the main analysis period (i.e. first 48 
weeks of the study). Unscheduled visit results are included in this definition and will be considered as 
the endpoint value if the unscheduled visit result is the last postbaseline result available within the 
analysis period. 
2.7. 
Imputation Rules for Missing AE Date/Time of Onset/Resolution 
Partial AE onset dates will be imputed as follows: 
 If the onset date of an 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 earliest, if 
month/year of the onset of AE and month/year of the study agent start date and 
month/year of the AE resolution date are same 
 If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of: 
 January 1 of the year of onset, as long as this date is on or after the study agent start date 
 Month and day of the study agent start date, if this date is the same year that the AE 
occurred 
 Last day of the year if the year of the AE onset is prior to the year of the study agent start 
date,  
 The AE resolution date. 
 Completely missing onset dates will not be imputed. 
Partial AE resolution dates not marked as ongoing will be imputed as follows: 


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 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 day of the date of death, if the death 
occurred in that month. 
 If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death occurred 
in that year. 
 Completely missing resolution dates will not be imputed. 
 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
An Interim Analysis has been performed on all subjects that received at least one study medication and 
either completed the week 16 period or discontinued the study prior to week 16. A separate SAP has 
been developed for this interim analysis (See attachment 1) 
4. 
SUBJECT INFORMATION 
Descriptive statistics (mean, standard deviation (SD), median, inter quartile (IQ) range, 95% confidence 
interval (CI), minimum and maximum) will be provided for continuous variables. Counts, percentages 
and 95% CI intervals will be provided for categorical variables. No formal statistical analyses for 
treatment group comparisons will be performed. All results in this section will be based on the Full 
Analysis Set and will be reported both overall, as well as per treatment group, unless otherwise specified. 
4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristic variables will be descriptively summarized by randomized 
treatment groups and overall. No formal statistical comparison is planned.  P-values will not be provided. 
4.1.1. 
Demographics 
Table 2 presents a list of the demographic variables that will be summarized. Demographic data will 
also be analyzed for the IUS Full Analysis Set. 
Table 2: Demographic Variables 
Continuous Variables: 
 Summary Type 
Age (years) 
Descriptive statistics (N, 
mean, standard deviation 
[SD], median, 95% CI and 
range [minimum and 
maximum] 
Weight (kg) 
Height (cm) 
Body Mass Index (BMI) (kg/m2) 
Temperature (ºC) 
Pulse (beats/min) 
Systolic Blood Pressure (mmHg) 
Diastolic Blood Pressure (mmHg) 
Categorical Variables: 
Frequency distribution with 
the number and percentage of 
subjects in each category. 
Age (18-25 years, 26-50 years, 51-64 years, and >65 years)   
Sex (male, female) 
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, 
overweight 25-
 
 


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4.1.2. 
Baseline Characteristics 
Table 3 presents a list of the baseline disease characteristics that will be summarized.   
Table 3: Baseline Disease Characteristics 
Continuous Variables: 
 Summary Type 
Time from diagnosis to first study agent administration (months) 
Descriptive 
statistics (N, 
mean, standard 
deviation [SD], 
median, 95% CI 
and range 
[minimum and 
maximum] 
CDAI 
Hematocrit (%) 
SES-CD 
IBDQ total score 
EQ-5D-5L VAS, Index score and levels of each of the 5 dimensions, 
i.e. mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression 
FACIT-F 
HADS-A and HADS-D subscale scores for anxiety and depression 
Time lost from work 
WPAI for absenteeism, presenteesism, work productivity loss, and 
activity impairment. 
CRP 
FC 
Categorical Variables: 
Frequency 
distribution with 
the number and 
percentage of 
subjects in each 
category. 
Location of disease (Ileal, Colonic, Ileocolonic, N/A) 
ECG method (6 Lead Standard,10 Lead Standard, 12 Lead Standard) 
ECG Overall Interpretation (Normal, Abnormal, Not Evaluable) 
Is ECG Abnormal Interpretation Clinically significant (Yes, No) 
What was Subject's Previous Experience with Tuberculosis (History 
of Tuberculosis, Occupational exposure to individuals with active TB, 
Personal exposure to individuals with active TB, None) 
Tuberculosis Chest Radiograph Result (Normal; Abnormal, no 
suspicion of TB; Abnormal, suspicion of TB) 
TB assessment performed (Quantiferon TB Gold In-Tube test; 
Tuberculin skin test) 
Quantiferon TB Gold In-Tube test result (Positive, Negative) 
Tuberculin skin test result (Positive, Negative) 
Has the subject had any Crohn's Disease Related Hospitalizations 
(Yes, No) 
Has the subject had any Crohn's Disease Related Surgeries (Yes, No) 
Number of open and draining (i.e. not closed) fistulas present 
Locations where open and draining fistulas are present (Perianal, 
Abdominal, Rectovaginal, Enterovesicular, Other) 
 (Ileocolonic, Ileal, Colonic, Not 
applicable) 
Prior exposure to biologics 
 (Biologic 
naïve, prior exposure to 1 biologic|) 


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Baseline SES-CD score (SES-CD 
, SES CD >16) 
 
EQ-5D-5L levels of each of the 5 dimensions i.e. mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression 
 
HADS-A and HADS-D subscale scores for anxiety and depression 
categorized as normal (score of 0 to 7), mild (score of 8 to 10), 
moderate (score of 11 to 14), and severe (score of 15 to 21). 
WPAI: Currently in paid employment (Yes, No) and 7-point 
improvement (yes, No) for each domain separately 
Number of draining fistulas 
 
