Conditions: Inflammatory Bowel Diseases
Keywords: Pediatric Inflammatory Bowel Disease Infliximab Pediatric Participants Pediatric Ulcerative Colitis Pediatric Crohn's Disease Dose Escalation
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate whether trough serum infliximab concentrations at the time of loss of clinical response will identify pediatric participants with inflammatory bowel disease (IBD) who would benefit (regain clinical response) from dose escalation above the currently approved dose \[5 milligram (mg)/kilogram (kg) every 8 weeks (q8wk)\] and the safety of that dose escalation.

Detailed description:
This is a multicenter (when more than one hospital or medical school team work on a medical research study), prospective (study following participants forward in time), open-label (all people know the identity of the intervention) study of infliximab in pediatric participants with inflammatory bowel disease. The study consists of 3 Phases: screening Phase (up to 4 weeks), open-label treatment Phase (56 weeks) and follow up safety Phase (8 weeks). The duration of participation in the study for each participant is approximately up to 68 weeks (including screening period). Participants' efficacy and safety outcomes will be monitored throughout the study.

Arms:
arm 1: Participants must have completed: a) recommended infliximab induction dosing regimen of 5 milligram (mg)/kilogram (kg) at Weeks 0, 2, and 6, followed by at least 1 maintenance doses of 5 mg/kg every 8 weeks (q8wk); or b) induction regimen with doses \>6 mg/kg and have received at least 2 maintenance doses of 5 mg/kg q8wk with clinical response for at least 28 days after the most recent 5 mg/kg maintenance dose; or c) maintenance doses \>6 mg/kg within past 6 months and at least 2 maintenance doses of 5 mg/kg q8wk with clinical response for at least 28 days after the most recent 5 mg/kg maintenance dose; d) must have lost clinical response, after first or subsequent q8wk maintenance dose of infliximab 5 mg/kg for participants who have completed the recommended infliximab induction dosing regimen or, after most recent (second or later) q8wk maintenance dose of infliximab 5 mg/kg for participants with an induction regimen with doses \>6 mg/kg or with previous maintenance doses \>6 mg/kg. arm 2: Participants must have completed: a) the recommended infliximab induction dosing regimen of 5 mg/kg at Weeks 0, 2, and 6, and have maintained a stable clinical response to infliximab after at least 1 maintenance doses of 5 mg/kg q8wk; or b) an induction regimen with doses \>6 mg/kg and have received at least 2 maintenance doses of 5 mg/kg q8wk and have maintained clinical response for at least 28 days after the most recent 5 mg/kg maintenance dose 5 mg/kg maintenance dose; or c) maintenance doses \>6 mg/kg within the past 6 months and at least 2 maintenance doses of 5 mg/kg q8wk and have maintained a clinical response for at least 28 days after the most recent 5 mg/kg maintenance dose 5 mg/kg maintenance dose.

Interventions: intervention 1: Infliximab
Intervention descriptions: intervention 1: Participants in the dose escalation group will escalate dose from infliximab 5 mg/kg q8w to 10 mg/kg q8w at the time of loss response. Participants in the reference group will be maintained on infliximab 5 mg/kg q8w.

Protocol document:
Prot_000.pdf: 
1
Status: Approved,  Date: 20 February 2018
Janssen Research & Development *
Clinical Protocol
A Phase 4, Multicenter, Open-label Study of Serum Infliximab Concentrations and 
Efficacy and Safety of Dose Escalation in Pediatric Patients with 
Inflammatory Bowel Disease
ADAPT
Protocol C0168IBD4020; Phase 4
Amendment 3
Remicade® (infliximab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Scientific Affairs, LLC.; Janssen Biotech, Inc.; 
Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen 
Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The 
term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is 
identified on the Contact Information page that accompanies the protocol.  
Status:
Approved
Date:
20 February 2018
Prepared by:
Janssen Scientific Affairs, LLC.  
EDMS number:
EDMS-ERI-99610475
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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
2
Approved, Date: 20 February 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES ............................................................................................... 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS................................................................................................................................................... 25
TIME AND EVENTS SCHEDULE.............................................................................................................. 30
ABBREVIATIONS ...................................................................................................................................... 33
1.
INTRODUCTION .............................................................................................................................. 35
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 35
2.1.
Objectives ...................................................................................................................................... 35
2.2.
Hypothesis ..................................................................................................................................... 36
3.
STUDY DESIGN AND RATIONALE................................................................................................. 36
3.1.
Overview of Study Design.............................................................................................................. 36
3.2.
Study Design Rationale.................................................................................................................. 38
3.2.1.
Trough Serum Infliximab Concentrations and Dose Escalation................................................. 38
3.2.2.
Antibodies to Infliximab and Dose Escalation............................................................................. 40
3.2.3.
Other Study Design Features ..................................................................................................... 41
4.
PATIENT POPULATION .................................................................................................................. 41
4.1.
Inclusion Criteria ............................................................................................................................ 41
4.2.
Exclusion Criteria ........................................................................................................................... 46
4.3.
Prohibitions and Restrictions ......................................................................................................... 51
5.
TREATMENT ALLOCATION AND BLINDING .............................................................................. 52
6.
DOSAGE AND ADMINISTRATION ................................................................................................. 52
7.
TREATMENT COMPLIANCE.......................................................................................................... 53
8.
PRESTUDY AND CONCOMITANT THERAPY ............................................................................... 53
9.
STUDY EVALUATIONS.................................................................................................................... 55
9.1.
Screening Procedures.................................................................................................................... 55
9.2.
Study Procedures........................................................................................................................... 56
9.3.
Clinical Assessments ..................................................................................................................... 56
9.3.1.
Evaluations ................................................................................................................................. 56
9.3.1.1.
Pediatric Crohn’s Disease Activity Index (PCDAI) .................................................................. 56
9.3.1.2.
Mayo and Partial Mayo Score ................................................................................................. 57
9.3.1.3.
Wong-Baker FACES Pain Scale ............................................................................................. 57
9.3.1.4.
Stool Frequency (Absolute Value)........................................................................................... 58
9.3.1.5.
Optional Evaluations................................................................................................................ 58
9.3.2.
Endpoints.................................................................................................................................... 58
9.4.
Serum Infliximab Concentrations and Antibodies to Infliximab...................................................... 59
9.5.
Safety Evaluations ......................................................................................................................... 59
9.5.1.
Adverse Events........................................................................................................................... 59
9.5.2.
Clinical Laboratory Tests ............................................................................................................ 60
9.5.3.
Physical Examination and Vital Signs ........................................................................................ 61
9.5.4.