4.2. 
Medical History 
The number and percentage of subjects with any abnormality will be summarized overall and per body 
system. Specifications of abnormalities ongoing at study entry as well as overall will be summarized per 
body system. 
4.3. 
Disposition Information 
The number of subjects in each analysis set will be summarized per treatment arm. In addition, the 
distribution of subjects in the Full Analysis Set by country will be presented. 
The subjects randomized at week 16 will be summarized. 
For the Full Analysis set the number of subjects per visit will be summarized. Subjects who discontinued 
study agent prior to Week 48 along with the reasons for discontinuation and the dose regimen at time of 
discontinuation, and subjects who terminated study participation prior to Week 48 along with the reasons 
for termination and the dose regimen at time of study termination, will be summarized per treatment 
arm. 
4.4. 
Treatment Compliance 
A listing of subjects who were randomized but were never treated will be provided. The number of 
subjects in the Treat to Target arm who did not meet the treatment target, but dose was not adjusted 
accordingly, will be summarized as frequency distribution through Week 48 based on the full analysis 
set. In addition, the number of subjects in the Treat to Target arm for whom dose was adjusted although 
treatment target was met, will be summarized as frequency distribution. Subjects in the RoC arm for 
whom dose was adjusted to 4 weekly regimen will be listed. 
4.5. 
Extent of Exposure 
Whether ustekinumab was administered (yes or no), how it was administered (Administered at site by 
site staff, Self-injected by patient at site, Self-injected by patient at home) and the dose that was 
administered, will be summarized by treatment group for each visit through week 48.  For week 0 the 
dose adminis
For each post-baseline visit the number (%) of subjects with a dose adjustment/dose not administered as 
well as the reason for dose adjustments/doses not administered will be summarized by treatment group 
and visit. For each visit at or after week 16 the dose regimen assigned and administered will also be 
summarized by treatment arm. The total number of injections administered as well as total number of 
injections administered per 4 weeks of treatment exposure, will be summarized descriptively by 


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treatment arm through Week 48 for the full analysis set, both overall and per assigned regimen at week 
16.  
The distribution of the time to first optimization of dosing frequency will be displayed with Kaplan-
Meier curves, per arm and per assigned regimen at week 16 within each arm. Subjects with any dose 
optimization from randomization till week 48 at any time will be conside
of dose optimization will be used in the time to event calculation. Subjects who complete the 48 weeks 
or discontinue prior to week 48 without any dose optimization will be censored and the date of 
completion or discontinuation will serve as the time of censoring. 
4.6. 
Protocol Deviations 
For all randomized subjects the number (%) of subjects with a major protocol deviation through Week 
48 will be summarized per treatment arm by the standard categories (Developed withdrawal criteria but 
not withdrawn; Entered but did not satisfy criteria; Received a disallowed concomitant treatment; 
Received wrong treatment or incorrect dose; Other). 
A listing of subjects who have a major protocol deviation will be provided. 
4.7. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHO-
DD). Prior medications are defined as any therapy used before the day of first dose of study agent. 
Concomitant medications are defined as any therapy used on or after the same day as the first dose of 
study agent, including those that started before and continued after the first dose of study agent.  
Summaries of prior and concomitant medications in the Full Analysis set will be presented by ATC term. 
The proportion of subjects who receive each concomitant medication will be summarized as well as the 
proportion of subjects who receive at least one concomitant medication. 
The number (%) of subjects that were prior exposed to 1 biologic or were biologic naïve will be 
summarized. For subjects prior exposed to 1 biologic the generic of the biologic will be summarized as 
well as the reason for discontinuation of the prior biologic (Inadequate response, Loss of response, 
Intolerance, Contraindications, Physicians decision, Non-Medical, Unknown, Other reason). 
The number (%) of subjects using corticosteroids at study entry, week 8, randomization visit, week 48 
visit and at endpoint will be summarized, including descriptive statistics for the prednisone equivalent 
dose. For the subjects using corticosteroids at randomization visit the number of subjects that were 
tapered down before week 48 and the number of subjects that started corticosteroids after tapering down 
will summarized descriptively 
5. 
EFFICACY 
The efficacy analyses described in this section will be based on the Full Analysis set, i.e. subjects 
randomized at Week 16 of this study. Results will be reported per treatment group. 
5.1. 
Analysis Specifications 
In general, descriptive statistics (e.g., mean, median, SD, IQ range, 95% CI, minimum and maximum) 
will be used to summarize continuous and ordinal variables. Counts, percentages and 95% CIs will be 
used to summarize categorical variables. Graphical data displays (e.g., line plots) may also be used to 
summarize the data whenever appropriate. 


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Analyses suitable for categorical data (e.g., chi-square tests, Cochran-Mantel-Haenszel chi-square tests, 
or logistic regression, as appropriate) will be used to compare the proportions of subjects achieving 
selected endpoints (e.g., endoscopic response). Continuous response parameters will be compared using 
an analysis of variance (ANOVA) or covariance (ANCOVA), unless otherwise specified. If the 
normality assumption is in question, an ANOVA or ANCOVA on the van der Waerden normal scores 
will be used. 
Time to event endpoints will be compared between each of the ustekinumab treatment groups and the 
using the stratified log-rank test with prior exposure to biologic and baseline SES-
 
as the stratification factors, unless otherwise specified.  The Kaplan-Meier curve by treatment group will 
be provided 
When stratification factors are used for analysis, the stratification factors will not be as determined by 
the IWRS but will be based on the actual data collected. 
5.1.1. 
Level of Significance 
All statistical tests will be interpreted at the 5% significance level (2-tailed), unless otherwise specified. 
5.1.2. 
Data Handling Rules 
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 post-baseline value will be 
carried forward for subjects with missing data. In addition observed case analysis can be added. 
5.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is endoscopic response at Week 48, based on the simple 
(SES-CD).   
5.2.1. 
Definition 
Endoscopic response at Week 48 is defined as showing (yes or no) a reduction from baseline in SES-
 
5.2.2. 
Estimand 
Population: adult subjects with moderate to severely active 
previously have had an inadequate response with, lost response to, have been intolerant to, or have 
medical contraindications to either conventional therapy, or one previous biologic therapy approved for 
the treatme
. 
Endpoint: the proportion of subjects with endoscopic response at Week 48. 
Intercurrent event: Premature discontinuation of study treatment 
Population-level summary: the proportion of subjects with endoscopic response at Week 48 for the 
T2T group vs RoC group. 
5.2.3. 
Analysis Methods 
For the primary endpoint, the number and proportion of subjects achieving an endoscopic response 
(defined as a reduction from baseline in SES-
48 will be summarized. The 
endpoints will be compared between the T2T treatment group and the RoC treatment group using 2-


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sided Cochran Mantel Haenszel chi-square test, stratified by whether the subject was biologic-naïve at 
ccording to baseline 
SES-
-CD >16 at a significance level of 0.05.  
Randomized subjects who stop treatment before reaching Week 48 due to any reason, or subjects without 
endoscopic data at Week 48 will be analyzed as non-responders. 
Sensitivity Analyses 
 
To assess the robustness of the primary endpoint analysis, the following two sensitivity analyses will 
be conducted. 
 
(1) Randomized subjects who stop treatment before reaching Week 48 due to reasons other than 
lack/loss of efficacy will be excluded from the analysis. 
(2) Last observation carried forward: subjects who have a missing SES-CD score at week 48 or 
who stopped treatment before reaching week 48 will have their last SES-CD score carried 
forward. 
 
5.3. 
Other Efficacy Endpoints 
The other efficacy endpoints will not be adjusted for multiplicity, and statements of significance for 
these endpoints will be based on nominal p-values.  
5.3.1. 
Secondary Efficacy Endpoints at (or through) Week 48 
Table 4 presents a list of secondary efficacy endpoints that will be summarized. 
Table 4: Secondary efficacy endpoints 
Categorical Variables: 
 Summary Type 
Endoscopic remission (defined as an SES-
16a, 
week 48 and endpoint 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 by SES-
 
 
 
Frequency 
distribution with the 
number and 
percentage of 
subjects in each 
category. 
 
 
 
 
 
 
 
Corticosteroid-free endoscopic response at week 16a, Week 48 and 
endpoint (defined as a reduction from baseline in SES-CD score of 
week 48 and endpoint, respectively)  
 all patients 
 for the subjects who were receiving corticosteroids at baseline, 
separately 
Endoscopic response (50%) at week 16a and endpoint  
Endoscopic response (25%, 100%) at week 16a, week 48 and 


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Endoscopic response (25%, 50%, 100%) at week 16a, week 48 and 
endpoint 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 by SES-
 
 by disease duration (quartiles) 
 by disease location 
Mucosal healing defined as the complete absence of mucosal 
ulcerations in any ileocolonic segment at week 16a, week 48 and 
endpoint 
Clinical remission (CDAI score of < 150 points) at week 8, week 16, 
week 48 and endpoint 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
-point reduction from the baseline CDAI score, 
or a CDAI score of < 150 points) at week 8, week 16, week 48 and 
endpoint 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
Corticosteroid-free clinical remission at Week 48 and endpoint 
(defined as a CDAI score < 150 and not taking any corticosteroids for 
at least 30 days prior to Week 48)   
 all patients 
 for the subjects who were receiving corticosteroids at baseline, 
separately 
CDAI-70 responders at week 8, week 16, week 48 and endpoint 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
number of draining fistulas) at Week 48 
assessment visit through and including week 48, and endpoint* 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 


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Complete biomarker response (i.e. both CRP and FC should be 
normalized) at week 8, week 16 and any assessment visit through and 
including week 48, and endpoint***  
 all  
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 
Complete biomarker response (i.e. both CRP and FC should be 
normalized) at week 8, week 16 and any assessment visit through and 
including week 48, and endpoint***  
 all  
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 
Normalized FC 
assessment visit through and including week 48, and endpoint **  
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 
 
CRP change (%) 
week 16 and 
any assessment visit through and including week 48, and endpoint 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 for subjects with elevated CRP at baseline (i.e. CRP > 3 mg/L) 
 for subjects with elevated CRP at baseline (i.e. CRP > 3 mg/L) 
and biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 
 
any assessment visit through and including week 48, and endpoint 
 all patients 
 for biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 for subjects with elevated FC at baseline (i.e. FC > 250 µg/g) 
 for subjects with elevated FC at baseline (i.e. FC > 250 µg/g) 
and biologic-naïve and prior exposed to 1 biologic subjects, 
separately 
 
 
a 
: For T2T arm only 
* 
: Subjects with normalized CRP at baseline will be excluded 
** 
: Subjects with normalized FC at baseline will be excluded 
*** : Subjects with normalized CRP and Normalized FC at baseline will be excluded 
Continuous Variables: 
 Summary Type 
SES-CD score at week 0, week 16a, week 48 and endpoint  
Descriptive 
statistics (N, mean, 
standard deviation 
[SD], median, 95% 
CI and range 
[minimum and 
maximum] 
SES-CD changes vs. week 0, at week 16a, week 48 and endpoint  
CDAI score at visits week 0, week 8, week 16, week 48 and endpoint  
CDAI changes vs. week 0 at week 8, week 16, week 48 and endpoint 
CRP value at week 0, week 8, week 16 and any assessment visit 
through and including week 48, and endpoint 
CRP changes vs. week 0 at week 8, week 16 and any assessment visit 
through and including week 48, and endpoint 


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FC value at week 0, week 8, week 16 and any assessment visit through 
and including week 48, and endpoint 
FC changes vs week 0 at week 8, week 16 and any assessment visit 
through and including week 48, and endpoint 
a : T2T arm only 
 
 
5.3.2. 
Secondary Efficacy Endpoints - PRO Endpoints 
Table 5 presents a list of secondary efficacy endpoints  PROs that will be summarized. 
 
Table 5: Secondary efficacy endpoints  PRO endpoints 
Continuous Variables: 
 Summary Type 
IBDQ total score and change vs. week 0 at week 16, week 48 and 
endpoint 
Descriptive 
statistics (N, mean, 
standard deviation 
[SD], median, 95% 
CI and range 
[minimum and 
maximum] 
IBDQ domain scores and change vs. week 0 at week 16, week 48 and 
endpoint 
EQ-5D-5L VAS and EQ-5D-5L Index score at week 0, week 16, 
week 48 and endpoint 
EQ 5D-5L VAS and EQ-5D-5L Index changes vs. week 0, week 16, 
week 48 and endpoint 
FACIT-F score at visits week 0, week 16, week 48 and endpoint 
FACIT F changes vs week 0 at visits week 16, week 48 and endpoint
HADS score for both Anxiety and Depression at visits week 0, week 
16, week 48 and endpoint 
HADS changes vs week 0 for both Anxiety and Depression at visits 
week 16, week 48 and endpoint 
Categorical Variables: 
 Summary Type 
IBDQ response 
-point improvement in IBDQ score from baseline) 
at week 16, week 48 and endpoint 
Frequency 
distribution with 
the number and 
percentage of 
subjects in each 
category. 
IBDQ remission 
at week 16, week 48 and endpoint 
EQ-5D-5L: Mobility, Self-care. Usual activity, Pain/Discomfort and 
anxiety/depression at week 0, week 16, week 48 and endpoint 
HADS-A and HADS-D categories (Normal, Mild, Moderate and 
Severe) at week 0, week 16, week 48 and endpoint 
 
5.3.3. 
Healthcare resource utilization endpoints 
Table 6 presents a list of Healthcare resource utilization endpoints that will be summarized. 
 