Screening Chest Radiograph ..................................................................................................... 61
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
3
Approved, Date: 20 February 2018
9.5.5.
Early Detection of Active Tuberculosis....................................................................................... 61
10.
PATIENT COMPLETION/WITHDRAWAL ..................................................................................... 62
10.1.
Completion ..................................................................................................................................... 62
10.2.
Discontinuation of Study Treatment............................................................................................... 63
10.3.
Withdrawal From the Study............................................................................................................ 64
11.
STATISTICAL METHODS................................................................................................................ 64
11.1.
Patient Information......................................................................................................................... 64
11.2.
Sample Size Determination ........................................................................................................... 65
11.3.
Efficacy Analyses ........................................................................................................................... 67
11.3.1.
Analyses for the Primary Endpoint ............................................................................................. 67
11.3.1.1.
Analyses .................................................................................................................................. 67
11.3.1.2.
Missing Data Handling for the Primary Endpoint Analyses..................................................... 68
11.3.2.
Analyses for the Secondary Endpoints....................................................................................... 69
11.3.3.
Other Planned Efficacy Analyses ............................................................................................... 70
11.4.
Serum Infliximab Concentrations and Antibodies to Infliximab...................................................... 70
11.5.
Safety Analyses ............................................................................................................................. 70
11.6.
Interim Analysis.............................................................................................................................. 72
11.7.
Safety Monitoring Committee......................................................................................................... 72
12.
ADVERSE EVENT REPORTING...................................................................................................... 72
12.1.
Definitions ...................................................................................................................................... 72
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 72
12.1.2.
Attribution Definitions.................................................................................................................. 74
12.1.3.
Severity Criteria .......................................................................................................................... 75
12.2.
Special Reporting Situations.......................................................................................................... 75
12.3.
Procedures..................................................................................................................................... 76
12.3.1.
All Adverse Events...................................................................................................................... 76
12.3.2.
Serious Adverse Events ............................................................................................................. 76
12.3.3.
Adverse Events of Special Interest............................................................................................. 77
12.3.4.
Pregnancy................................................................................................................................... 78
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 78
13.
PRODUCT QUALITY COMPLAINT HANDLING ........................................................................... 78
13.1.
Procedures..................................................................................................................................... 78
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 79
14.
INFLIXIMAB INFORMATION......................................................................................................... 79
14.1.
Physical Description of Infliximab .................................................................................................. 79
14.2.
Packaging ...................................................................................................................................... 79
14.3.
Labeling.......................................................................................................................................... 79
14.4.
Preparation, Handling, and Storage............................................................................................... 79
14.5.
Drug Accountability ........................................................................................................................ 80
15.
STUDY-SPECIFIC MATERIALS ...................................................................................................... 80
16.
ETHICAL ASPECTS ......................................................................................................................... 81
16.1.
Study-Specific Design Considerations........................................................................................... 81
16.2.
Regulatory Ethics Compliance....................................................................................................... 81
16.2.1.
Investigator Responsibilities ....................................................................................................... 81
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 82
16.2.3.
Informed Consent/Assent ........................................................................................................... 83
16.2.4.
Privacy of Personal Data ............................................................................................................ 84
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 85
16.2.6.
Country Selection ....................................................................................................................... 85
17.
ADMINISTRATIVE REQUIREMENTS............................................................................................ 85
17.1.
Protocol Amendments.................................................................................................................... 85
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
4
Approved, Date: 20 February 2018
17.2.
Regulatory Documentation ............................................................................................................ 85
17.2.1.
Regulatory Approval/Notification ................................................................................................ 85
17.2.2.
Required Prestudy Documentation............................................................................................. 86
17.3.
Patient Identification, Enrollment, and Screening Logs ................................................................. 86
17.4.
Source Documentation................................................................................................................... 87
17.5.
Case Report Form Completion ...................................................................................................... 87
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 88
17.7.
Record Retention ........................................................................................................................... 89
17.8.
Monitoring ...................................................................................................................................... 89
17.9.
Study Completion/Termination....................................................................................................... 90
17.9.1.
Study Completion ....................................................................................................................... 90
17.9.2.
Study Termination....................................................................................................................... 90
17.10.
On-Site Audits ................................................................................................................................ 91
17.11.
Use of Information and Publication................................................................................................ 91
REFERENCES ............................................................................................................................................ 93
ATTACHMENT 1:
TUBERCULOSIS TESTING...................................................................................... 94
ATTACHMENT 2:
HEPATITIS B VIRUS (HBV) SCREENING WITH HBV DNA TESTING .................. 97
ATTACHMENT 3:
DEFINITION OF INITIAL RESPONSE AND LOSS OF RESPONSE TO 
INFLIXIMAB THERAPY FOR PATIENTS WITH CROHN’S DISEASE............................................ 98
ATTACHMENT 4:
DEFINITION OF INITIAL RESPONSE AND LOSS OF RESPONSE TO 
INFLIXIMAB THERAPY FOR PATIENTS WITH ULCERATIVE COLITIS....................................... 99
ATTACHMENT 5:
LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS.............................................................................................................................. 100
INVESTIGATOR AGREEMENT.............................................................................................................. 104
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Precision estimation for anticipated clinical response rates, adjusting for 5% non-
efficacy related dropout rate prior to Week 16.......................................................................... 67
FIGURES
Figure 1:
Dose escalation study diagram................................................................................................. 38
Figure 2:
Sustained response to 5 mg/kg infliximab maintenance treatment by quintile of 
Week 14 serum infliximab concentrations in adult Crohn’s disease patients 
(ACCENT 1).............................................................................................................................. 39
Figure 3:
Infliximab concentration (ug/mL) at the time of loss of response in pediatric 
inflammatory bowel disease patients in the DEVELOP registry (n=39) ................................... 40
Figure 4:
Sample size details by diagnosis with crossover assumptions ................................................ 66
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
5
Approved, Date: 20 February 2018
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
03 August 2015
Amendment 1
25 January 2016
Amendment 2
07 December 2016
Amendment 3
20 February 2018
Amendment 3 (20 February 2018)
This amendment is considered 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 reasons for the amendment are to:
Clarify several entry criteria
Extend the screening period
Add details for corticosteroid tapering
Include complete instructions to ensure safety procedures related to any potential cases of hepatotoxicity
Update text describing informed consent procedures
Edits and additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable Section(s)
Description of Change(s)
Rationale:  The Screening period has been extended from 14 ± 7 days to 28 days to ensure time for screening 
laboratory tests to be returned, to assess eligibility.