Table 6: Healthcare resource utilization endpoints 
Continuous Variables: 
 Summary Type 
Time lost from work at week 0, week 16, week 48 and endpoint 
Descriptive 
statistics (N, mean, 
standard deviation 
[SD], median, 95% 
CI and range 
Time lost from work changes vs week 0 at week 16, week 48 and 
endpoint 
WPAI scores for Absenteeism, Presenteeism, Work Productivity Loss 
and Activity Impairment at week 0, week 16, week 48 and endpoint 


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WPAI changes vs week 0 for Absenteeism, Presenteeism, Work 
Productivity Loss and Activity Impairment at week 16, week 48 and 
endpoint 
[minimum and 
maximum] 
Categorical Variables: 
 Summary Type 
Crohn's disease-
-related 
surgeries 
Frequency 
distribution with 
the number and 
percentage of 
subjects in each 
category. 
WPAI: Currently Employed (Yes/No) at week 0, week 16, week 48 and 
endpoint 
WPAI: 7-point improvement from baseline for each domain 
 
5.3.3.1. 
Definition 
5.3.3.1.1. 
Video Ileocolonoscopy 
Centrally-read ileocolonoscopy will be used to assess SES-CD at week 0, week 16 (for T2T arm only) 
and week 48 or early termination. The SES CD is a simple, reproducible, and easy-to-use endoscopic 
scoring system for Crohn's disease, by which endoscopic parameters (ulcer size, ulcerated and affected 
surfaces, stenosis) are scored from 0 to 3. Endoscopic response is defined as showing (yes or no) a 
reduction from baseline in SES-
 Endoscopic remission is defined as SES-CD score 
. 
Mucosal healing is defined as the complete absence of mucosal ulcerations in any ileocolonic segment.
5.3.3.1.2. 
Cr
ex (CDAI) 
CDAI is assessed at week 0, week 8, week 16 and week 48 or early termination and is defined as the 
 based information of 
-related 
variables (attachment 2). These 8 variables are: 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 wellbeing. The last 4 variables are scored over 7 days by the subject on a diary card. 
Subject is defined as CDAI-70 responder at a visit when the CDAI Total Score at that visit is improved 
with at least 70 points versus baseline.  
 100-point reduction from the baseline CDAI Total score, or a CDAI 
Total score < 150. 
Clinical remission is defined as CDAI Total score of <150 points. 
5.3.3.1.3. 
C-reactive Protein and Fecal Calprotectin 
C-reactive protein and fecal calprotectin will be evaluated at week 0, week 8, week 16, each assessment 
or disease flare visit during maintenance, and week 48 or early termination, to monitor efficacy. 
 
 Complete 
biomarker response is defined as both CRP and FC normalized. Subjects with normalized CRP and 
Normalized FC at baseline will be excluded for the analysis of complete biomarker response. 
5.3.3.1.4. 
Fistula Assessment 
All subjects will be assessed for fistulas at week 0 and week 48 or early termination. For subjects with 
fistulizing disease, fistula closure will be assessed. For subjects with fistulas at baseline fistula response 
at week 48 will be analyzed, defined as 
 draining fistulas. 


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5.3.3.1.5. 
Inflammatory Bowel Disease Questionnaire (IBDQ) 
The IBDQ, assessed at week 0, week 16 and week 48 or early termination, is a 32-item self-report 
questionnaire (attachment 3) for subjects with IBD to evaluate the PROs across 4 dimensions: bowel 
symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social 
function (work attendance, need to cancel social events), and emotional function (anger, depression, 
irritability). IBDQ Total score will be defined as the total of the 32 IBDQ questions and will range from 
32 to 224 with higher score indicating better quality of life. IBDQ domain scores are based on the 
following 4 dimensions: 
 Bowel symptoms (question 1, 5, 9, 13, 17, 20, 22, 24, 26, 29) 
 Emotional function (questions 3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32) 
 Systemic symptoms (question 2, 6, 10, 14, 18) 
 Social Function (questions 4, 8, 12, 16, 28) 
 
-point improvement in IBDQ score from baseline. 
IBDQ remission is defined as achieving a IBDQ score  170.  
5.3.3.1.6. 
EuroQoL-5D-5L Health Questionnaire (EQ-5D-5L) 
The EQ-5D-5L (attachment 4) is a frequently used generic instrument to measure health-related QoL 
assessed at week 0, week 16 and week 48 or early termination. It comprises 5 dimensions, i.e. mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no 
problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems.
The EQ-5D-
-rated health on a 20 cm vertical, visual analogue scale 
imagine. 
With the levels of the 5 dimensions the EQ-5D-5L index value is calculated 
health state ranging from 0 to 1, with higher index value indicating better health state.  
5.3.3.1.7. 
 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
The FACIT-F scale, assessed at week 0, week 16 and week 48 or early termination, is a 13-item fatigue 
scale with a 7-day recall period (attachment 5).  It measures the level of fatigue during the usual daily 
activities. The level of fatigue is measured on a 4-point Likert scale (0=very much fatigued to 4=not at 
all fatigued). The higher the score the better the QoL. 
5.3.3.1.8. 
Hospital Anxiety and Depression Scale (HADS) 
The HADS (attachment 6) is a validated 14-item scale with 7 of the items relating to anxiety and 7 
relating to depression, assessed at week 0, week 16 and week 48 or early termination. Each item is scored 
from 0 to 3, with higher scores indicating greater likelihood of depression or anxiety. Cases of anxiety 
or depression are each defined by subscale scores of 8 or greater and categorized as normal (score of 0 
to 7), mild (score of 8 to 10), moderate (score of 11 to 14), and severe (score of 15 to 21).  
5.3.3.1.9. 
Work Productivity and Activity Impairment (WPAI) 
The WPAI, assessed at week 0, week 16 and week 48 or early termination, is a validated 6-question 
daily activities (attachment 7).  The recall period for the WPAI-CD is up to the previous 7 days.  


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5.3.3.1.10. 
Time Lost From Work 
Time lost from work will be collected at week 0, week 16 and week 40 or early termination, by asking 
the subjec
 
5.3.3.2. 
Analysis Methods 
Descriptive statistics will include counts and percentages for categorical data, and median, mean, SD, 
95% CI, and range for continuous data. 
The proportions will be summarized and compared between the two treatment groups using 2-sided 
Cochran-Mantel Haenszel-chi-square test, stratified by whether the subject was biologic naïve at 
by baseline SES-CD 
score (
), unless otherwise specified. 
Continuous response parameters (such as changes from baseline) will be compared between the 
treatment groups using an analysis of covariance (ANCOVA), with baseline value and stratification 
factors as a covariate, unless otherwise specified. If the normality assumption is in question, an 
ANCOVA on the van der Waerden normal scores will be used. Nominal p values will be presented for 
all analyses unless specified otherwise. 
5.3.3.3. 
Data Handling Rules 
5.3.3.3.1. 
Video- Ileocolonoscopy 
If SES-CD is missing at week 0 or week 48 
Non-responder
 
5.3.3.3.2. 
CDAI 
Subjects with a missing CDAI Total score at week 48 
Non-responder
-70 
response at week 48.  Same approach is used for CDAI-70 responder at as well as for Clinical remission 
and Clinical response at each visit analyzed. 
5.3.3.3.3. 
IBDQ 
Total IBDQ score will be the sum of the scores of the 32 items if no more than 4 questions are missing 
for the full IBDQ. If no response is given for a particular question, provided only one response per 
domain is missing, the score should be imputed by the mean score of the other items in the domain. If 
more than 4 questions are missing, then total IBDQ score will be left missing. If more than 1 item is 
missing in a domain, the score for that domain will be left missing.  
Calculation for the 4 domains will be as follows:  
Bowel symptoms: Add up scores for questions (1, 5, 9, 13, 17, 20, 22, 24, 26, 29). 
Emotional function: Add up scores for questions (3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32). 
Systemic symptoms: Add up scores for questions (2, 6, 10, 14, 18). 
Social function: Add up scores for questions (4, 8, 12, 16, 28). 


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5.3.3.3.4. 
EQ-5D-5L 
The EQ-5D descriptive system can be converted into a single summary EQ-5D Index. EQ-5D index 
scores in this analysis will be derived with the algorithm and software provided by the developer based 
on the UK model. 
5.3.3.3.5. 
HADS 
The sum of the 7 items relating to Anxiety provides the Total score for Anxiety and the sum of the 7 
items relating to Depression provides the Total score for Depression (attachment 6). 
5.3.3.3.6. 
FACIT-F 
The Fatigue Subscale score is the sum of the 13-item score. First reversals for all items scores (except 
Question 7 (I have energy) and Question 8 (I am able to do my usual activities)) should be performed. 
The sum of these reversed item scores should be multiplied by 13 and divided by the number items 
answered (attachment 5). Missing items in each subscale will be imputed with the subscale mean value 
unless more than half of the items are missing. 
5.3.3.3.7. 
WPAI 
The WPAI:CD is a validated, self-administered questionnaire that assesses work and activity impairment 
during the past 7 days (see attachment 7). The WPAI produces 4 types of scores:  
- Absenteeism (work time missed)  
- Presenteeism (impairment at work/reduced on-the-job effectiveness)  
- Work Productivity Loss (overall work impairment/absenteeism plus presenteeism)  
- Activity Impairment.  
 
The WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity, i.e., worse outcomes.  
Scoring system   
Questions:  
Q1 = currently employed  
Q2 = hours missed due to 
 
Q3 = hours missed other reasons  
Q4 = hours actually worked  
Q5 = degree 
 affected productivity while working  
Q6 = degree 
 affected regular activities  
 
Multiply scores by 100 to express in percentages.  
 Percent work time missed (absenteeism) due to 
: 100 * Q2/(Q2+Q4)  
 Percent impairment while working (presenteeism) due to 
: 100 * Q5/10  
 Percent overall work impairment (work productivity loss) due to 
: 


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 Percent activity impairment due to 
: 100 * Q6/10  
For the WPAI the following will be provided: 
For all visits through week 48 and LOCF endpoint, the nu
. 
The 4 WPAI parameters are analyzed separately. The Activity Impairment score is calculated for all 
patients. The Absenteeism, Presenteesism and Work Productivity Loss scores are calculated only for 
currently employed patients (variable Currently Employed=YES). 
5.3.3.4. 
Treatment failure rules 
No treatment failure rules are applied. 
5.3.3.5. 
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. Observed data for continuous endpoint will also be available.
6. 
Exploratory IUS Variable(s) 
Intestinal ultrasound (IUS) assessments have been performed on a subgroup of the total population 
(substudy of CNTO1275CRD3005). Participation in this substudy was optional for subjects participating 
in the main study. IUS assessments are performed at week 0, week 4, week 8, week 16 and week 48. 
The gastroenterologist or radiologist performing ultrasonography at the study site will be neither the 
person performing ileocolonoscopy, nor the investigator making prescribing decisions. 
Table 8 presents a list of IUS variables that will be summarized for the IUS Analysis set. Results will be 
reported per treatment arm and overall, unless otherwise specified. The analysis on IUS variables will 
be as observed. As a sensitivity analysis NRI imputation for response variables and LOCF for continuous 
variables might be done.  
Table 8: IUS Variables descriptive statistics 
Categorical Variables: 
 Summary Type
Summary of the most affected part of the bowel at week 0
Frequency 
distribution with 
the number and 
percentage of 
subjects in each 
category. 
IUS response at week 4, 8, 16 and week 48 for the most affected part of the 
bowel as well as for most affected part of the bowel being Ileum or Colon 
IUS remission at week 4, 8, 16 and week 48 for the most affected part of the 
bowel as well as for most affected part of the bowel being Ileum or Colon 
Percentage of subjects with normalization of BWT at week 0, 4, 8, 16 and 
week 48 for the most affected part of the bowel as well as for most affected 
part of the bowel being Ileum or Colon 
Percentage of subjects with normalization of color Doppler signal (defined 
 at week 0, 4, 8, 16 and week 48 for the most affected part of the 
bowel as well as for most affected part of the bowel being Ileum or Colon 