4, Patient Population
(also reflected in the Time and 
Events Schedule, Screening 
column and Note 1); 9.2, Study 
Procedures
Screening for eligible patients will be performed within 28 14 ± 7 days 
before the Week 0 administration of infliximab.
The maximum acceptable visit window for all visits including after the
Screening visit is ± 7 days.
Rationale: The inclusion criterion pertaining to prior use of infliximab is being modified to align with standard 
of care. 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
6
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
4.1, Inclusion Criteria, #10; 2 
sub-bullets added for (both) 
Patients in the Dose Escalation 
Group and Patients in the 
Reference Group
Also reflected in 3.1, Overview 
of Study Design for (both) 
Patients in the Dose Escalation 
Group and Patients in 
the 
Reference Group
Synopsis, Patient Population; 
4.1, Inclusion Criteria, #10d for 
Patients in Dose Escalation 
Group
Patients who have received an induction regimen with doses greater than 
6 mg/kg must have received at least 2 maintenance doses of 5 mg/kg 
q8wk (the last 2 doses occurring at least 48 days, but no more than 64 
days, apart, with allowable dose range of 4.5 to 6 mg/kg) and have 
demonstrated a clinical response for at least 28 days after the most 
recent (second or later) 5 mg/kg maintenance dose according to the 
criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients            
Patients who have received maintenance doses greater than 6 mg/kg 
within the past 6 months must have received at least 2 maintenance 
doses of 5 mg/kg q8wk (the last 2 doses occurring at least 48 days, but no 
more than 64 days, apart, with allowable dose range of 4.5 to 6 mg/kg) 
and have demonstrated a clinical response for at least 28 days after the 
most recent (second or later) 5 mg/kg maintenance dose according to the 
criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients
Must have lost clinical response, according to the criteria in Attachment 3
for CD patients or Attachment 4 for UC patients, after the first or subsequent 
q8wk maintenance dose of infliximab 5 mg/kg, for patients who have 
completed the recommended infliximab induction dosing regimen (5 
mg/kg at weeks 0, 2, and 6) or, after the most recent (second or later)
q8wk maintenance dose of infliximab 5 mg/kg for patients with an 
induction regimen with  doses >6 mg/kg or for patients with previous 
maintenance doses >6 mg/kg
Rationale: The exclusion criterion pertaining to prior medications is being clarified.
4.2, Exclusion Criteria, #11d
Any immunosuppressant biologic investigational
drug (approved or 
investigational including investigational vaccines, vedolizumab, ustekinumab, 
etc.) within 4 weeks prior to first administration of infliximab or within 5 half-
lives of the investigational agent, whichever is longer, or is currently enrolled 
in an interventional investigational study
Rationale:  Since corticosteroid tapering is permitted in this study, a recommended corticosteroid dose tapering 
schedule is being added to the protocol to ensure uniform treatment for all patients.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
7
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
8, Prestudy and 
Concomitant Therapy
For patients in both the Dose Escalation and the Reference Group:
Treatment with and tapering of corticosteroids (including budesonide) is at the 
discretion of the investigator. For those patients whom the investigator determines 
it is appropriate to taper the use of corticosteroids and budesonide, the following 
tapering schedule is recommended:
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 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
Patients receiving budesonide should have their daily dose tapered by 3 mg every 3 
weeks until 0 mg/day.
Rationale:  Details for recording stools for the PCDAI are being clarified to ensure accurate PCDAI scores are 
collected.
9.1, Screening, 5th
paragraph
CD patients (or their legally acceptable representatives) will be instructed to 
ensure that liquid stools reported on the PCDAI are indeed loose or watery.
Rationale:  An endpoint is being added to specify the analyses that will be performed for clinical and 
pharmacokinetic results.
9.3.2, Endpoints, 
Secondary Endpoints
11.4, Serum 
Infliximab 
Concentrations and 
Antibodies to 
Infliximab, new 5th
paragraph
Other pharmacokinetic and clinical remission secondary endpoint:  The 
relationship between trough infliximab levels and clinical remission at Week 16 
will be analyzed with the Reference Group and the Dose Escalation Group patients 
in a combined analysis
The relationship between trough infliximab levels and clinical remission at Week 
16 will be analyzed with the Reference Group and the Dose Escalation Group 
patients in a combined analysis.
Rationale:  To ensure patient safety, detailed instructions for the management of patients with elevated hepatic 
enzymes at screening or during the study are being added.
4.1, Inclusion 
Criteria, #6e
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels not 
exceeding 2.0 times the upper limit of normal. If patients have ALT or AST levels 
between the ULN and 2x the ULN, clinically appropriate evaluations must be 
performed (and documented in the record) prior to enrollment to rule out 
etiologies that would contraindicate treatment with infliximab.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
8
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
9.5.2, Clinical 
Laboratory Tests
10.2, Discontinuation 
of Study Treatment 
(new bullet)
Attachment 5 added: 
(Liver Safety: 
Suggested Actions 
and Follow-up 
Assessments)

Abnormal liver function tests. If laboratory testing for a patient who is enrolled 
in the study and receiving study drug reveals an increase of serum 
aminotransferases (ALT or AST) to >3 x ULN and an increase of bilirubin to >2 
x ULN, study agent administration should be suspended immediately. In 
addition, laboratory tests for ALT, AST, alkaline phosphatase, and total 
bilirubin should be confirmed by a retest within 24 hours if possible, but no 
later than 72 hours after notification of test results. See Attachment 5 (Liver 
Safety: Suggested Actions and Follow-up Assessments) for additional 
information on monitoring and assessment of abnormal liver function tests.
During the study, all abnormal laboratory values will require further 
explanation from the investigator. Clinically significant abnormal laboratory 
values should be repeated until they return to normal or are otherwise 
explained by the investigator.

Severe hepatic function abnormalities, as described in Section 9.5 and 
Attachment 5
The Guideline Algorithm for Monitoring, Assessment, and Evaluation of Abnormal 
Liver Tests in Participants with No Underlying Liver Disease and Normal Baseline 
ALT, AST, Alkaline Phosphatase, and Bilirubin was added along with instructions for 
procedures to be followed in cases of potential lover toxicity. This information is based 
on the FDA Guidance for Industry, “Drug Induced Liver Injury: Premarketing Clinical 
Evaluation”.
Rationale:  To ensure consistency with screening procedures, instructions are being added to ensure that both 
informed consents and assents are obtained for all patients.
16.2.4, Privacy of 
Personal Data, 3rd
paragraph
Written informed consent must be obtained from the patient’s parent or legal 
guardian, and assent must be obtained from the patient. Informed consent and 
assent must be obtained for this study by the principal investigator or designee 
prior to conducting any protocol-specific procedure.
Rationale:  The table for enrollment eligibility based on hepatitis B and C status (in Attachment 2) is being 
updated (and reformatted) to provide additional clarity.
Attachment 2: Table 
for “Eligibility based 
on hepatitis C and B 
virus test results”
(added): Not eligible: Seropositive for antibodies to hepatitis C virus.
Rationale: The screening procedure regarding PCDAI and Mayo scores is being updated to align with the 
standard of care and to acknowledge that disease status may change slightly between screening and Week 0.
Time and Events 
Schedule, footnote r;
and footnote w added 
For calculation of PCDAI at Screening and/or Week 0…..
The Week 0 PCDAI or partial Mayo score should be the highest of any values 
obtained during a period of up to 28 days prior to, or including, Week 0.
Rationale: All references to the Investigator’s Brochure are being changed to references to the local label since 
the sponsor is now using the local labels rather than the Investigator’s Brochure for all trials involving Remicade.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
9
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Throughout the 
protocol
….Investigator’s Brochure local label….
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
10
Approved, Date: 20 February 2018
Amendment 2 (07 Dec 2016) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reasons for the amendment are to: 
Modify the inclusion criteria (for PCDAI and partial Mayo score) to ensure adequate disease severity
Define loss of response
Obtain history of infliximab treatment at initiation, time of response and loss of response, including 
number of infliximab doses, for the Dose Escalation group
Define “initial response”
Add 2 secondary endpoints (and the corresponding analyses), to evaluate any association between clinical 
remission/response
Revise wording for several entry criteria, for clarity
Correct or clarify inadvertent errors
Changes reflect feedback from the Food and Drug Administration (FDA) received in August 2016. Edits and 
additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable Section(s)
Description of Change(s)
Rationale: In line with the FDA Type C meeting Written Response Only (WRO) feedback received on 26 August 
2016, clinical response has been more clearly defined in the newly added Attachment 3 (for patients with Crohn’s 
disease [CD]) and Attachment 4 (for patients with ulcerative colitis [UC]). The conditions and evidence of response 
for both CD and UC are defined using clinical signs and symptoms, eg, an assessment by the patient’s physician.  
Synopsis, Patient 
Population, Patients in the 
Dose Escalation Group; 
and a similar change in 
Section 3.1, Overview of 
Study Design, Dose
Escalation Group
a.
Must have completed the recommended infliximab induction dosing 
regimen …. and have demonstrated a clinical response according to the 
investigator’s assessment the criteria in Attachment 3 for CD patients or 
Attachment 4 for UC patients
b.
Must have lost clinical response, according to the investigator's assessment  
the criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients…
Synopsis, Patient 
Population, Patients in the 
Reference Group; and 
Section 3.1, Overview of 
Study Design, Reference 
Group
a.
Must have completed the recommended infliximab induction dosing 
regimen of 5 mg/kg at weeks 0, 2, and 6 and have achieved and maintained 
a stable clinical response* to infliximab after at least 1 maintenance dose of 
5 mg/kg q8wk according to the criteria in Attachment 3 for CD patients 
or Attachment 4 for UC patients …. 
*    Patients with a stable clinical response to infliximab are defined as 
those patients who have achieved clinical response according to 
criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients and who did not initiate or receive increased doses of 5-
aminosalicylic acid (5-ASA), corticosteroids, immunomodulators or 
antibiotics for the treatment of IBD for 4 weeks prior to screening.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
11
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Section 4.1 Inclusion 
Criterion #10, 
Patients in the Dose 
Escalation Group:
Patients in the Reference 
Group:
a. Must have completed the recommended infliximab induction dosing regimen … 
and have demonstrated a clinical response according to the investigator’s 
assessment the criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients.
b. Must have lost clinical response, according to the investigator's assessment the 
criteria in Attachment 3 for CD patients or Attachment 4 for UC patients…..
a. Must have completed the recommended infliximab induction dosing regimen… 
and have maintained a stable clinical response* according to the criteria in 
Attachment 3 for CD patients or Attachment 4 for UC patients…. 
*
Patients with a stable clinical response to infliximab are defined as those 
patients who have achieved clinical response according to criteria in 
Attachment 3 for CD patients or Attachment 4 for UC patients and who 
did not initiate or receive increased doses of 5-aminosalicylic acid (5-ASA), 
corticosteroids, immunomodulators or antibiotics for the treatment of IBD 
for 4 weeks prior to screening.
Rationale: In line with the FDA Type C Meeting WRO feedback received on 26 August 2016, baseline assessments 
will include assessment and collection of qualitative and quantitative signs and symptoms present at initiation of on-
study infliximab therapy.
Synopsis, Overview of 
Study Design, Paragraph 2, 
Sentence 1; and Section 
3.1, Overview of Study 
Design, Paragraph 4, 
Sentence 1
After obtaining informed consent/assent, detailed demographic and medical history, 
including qualitative and quantitative signs and symptoms present at initiation 
of infliximab therapy and the time of response, will be collected on all patients 
meeting inclusion and exclusion criteria at the time of enrollment.
Rationale: Per discussions between the Sponsor and the FDA, the Sponsor is modifying the inclusion criteria for 
the PCDAI and partial Mayo score in lieu of the requirement of ileocolonoscopy, for the Dose Escalation Group.
Synopsis, Patient 
Population, Patients in the 
Dose Escalation Group;
Section 4.1, Inclusion 
Criterion #10, Patients in
Dose Escalation Group
f. Must have a PCDAI of > 30 points with both an abdominal pain and stool 
frequency sub-score of ≥ 5 (patients with CD)
g. Must have a partial Mayo score of ≥ 5 points with both stool frequency and 
rectal bleeding sub-scores of ≥ 1 (patients with UC)
Rationale:  Screening procedures for the Dose Escalation group are being revised to also account for infliximab 
concentrations. 
Time and Events Schedule, 
footnote i; and added to 
Section 4.1, Inclusion 
Criteria as footnote for 
Inclusion criterion #10e 
and 10h for the Dose 
Escalation group
For patients undergoing screening for the Dose Escalation Group, those who do not 
meet entry criteria based on infliximab concentration and/or fecal calprotectin and/or 
CRP levels may have repeat infliximab concentration and/or fecal calprotectin 
and/or CRP levels performed during the screening process, provided that all entry 
criteria are met within 14 days prior to administration of the first 10 mg/kg dose of 
infliximab.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
12
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Per the FDA Type C Meeting WRO received on 26 August 2016, the Sponsor is adding 2 secondary 
endpoints (and the corresponding analyses), to evaluate any association between Wong-Baker FACES scale 
results with abdominal pain PCDAI sub-score in patients with Crohn’s disease, and with clinical response.