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Percentage of subjects with normalization of echostratification (defined as 
normal/preserved echostratification) at week 0, 4, 8, 16 and week 48 for the 
most affected part of the bowel as well as for most affected part of the bowel 
being Ileum or Colon 
Percentage of subjects with normalization of inflammatory mesenteric fat at 
week 0, 4, 8, 16 and week 48 for the most affected part of the bowel as well 
as for most affected part of the bowel being Ileum or Colon
Fasting status at week 0, 4, 8, 16 and week 48 
Continuous variables: 
Descriptive 
statistics (N, 
mean, standard 
deviation [SD], 
median, 95% CI 
and range 
[minimum and 
maximum] 
BWT at baseline, week 4, week 8, 16 and week 48 and change (both 
absolute and %) form baseline in BWT in mm at week 4, 8, 16 and week 48 
for the most affected part of the bowel, as well as for most affected part of 
the bowel being Ileum or Colon 
 
Table 9 presents a list of IUS variables that will be cross-tabulated or correlated with clinical variables 
for the IUS Analysis set. Results will be reported on the overall analysis set, not per treatment arm. 
Table 9: Correlation of IUS Variables and clinical data 
Correlations  
Summary 
Normalization of BWT (Yes, No) of the most affected segment 
versus SES-CD (<= 16, > 16) at baseline and week 48 
Number and percentage within 
statistic for agreement at each 
visit. 
Normalization of Pathologic BWT of the most affected segment 
(Yes, No) versus 
 
CDAI (score < 220, >= 220)  
 
 
 
 
 
 
at baseline, week 8, week 16 and week 48 


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Correlation of IUS response at week 4, week 8 and week 16 vs. 
clinical outcome and biomarkers at week 8, week 16 and week 48: 
 
Clinical outcome 
 CDAI-70 responders 
 Clinical remission  
 Clinical response  
 SES-CD improvement at week 48 vs. week 0  
 
 
 
 
 < 100%, 100% 
 Biomarkers 
 
 
 
 
 Complete biomarker response 
 
 
 
 
Correlation of BWT value and change from baseline of the most 
affected segment versus 
 
SES-CD value  
 
At baseline and Week 48 
Descriptive statistics and 
Spearman correlation 
coefficient for both the values 
at each visit and the changes 
from baseline 
Correlation of BWT value and change from baseline of the most 
affected segment versus 
 CDAI value  
 CRP value 
 
FC value
At baseline, Week 8, Week 16 and Week 48 
Correlation of Color Doppler, Echostratification, and 
Inflammatory Mesenteric Fat of the most affected part of the 
bowel with  
 FC (all subjects and those with abnormal FC at baseline) 
 CDAI 
 SES-CD 
At baseline, Week 8, Week 16 and Week 48 for FC and CDAI and 
at baseline and Week 48 for SES-CD 
 
6.1. 
Definition 
Bowel wall thickness will be determined as the mean of 4 measurements (2 in transverse and 2 in 
longitudinal section) of the most affected part of each bowel segment (ie, terminal ileum, cecum, 
ascending colon, transverse colon, and sigmoid colon).  


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IUS re
 
IUS remission defined as normalization of all the 4 IUS parameters: 
 
BWT 
 
Vascularization (color Doppler signal) 
 
Echostratification 
 
Inflammatory mesenteric fat. 
 
Normalization of the IUS parameters is defined as: 
 BWT; normalization of BWT will be defined as 
2.0 mm for the terminal ileum and 
3.0 mm 
for the colon (i.e. cecum, ascending colon, transverse colon, and sigmoid colon);  
 Vascularization (color Doppler signal); normalization of color Doppler signal will be defined as 
1; 
 Echostratification; normalization of echostratification will be defined as normal/preserved 
echostratification; 
 Inflammatory mesenteric fat; normalization of inflammatory mesenteric fat will be defined as 
absence of inflammatory fat. 
Bowel wall thickness will be assessed at each substudy visit. Other IUS parameters will only be 
determined if BWT is pathologic (ie, > 2.0 mm for the terminal ileum; > 3.0 mm for the colon), in which 
case the same parts of the bowel segments that are used for measurement of BWT will also be assessed 
for vascularization (color Doppler signal), echostratification, and inflammatory mesenteric fat. Analyses 
of IUS response and IUS remission will be based on the most affected (most thickened) part of the bowel 
wall. 
6.1.1. 
Analysis Methods 
For the analysis of IUS response and IUS remission the most affected part of the bowel at week 0 should 
be determined, based on the BWT for each of the 5 segments. IUS response and IUS remission will be 
calculated based on this most affected segment.  
Descriptive statistics of each IUS endpoint will be used to summarize the data per treatment arm and 
overall. To explore the correlation between continuous IUS and clinical endpoints, Spearman correlation 
coefficient will be reported, and the total population will be used. Overall population will also be used 
to analyze the agreement between categorical IUS and clinical endpoints and Cohen  Kappa statistic 
will be reported. Kappa results will be interpreted, as suggested by Cohen: 
 
0.01 0.20 as none to slight 
0.21 0.40 as fair 
0.41  0.60 as moderate 
0.61 0.80 as substantial 
0.81 1.00 as almost perfect agreement 
 
For calculating the level of agreement, Pathologic BWT will be considered as the new test and the 4 
clinical variables SES-CD, CDAI, CRP and FC as the imperfect reference test. 


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Level 1 and level 2 depends on the clinical variable (see table below).  
Clinical variable Level 1 
Level 2 
SES-CD 
<= 16 
> 16 
CDAI 
< 220 
>= 220 
CRP 
 10 mg/L 
> 10 mg/L 
CRP 
 
> 3 mg/L 
FC 
 250 µg/g > 250 µg/g 
 
Same approach will be used for the correlation of IUS response versus clinical data and biomarker data 
using the following levels 1 and 2. 
Variable  
Level 1 
Level 2 
IUS response 
Yes 
No 
 
 
 
CDAI-70 response 
<= 16 
> 16 
Clinical response 
< 220 
>= 220 
Clinical remission 
 10 mg/L 
> 10 mg/L 
SES-CD improvement of 
 
 
 
25% 
 
< 25% 
 
50% 
 
< 50% 
 
100% 
100% 
< 100% 
 
 
 
CRP 
 
> 3 mg/L 
FC 
 250 µg/g 
> 250 µg/g 
Complete biomarker response 
Yes 
No 
CRP change (%) from baseline  
 
< 50% 
FC change (%) from baseline  
 
< 50% 
 
7. 
SAFETY 
All safety analyses will be based on the safety analysis set, unless otherwise specified. 
For all continuous safety variables, descriptive statistics will include the N, mean, standard deviation, 
median, minimum, and maximum. Categorical variables will be summarized using frequency counts and 
percentages. 