Synopsis, Secondary 
Endpoints, Other 
secondary efficacy 
endpoints; Section 9.3.2 
Endpoints, Secondary 
Endpoints, Other 
Secondary Efficacy 
Endpoints
3. Correlates of Wong-Baker FACES scale with clinical remission and response
at Week 16     
4. The association between abdominal pain PCDAI sub-score and the Wong-
Baker FACES scale for CD patients
Section 11.3.2 Analyses for 
the Secondary Endpoints, 
Paragraphs 3 and 4
The Sponsor will analyze how the Wong-Baker FACES scale correlates with 
clinical remission/response by performing a logistical regression to evaluate the 
association between Wong-Baker FACES scale and clinical response at 
Week 16.   
In a secondary analysis, an ordinary regression model will be used to evaluate 
the association between abdominal pain PCDAI sub-score and Wong-Baker 
FACES scale for CD patients.
Rationale:  A clarification to the full body, physical examination is being made.
Time and Events Schedule, 
Row for Physical 
Examination
Time and Events Schedule, 
footnote g; Section 9.5.3, 
Physical Examination and 
Vital Signs, Paragraph 1
Physical examination (including skin examination)
Complete physical examinations (excluding genitourinary examination but including 
skin and genitourinary examination) are to be conducted.
Rationale:  Consent for the collection of the stool sample has been clarified.  
Time and Events Schedule, 
footnote d added for 
Informed consent/assent
Pre-screening stool sample consent may be obtained prior to the screening visit 
per local or site requirements.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
13
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Time and Events Schedule, 
row for Stool Culture; 
footnote h added
Section 9.1, Screening 
Procedures
Section 17.4, Source 
Documentation
h. 
Sample to be collected at or up to 24 hours prior to screening visit (with 
completion of appropriate stool sample consent), however, if not done, 
patient/caregiver may collect at home and return to the site within 24 hours 
of collection. The following medications should be avoided for 48 hours 
prior to the sample collection: antacids, barium, bismuth, antidiarrheal 
medication, and oily laxatives. Please refer to the Covance laboratory 
manual for further instructions. 
Pre-screening stool sample consent may be obtained prior to the screening visit 
per local or site requirements.
At a minimum, source documentation must be available for the following to confirm 
data collected in the CRF: patient identification, eligibility, and study identification; 
study discussion and date of signed study and (if applicable) pre-screening stool 
sample collection informed consents;….
Rationale:    A correction to the entry criteria regarding prior maintenance doses is being made, that was erroneous 
in Protocol Amendment 1.
Synopsis, Patient 
Population, Patients in the 
Dose Escalation Group;
Section 4.1, Inclusion 
Criteria, #10 - Patients in 
Dose Escalation Group
b. Must have lost clinical response, according to the criteria in Attachment 3 for CD 
patients or Attachment 4 for UC patients, after the first second or subsequent 
q8wk maintenance dose of infliximab 5 mg/kg
Rationale:  An entry criterion regarding immunization is being changed to avoid unnecessary blood draws if proof 
of prior immunization is available.
Section 4.1, Inclusion 
Criteria, #8
Must have positive protective antibody titers to varicella and measles prior to the first 
administration of infliximab at Week 0
Must have acceptable evidence of immunity to measles and varicella prior to the 
administration of infliximab at Week 0, including any of the following:  
(a) Documentation of age-appropriate vaccination for varicella and/or measles 
(that includes two doses of each vaccine), or
(b) Verification of past varicella and/or measles infection by a healthcare 
provider (school or occupational clinic nurse, nurse practitioner, physician 
assistant, or physician), or
(c) In the absence of (a) or (b) for varicella and/or measles, must have 
documentation of positive protective antibody titers (performed prior to or 
during screening) to varicella and/or measles.
Time and Events Schedule, 
rows for “Varicella 
antibody titers”, “Measles 
antibody titers”
Added footnote m: Varicella and measles titers do not need to be obtained if 
proof of age-appropriate immunization or proof of prior infection is obtained.
Rationale: Text for laboratory assessments is being clarified.   
Time and Events Schedule, 
Footnote o, Sentence 2
Note that at these visits, routine hematology and chemistry laboratory studies are not 
obtained; therefore, hHematocrit and albumin laboratory studies must be performed 
at each of these visits in order to calculate PCDAI.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
14
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Clarification is being added for the 7-day window allowed for the screening visit.
Section 4, Patient 
Population, Paragraph 1
Screening for eligible patients will be performed within 14 ± 7 days before the Week 
0 administration of infliximab.
Rationale:  Clarification is being made for the entry criterion related to prior discontinuation of infliximab.
Synopsis, Patient 
Population, Dose 
Escalation Group (bullet c) 
and Reference Group 
(bullet b)
Section 4.1, Inclusion 
Criteria, #10c for Dose 
Escalation Group and #10a 
for Reference Group
Must not have discontinued infliximab therapy (discontinuation defined as period 
of ≥ 6 months without receiving a dose)
Rationale: Clarification is being made for timing of ileocolonoscopy
Synopsis, Patient 
Population, Dose 
Escalation Group, bullet 
h.iii.
The ileocolonoscopy must have occurred within 6 weeks prior to the first 
infliximab 10 mg/kg dose
Section 3.1, Overview of 
Study Design (last 
paragraph)
If a UC patient in the Dose Escalation Group undergoes optional ileocolonoscopy at 
screening and at least 24 weeks after dose escalation or later, Mayo scores will also 
be obtained.
Section 9.3.1.5, Optional 
Evaluations;
Time and Events Schedule, 
footnote f
For patients in the Dose Escalation Group, investigators may perform optional 
ileocolonoscopy during screening, unless ileocolonoscopy was performed or as 
standard care within 6 weeks prior to the first infliximab 10 mg/kg dose within 4 
weeks prior to screening, and again at Week 24 or later.
Rationale:  Clarifications are being made to several entry criteria.
Section 4.2, Exclusion 
Criteria, #8-9, #11, #27
8. Patients with UC must not have a history of extensive colonic resection…..
9. Must not have a history of dysplasia or adenomatous colonic polyps that were not 
removed
11. Has previously received:
   a. Natalizumab  or vedolizumab within 12 months of first infliximab administration
d. Any investigational drug (including investigational vaccines, vedolizumab,
ustekinumab, etc.) within 4 weeks….
27. Must not have had a fever of unknown origin for longer than 3 weeks duration 
within 3 months prior to screening, unless thought likely to be associated with IBD
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
15
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Text for TB screening is being revised for clarity.
Time and Events Schedule, 
footnote l (shortened)
Section 4.1, Inclusion 
Criteria, #4g
Section 9.5.4, Screening 
Chest Radiograph, 
Paragraph 1
Section 9.5.4, Screening 
Chest Radiograph, 
Paragraph 2
Unless country or site guidelines do not recommend a chest radiograph as a necessary 
screening process prior to initiation of anti-TNF therapies, a chest radiograph (both 
posterior-anterior and lateral views) must have been performed within 3 months prior 
to infliximab administration at Week 0 and read by a qualified radiologist; the results 
of which must show no evidence of current active TB or old inactive TB. 
….a chest radiograph (both posterior-anterior and lateral views) must have been 
performed within 3 months prior to infliximab initiation or during treatment and 
read by a qualified radiologist; the results of which must show no evidence of current 
active TB or old inactive TB. Chest radiographs (both posterior-anterior and lateral 
views) must be performed as part of the screening process in all cases when either the 
tuberculin skin test and/or QFT-TB Gold test results for TB are positive or proof of 
previously performed negative chest radiograph cannot be obtained.
Unless country or site guidelines do not recommend a chest radiograph as a necessary 
screening process prior to initiation of anti-TNF therapies, a chest radiograph (both 
posterior-anterior and lateral views) must have been performed within 3 months prior 
to infliximab initiation or during the pre-study infliximab treatment
administration at Week 0 and read by a qualified radiologist;….
Chest radiographs (both posterior-anterior and lateral views) must be performed as 
part of the screening process in all cases when either the tuberculin skin test and/or 
QFT-TB Gold test results for TB are positive or proof of negative chest radiograph 
performed prior to initiation of infliximab cannot be obtained.
Rationale:  Text in the Time and Events Schedule for TB testing is being clarified to match instructions elsewhere 
in the protocol.
Time and Events Schedule, 
row for QFT-TB Gold test
QFT-TB Gold test (or tuberculin skin test in countries where the QFT-TB Gold test is 
not accepted/required approved/registered or is not required per local guidelines)
Rationale: Clarification is being added for the time period to which the dose range for prior induction and 
maintenance doses applies.
Synopsis, Patient 
Population, Patients in the 
Dose Escalation Group and
Patients in the Reference 
Group; Section 4.1, 
Inclusion Criteria, #10, 
Patients in the Dose 
Escalation Group and
Patients in the Reference 
Group
a.  ….(allowable dose range of 4.5 to 6 mg/kg with a ± 7 day window for induction 
and maintenance doses ) and have demonstrated a clinical response according to 
the criteria in Attachment 3 for CD patients or Attachment 4 for UC patients (the 
last 2 doses occurring at least 48 days, but no more than 64 days, apart, with 
allowable dose range of 4.5 to 6 mg/kg)
Paragraph 3, Sentence 1
Upon meeting enrollment criteria for the Reference Group, patients will continue to  
receive 5 mg/kg q8wk.
Section 3.1, Overview of 
Study Design, Dose 
Escalation Group and
Reference Group
…. (allowable dose range of 4.5 to 6 mg/kg with a ± 7 day window for induction and 
maintenance doses the last 2 doses occurring at least 48 days, but no more than 64 
days, apart, with allowable dose range of 4.5 to 6 mg/kg).
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
16
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Clarifications are made related to the timing of infliximab administration. 
Section 4.1, Inclusion 
criteria #4d - #5
…first on-study administration of infliximab…
Section 9.2 Study 
Procedures, Paragraph 2
All visit-specific assessments should be completed before administration of 
infliximab. The maximum acceptable visit window for all visits including screening 
is ± 7 days. Patients must meet all enrollment criteria prior to the first on-study 
administration of infliximab at Week 0 for the Week 0 visit prior to the 
administration of infliximab.
Rationale:  Clarification is being made for the major secondary efficacy endpoint.
Synopsis, Secondary 
Endpoints
Section 9.3.2, Secondary 
Endpoints
Major secondary efficacy endpoint:   Sustained clinical response through 56 weeks 
after dose escalation
Rationale: Text for infliximab treatment at study entry is being deleted as it was erroneously included in this 
section. 
Synopsis, Dosage and 
Administration
Section 6, Dosage and 
Administration
At the time of enrollment in the trial, patients must be receiving infliximab at a dose 
of 5 mg/kg q8wk (allowable dose range of 4.5 to 6 mg/kg with a ± 7 day window for 
maintenance doses) as described in Section 3.1.
Rationale:  Clarification for the study evaluations is being added. 
Section 9.1, Screening 
Procedures, Paragraph 5
At screening and subsequent visits, PCDAI and Mayo diary cards will be distributed 
for patients to use over the course of the study. Patients (or their legally-acceptable 
representatives) will be instructed on how to complete the diary cards…
Section 9.3.1, Evaluations
The disease activity assessments listed below should be performed for both 
Reference and Dose Escalation Group patients. 
Section 9.3.1.1, PCDAI, 
Paragraph 1, Sentence 2
The PCDAI is a validated clinical tool used to assess disease severity in pediatric 
patients with CD.10 This assessment should be performed for all study visits at 
which infliximab is administered (Week 0 - Week 56/End of Treatment).
Section 9.3.1.2, Mayo and 
Partial Mayo Score, 
Paragraph 1, Sentence 2
The Mayo score is a validated clinical tool used to assess disease activity in patients 
with UC.11 This assessment should be performed for all study visits at which 
infliximab is administered (Week 0 - Week 56/End of Treatment).  
Rationale: Clarification is being made to differentiate between patients with UC and CD, for possible 
discontinuation of study treatment.
Section 10.2, 
Discontinuation of Study 
Treatment

If, in the opinion of the patient and the investigator, a UC  the patient requires a 
colectomy (partial or total)
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
17
Approved, Date: 20 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  Clarification is being made to the statistical analysis section, for secondary efficacy analyses.
Section 11.3.2, Analyses 
for the Secondary 
Endpoints
The analysis will be performed for both the Dose Escalation and Reference 
groups.
Rationale:  Clarification is being added regarding additional study-specific documents being provided to sites.
Section 15, STUDY-
SPECIFIC MATERIALS, 
Additions

CDC Growth Charts

Wong-Baker FACES Pain Scale 

Stool frequency questionnaire 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
18
Approved, Date: 20 February 2018
Amendment INT-1 (25 January 2016)
This amendment is considered 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.  No patient was enrolled at the time of this 
amendment.