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7.1. 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study agent through the day of last dose administered during the maintenance phase 
plus 16 weeks (unless event started in extension phase), 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 is known to be prior to the first administration of study agent based on partial onset date or 
resolution date. All reported treatment-emergent adverse events will be included in the analysis.  For 
each adverse event, the number and percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by treatment group and overall. 
Summary tables will be provided for treatment-emergent adverse events: 
 
AEs 
 
Serious AEs (SAEs) 
 
AEs leading to discontinuation of study agent/termination of study participation 
 
AEs by severity 
 
AEs by relationship to study agent 
 
In addition to the summary tables, listings will be provided for subjects who: 
 
Had SAEs 
 
Had AEs leading to discontinuation of study agent/termination of study participation 
 
Incidence of the following treatment-emergent adverse events of special interest will be summarized.  
 infusion reactions  
 injection-site reactions  
 infections, including infections requiring oral or parenteral antimicrobial treatment
 serious infections. 
Inclusion of any AE into the class of Infusion reactions, Injection-site reactions or Infections is based on 
the checkboxes on the AE CRF page and are based on investigator judgment. 
A listing of subjects who died during the maintenance phase will be provided. 
7.2. 
Vital Signs and Physical Examination Findings 
Continuous vital sign parameters including weight, pulse, blood pressure (systolic and diastolic), and 
Body Mass Index (BMI) will be summarized at each assessment time point during induction and 
maintenance phase. Body Mass Index will be calculated as weight (kg)/(height (m))2, at each time point 
that body weight is measured. The height measurement collected at screening/week 0 will be used in the 
calculation. Changes from baseline will be summarized by visits up till week 48. Descriptive statistics 
(mean, standard deviation, median, minimum and maximum) will be presented by visit and treatment 
group. 


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8. 
PHARMACOKINETICS/PHARMACODYNAMICS 
PK analyses will be based on the PK Analysis Set. 
8.1. 
Pharmacokinetics 
Blood samples for determining the serum ustekinumab concentrations will be drawn at Weeks 0 (both 
preadministration and 1 hour postadministration), 8, 16, each assessment visit during maintenance phase 
and at week 48 or if applicable at early termination, according to the Time and Events Schedule in the 
protocol.  
Serum ustekinumab concentrations will be summarized through Week 48 for the PK Analysis Set.  All 
serum ustekinumab concentration summaries will be based on observed data (i.e., no data imputation). 
Concentrations below the lowest quantifiable concentration will be treated as 0 in the summary statistics 
and labeled as 0 in any listings that contain serum concentration data. The proportion of subjects with 
concentration below the lowest quantifiable concentrations at each visit will be summarized by treatment 
group. All serum ustekinumab concentration summaries for a particular visit will include data obtained 
from treated subjects at the visit of interest without imputing any missing data. 
In addition, serum ustekinumab concentrations will be summarized through Week 48 by Biologic-naïve 
and prior exposure to biologic subjects at baseline. 
An evaluation of ustekinumab concentration (quartiles) versus the change from baseline in CDAI total 
score at Week 8, week 16 and week 48, the change from baseline in SES-CD score at week 48, the 
change from baseline in CRP at week 8, week 16 and week 48 as well as the change from baseline in 
FC score at week 8, week 16 and week 48 will also be performed to determine the influence of 
ustekinumab concentration on the efficacy of ustekinumab induction therapy. 
An evaluation of ustekinumab concentration versus CDAI-70 responder, Clinical remission, Clinical 
Response, Normalization of CRP and Normalization of FC at week 8, week 16 and week 48 will be 
performed as well as the evaluation of ustekinumab concentration versus Endoscopic response (both 
25% and 50% improvement) as well as endoscopic remission at week 48 to determine the influence of 
ustekinumab concentration on the efficacy of ustekinumab induction therapy.  
As an exploratory analysis ustekinumab concentrations versus IUS response and IUS remission at week 
8, week 16 and week 48 will be performed. 
Descriptive statistics (N, mean, SD, median, range) will be used to summarize Ustekinumab 
concentrations at each sampling time point. 
In particular, the following efficacy endpoints will be summarized by ustekinumab concentrations (<1st 
quartile, >= 1st quartile and < 2nd quartile, >= 2nd quartile and < 3rd quartile, and >= 3rd quartile):


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1. Ustekinumab concentrations (quartiles) at week 8 vs  
a. CDAI change at week 8 
b. CRP change at week 8 
c. FC change at week 8 
2. Ustekinumab concentrations (quartiles) at week 16 vs  
a. CDAI change at week 16 
b. CRP change at week 16 
c. FC change at week 16 
3. Ustekinumab concentrations (quartiles) at week 48 vs  
a. CDAI change at week 48 
b. SES-CD change at week 48  
c. CRP change at week 48 
d. FC change at week 48 
4. Ustekinumab concentrations (quartiles) at week 8 vs  
a. CDAI-70 responder at Week 8 
b. Clinical remission at Week 8 
c. Clinical response at week 8 
d. IUS response at week 8 
e. IUS remission at week 8 
5. Ustekinumab concentrations (quartiles) at week 16 vs  
a. CDAI-70 responder at Week 16 
b. Clinical remission at Week 16 
c. Clinical response at week 16 
d. Endoscopic response (25% improvement) at week 16 
e. Endoscopic response (50% improvement) at week 16 
f. Endoscopic remission at week 16 
g. IUS response at week 16 
h. IUS remission at week 16 
 
6. Ustekinumab concentrations (quartiles) at week 48 vs  
a. CDAI-70 responder at Week 48 
b. Clinical remission at Week 48 
c. Clinical response at week 48  
d. Endoscopic response (25% improvement) at week 48 
e. Endoscopic response (50% improvement) at week 48 
f. Endoscopic remission at week 48 
g. IUS response at week 48 
h. IUS remission at week 48 
 
8.2. 
Immunogenicity  
Blood samples will be collected to determine immunogenicity to ustekinumab at Weeks 0, 8, 16, each 
assessment visit during maintenance phase and week 48, and if applicable, at early termination visit 
according to the Time and Events Schedule in the protocol. The incidence and titers of antibodies to 
ustekinumab through 16 weeks will be summarized for all subjects in the PK Analysis Set who have 
appropriate samples for detection of antibodies to ustekinumab (ie, subjects with at least 1 sample 
obtained after their dose of ustekinumab).  
In addition, the Neutralizing Antibody (NAB) Status will be summarized through week 48 for the PK 
Analysis Set.   


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An evaluation of antibody to ustekinumab status versus Endoscopic response, Clinical response, CDAI-
70 response and clinical remission at week 48 will be performed based on the PK Analysis Set to 
determine the influence of antibodies to ustekinumab on the efficacy of ustekinumab, if the number of 
subjects with positive antibody status permits.  
A listing of subjects who are positive for antibodies to ustekinumab through week 48 visit will be 
provided.   
9. 
HEALTH ECONOMICS 
Health Economics parameter are described in section 5.3.4. Healthcare resource utilization endpoints. 
REFERENCES 
 
 
ATTACHMENTS 
 
1. 
STATISTICAL ANALYSIS PLAN FOR INTERIM ANALYSIS 
 
 
 


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2. 
VITY INDEX (SAMPLE) 
 
 


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3. 
INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (IBDQ) 
 
 
 
PPD


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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  
 
  
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 
 


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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 
  
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 


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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 
  
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. 
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 


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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 
  
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 


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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 
  
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 
  
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 


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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 
  
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 
4. 
EUROQOL-5D-5L HEALTH QUESTIONNAIRE (EQ-5D-5L)  SAMPLE UK 
ENGLISH VERSION 
 
 


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5. 
FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY-FATIGUE 
(FACIT-F)  
 
Source: http://www.facit.org/FACITOrg/Questionnaires 
 
 


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6. 
HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) [SAMPLE] 
Hospital Anxiety and Depression Scale (HADS) 
Instructions: Doctors are aware that emotions play an important part in most illnesses. If your doctor knows about these feelings he or she 
will be able to help you more. This questionnaire is designed to help your doctor know how you feel. Read each item and circle the reply 
which comes closest to how you have been feeling in the past 
item will probably be more accurate than a long thought out response.  
 
  
A
 
I feel as if I am slowed down:  
D  
Most of the time  
3 
 
Nearly all of the time  
3  
A lot of the time  
2 
 
Very often  
2  
Time to time, occasionally  
1 
 
Sometimes  
1  
Not at all  
0 
 
Not at all  
0  
 
 
 
 
 
I still enjoy the things I used to enjoy:  
D   
I get a sort of frightened feeling like 
  
A  
Definitely as much  
0  
Not at all  
0  
Not quite so much  
1  
Occasionally  
1  
Only a little  
2  
Quite often  
2  
Not at all  
3  
Very often  
3  
 
  
 
 
I get a sort of frightened feeling like something 
awful is about to happen:  
A
 
I have lost interest in my appearance:  
D  
Very definitely and quite badly  
3 
 
Definitely  
3  
Yes, but not too badly  
2 
 
 
2  
 
1 
 
I may not take quite as much care  
1  
Not at all  
0 
 
I take just as much care as ever  
0  
 
 
 
 
 
I can laugh and see the funny side of things:  
D   
I feel restless as if I have to be on the move: A  
As much as I always could  
0   
Very much indeed  
3  
Not quite so much now  
1   
Quite a lot  
2  
Definitely not so much now  
2   
Not very much  
1  
Not at all  
3   
Not at all  
0  
 
  
 
 
Worrying thoughts go through my mind:  
A
 
I look forward with enjoyment to things:  
D  
A great deal of the time  
3 
 
A much as I ever did  
0  
A lot of the time  
2 
 
Rather less than I used to  
1  
From time to time but not too often  
1 
 
Definitely less than I used to  
3  
Only occasionally  
0 
 
Hardly at all  
2  
 
 
 
 
 
I feel cheerful:  
D  
I get sudden feelings of panic:  
A  
Not at all  
3  
Very often indeed  
3  
Not often  
2  
Quite often  
2  
Sometimes  
1  
Not very often  
1  
Most of the time  
0  
Not at all  
0  
 
  
 
 
I can sit at ease and feel relaxed:  
A
 
I can enjoy a good book or radio or TV 
programme:  
D  
Definitely  
0 
 
Often  
0  
Usually  
1 
 
Sometimes  
1  
Not often  
2 
 
Not often  
2  
Not at all  
3 
 
Very seldom  
3  


CNTO1275  (ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275CRD3005 
47 
Fi
l D t
30 J
2020
Questions relating to anxiety are indicated by an 'A' while those relating to depression are shown by 
a 'D'. Scores of 0-7 in respective subscales are considered normal, with 8-10 borderline and 11 or 
over indicating clinical 'caseness'. 
 
 


CNTO1275  (ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275CRD3005 
48 
Fi
l D t
30 J
2020
7. 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT (WPAI) [SAMPLE] 
normal daily activities. Please fill in the blanks or circle a number, as indicated. 
 
1. Are you currently in paid employment?  ______NO 
______YES 
NO, 
 
The next questions refer to the past seven days, not including today. 
 
2. During the past seven days, how many hours did you miss from work because of problems 
? Include hours you missed on sick days, times you went in 
in this study. 
 
______HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of any other reason, 
such as annual leave, holidays, time off to participate in this study? 
 
______HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
 ______HOURS 
 
 
 


CNTO1275  (ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275CRD3005 
49 
Fi
l D t
30 J
2020
5. 
while you 
were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual. If 
 
 
disease 
had no effect on 
my work 
 
 
 
 
 
 
 
 
 
 
 
disease 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. 
normal daily activities, excluding your job?  
 
By normal activities, we mean the usual activities you perform, such as working around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the amount or 
kind of activities you could perform and times you accomplished less than you would like. If 
 Choose a high number 
 
 
had no effect on 
my daily 
activities 
 
 
 
 
 
 
 
 
 
 
 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
WPAI-CD (UK English)