The overall reason for the amendment: The overall reasons for the amendment are to revise entry criteria 
regarding prior maintenance doses of infliximab and time of loss of response, and to correct or clarify inadvertent 
errors.
Edits and additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable 
Section(s)
Description of Change(s)
Rationale: The wording for age at entry was clarified.
Section 4.1, Inclusion 
criterion #1;
Synopsis, Patient 
Population
[Patients] must be male or female at least 6 years of age and less than 17 years of age, 
inclusive, at the time of enrollment.
Rationale:  Text mentioning situations where the QFT-TB Gold test for tuberculosis may not be done was clarified 
to account for local guidelines.  
Section 4.1, Inclusion 
criterion #4e; Time 
and Event Schedule
If the QFT-TB Gold test is not approved/registered in that country or is not required per 
local guidelines,….
Rationale: The criterion regarding the number of maintenance doses received prior to enrollment was changed 
based on the investigators’ feedback that modifying criteria to include patients after 1 maintenance dose, rather than 
2, will potentially increase enrollment.  This change was made everywhere prior maintenance doses were mentioned 
in the protocol.
Synopsis, Patient 
Population, Patients 
in the Dose Escalation 
Group, criterion a.
Synopsis, Patient 
Population, Patients 
in the Reference 
Group, criterion a; 
Section 4.1, Inclusion 
Criteria, Criterion 
#10.a for Patients in 
the Reference Group
Section 3.1, Overview 
of Study Design, 
Dose Escalation 
Group and Reference 
Group
Must have completed the recommended infliximab induction dosing regimen of 5 mg/kg at 
weeks 0, 2, and 6 and at least 21 maintenance doses of 5 mg/kg q8wk (allowable dose 
range of 4.5 to 6 mg/kg with a ± 7 day window for induction and maintenance doses) and 
have demonstrated a clinical response according to the investigator’s assessment.
Must have completed the recommended infliximab induction dosing regimen of 5 mg/kg at 
weeks 0, 2, and 6 and have maintained a stable clinical response* to infliximab after at 
least 21 maintenance doses of 5 mg/kg q8wk (allowable dose range of 4.5 to 6 mg/kg with 
a ± 7 day window for induction and maintenance doses).
Pediatric patients with IBD …. the recommended infliximab induction dosing regimen of 
5 mg/kg at weeks 0, 2, and 6, followed by at least 21 maintenance doses of 5 mg/kg q8wk
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
19
Approved, Date: 20 February 2018
Applicable 
Section(s)
Description of Change(s)
Section 4.1, Inclusion 
Criteria, Criterion # 
10a for Patients in the 
Dose Escalation 
group
Figure 1
Must have completed the recommended infliximab induction dosing regimen of 5 mg/kg at 
weeks 0, 2, and 6, and at least 21 maintenance doses of 5 mg/kg q8wk (allowable dose 
range of 4.5 to 6 mg/kg with a ± 7 day window for induction and maintenance doses) and 
have demonstrated a clinical response according to the investigator’s assessment.
≥ 21 maintenance doses
Rationale: Criterion was changed based on the investigators’ feedback that inclusion of patients with loss of 
response 4-10 weeks, rather than 6-10 weeks, after the last infliximab dose in the Dose Escalation will potentially 
increase enrollment.
Synopsis, Patient 
Population, Patients 
in the Dose Escalation 
Group, criterion d; 
Section 4.1, Inclusion 
Criteria, Dose 
Escalation Group, 
#10d.
Must have received the last maintenance dose of infliximab at least 64 weeks but not more 
than 10 weeks prior to at the time of screening.
Rationale:  The time period for donation of eggs for assisted reproduction was clarified and made consistent with 
prior protocols.
Section 4.1,
Inclusion Criterion 13
A female patient must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction for a period of 6 months after last dose of study medication.  
Rationale:  Details for effective birth control for female patients were added, for completeness.
Section 4.3, 
Prohibitions and 
Restrictions
If sexually active, female patients must be practicing a highly effective method of birth 
control (eg, prescription oral contraceptives, contraceptive injections, contraceptive 
patch, intrauterine device, double-barrier method [eg, condoms, diaphragm, or 
cervical cap, with spermicidal foam, cream, or gel], or male partner sterilization) as 
local regulations permit, during the study and for 6 months after receiving the last 
administration of infliximab
Rationale: Instructions were clarified regarding how baseline PCDAI and Mayo score criteria will be collected.
Section 9.1, 
Screening Procedures
At screening and subsequent visits, information needed for the PCDAI or partial Mayo 
scores with respect to questions such as stool frequency or quality, abdominal pain, and 
general well-being will be obtained from recall. At that visit, diary cards will be distributed 
for patients to use over the course of the study. PCDAI and Mayo diary cards will be 
distributed for patients to use over the course of the study. Patients (or their legally-
acceptable representatives) will be instructed on how to complete the diary cards daily and 
will be reminded to bring the diary cards to each visit for data collection and review by the 
investigator/study coordinator. Information needed for the PCDAI or partial Mayo 
scores with respect to questions such as stool frequency or quality, abdominal pain, 
and general well-being will be obtained from the patient diary and/or recall at 
Week 0 and subsequent visits.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
20
Approved, Date: 20 February 2018
Applicable 
Section(s)
Description of Change(s)
Rationale: Footnote “h” referring to the Fecal Calprotectin Test in the Time and Events Schedule was updated for 
clarity.
Time and Events 
Schedule, Footnote 
“h”
At screening, only to be performed for patients in the Dose Escalation Group or for 
patients in the Reference Group prior to crossing over to the Dose Escalation Group.
Rationale: In inclusion criterion #6-f, the youngest age range presented in the protocol is not applicable for this 
study and was removed.
Section 4.1, Inclusion 
Criterion #6-f
Modified Text: 
Serum creatinine not to exceed:
-
2 to 5 years of age:  
0.5 mg/dL (SI: 44 µmol/L)
-
6 to 10 years of age: 
0.7 mg/dL (SI: 62 µmol/L)
-
11 to 12 years of age: 
1.0 mg/dL (SI: 88 µmol/L)
-
≥ 13 years of age:  
1.2 mg/dL (SI: 106 µmol/L)
Rationale:  Antibiotics for the treatment of IBD were inadvertently omitted from the list of allowed prior and 
concomitant medications.  Antibiotics for the treatment of IBD have been added to the list of accepted prior and 
concomitant medications, throughout the protocol. 
Synopsis, Patient 
Population, Patients 
in the Reference 
Group, note (*) to 
criterion a
Section 3.1, Overview 
of Study Design, 
Reference Group, (*)
Section 4.1, Inclusion 
Criteria, * note to 
Criterion #10.a for 
patients in the 
Reference Group
Patients with a stable clinical response to infliximab are defined as those patients who did 
not initiate or receive increased doses of 5-aminosalicylic acid (5-ASA), corticosteroids, or
immunomodulators or antibiotics for the treatment of IBD for 4 weeks prior to 
screening.
Patients with a stable clinical response to infliximab are defined as those patients who did 
not initiate or receive increased doses of 5-aminosalicylic acid (5-ASA), corticosteroids, or 
immunomodulators, or antibiotics for the treatment of IBD for 4 weeks prior to 
screening.
A stable clinical response to infliximab is defined as those patients who did not initiate or 
receive increased doses of 5-ASA, corticosteroids, antibiotics for the treatment of IBD,
or immunomodulators for 4 weeks prior to screening.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
21
Approved, Date: 20 February 2018
Applicable 
Section(s)
Description of Change(s)
Section 8, 
PRESTUDY AND 
CONCOMITANT 
THERAPY
Section 8, 
PRESTUDY AND 
CONCOMITANT 
THERAPY
Section 8, Bullets 1 
and 2 for patients in 
the Dose Escalation 
Group; and Bullet 4
Section 8, Bullets 1 
and 2 for patients in 
the Reference Group 
who cross over to the 
Dose Escalation 
Group; and Bullet 4
….(eg, 5-ASAs; corticosteroids; immunomodulators, including thiopurines; biologics; 
antibiotics)
The following concomitant medications for IBD are allowed in this study: 5-ASAs, 
corticosteroids, and immunomodulators (ie, 6-MP, AZA, MTX), and antibiotics.
… 5-ASAs, and/or corticosteroids, and/or immunomodulators, and/or antibiotics ….
For patients receiving immunomodulators (ie, 6-MP, AZA, or MTX), or corticosteroids, or 
antibiotics at baseline, the immunomodulators and antibiotics may be tapered or may be 
discontinued at any time during the study, and corticosteroids may be tapered beginning at 
Week 0
  … (ie, 5-ASAs, and/or corticosteroids, and/or immunomodulators, and/or antibiotics…
For patients receiving immunomodulators (ie, 6-MP, AZA, or MTX), or corticosteroids, or 
antibiotics at the time of dose escalation, the immunomodulators and antibiotics may be 
tapered or may be discontinued at any time during the study, and corticosteroids may be 
tapered beginning at the time of dose escalation
Rationale: The instructions for infusion preparation and administration were clarified, per investigators’ request.
14.4, Preparation, 
Handling, and Storage 
Aseptic procedures must be used during the preparation and administration of the study 
material.  The infusion must be administered over a period of not less than 2 hours 
and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-
binding filter (pore size of 1.2 μm or less). The vials do not contain antibacterial 
preservatives. Therefore, any unused portion of the infusion solution should not be 
stored for reuse.
Additional details for the preparation and administration of infliximab are provided in the 
site investigational product manual.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
22
Approved, Date: 20 February 2018
Applicable 
Section(s)
Description of Change(s)
Rationale: Other secondary efficacy endpoints were revised to include the addition of the Wong-Baker FACES 
pain scale and stool frequency in absolute values.
Synopsis, Other 
Secondary Efficacy 
Endpoints; 
Section 9.3.2, Other 
Secondary Efficacy 
Endpoints; Section 
11.3.2, Analyses for 
the Secondary 
Endpoints
Time and Event 
schedule, FACES 
(Wong-Baker pain 
scale) and Stool 
Frequency
1.
Changes from baseline at Week 16 and at Week 56 in abdominal pain and 
loose/watery  stool frequency sub scores of the PCDAI in CD patients
2.
Changes from baseline at Week 16 and at Week 56 in stool frequency and rectal 
bleeding sub scores of the Mayo score for UC patients
1. For CD patients changes from baseline at Week 16 and at Week 56 in: 

Abdominal pain and loose/watery stool frequency sub-scores of the 
PCDAI 

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency
2. For UC patients changes from baseline at Week 16 and at Week 56 in:

Stool frequency and rectal bleeding sub-scores of the partial Mayo    
       score 

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency
Added Row/Timing, to indicate are to be collected at Weeks 0, 16, 56/End of Treatment, 
with explanatory footnotes:
p. For cross over patients, the Wong-Baker FACES pain scale will be administered 
prior to the administration of the first and the third dose of 10 mg/kg infliximab.  
q. For cross over patients stool frequency data will be collected prior to the 
administration of the first and the third dose of 10 mg/kg infliximab.
Rationale: Instructions for performing the Wong-Baker FACES Pain scale (with a description and reference) and 
the stool frequency measurement were added.
Sections 9.3.1.3 and 
9.3.1.4 were added.
9.3.1.3.The Wong-Baker FACES Pain Scale
The Wong-Baker FACES Pain Scale is a pain scale that combines pictures and
numbers to allow pain to be rated by children over the age of 3. 4 The scale shows a 
series of faces ranging from a happy face at 0, "No hurt" to a crying face at 10 
"Hurts worst". The patient must choose the face that best describes how they are 
feeling.
The Wong-Baker FACES Pain Scale should be completed prior to infliximab 
administration at Week 0, Week 16 and Week 56 visits for the Dose Escalation Group 
and Reference Group or prior to the administration of the first and third 10 mg/kg 
dose for patients crossing over from the Reference Group. In addition, all patients 
who discontinue treatment will complete the Wong-Baker FACES pain scale at the 
time of treatment discontinuation visit.
9.3.1.4.     Stool Frequency (absolute value)
Absolute stool frequency values will be recorded from patients’ recall prior to 
infliximab administration at Week 0, Week 16 and Week 56 visits for the Dose 
Escalation Group and Reference Group or prior to the administration of the first and 
third 10 mg/kg dose for patients crossing over from the Reference Group. In 
addition, stool frequency information should be obtained from all patients who 
discontinue treatment at the time of treatment discontinuation visit.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
23
Approved, Date: 20 February 2018
Applicable 
Section(s)
Description of Change(s)
Rationale: The timing of screening and follow-up endoscopy was clarified, including allowing it to be performed at 
least 24 weeks after dose escalation. 
Synopsis, Overview 
of Study Design; 
Section 3.1, Overview 
of Study Design
If a UC patient in the Dose Escalation Group undergoes optional ileocolonoscopy at 
screening and at least 24 weeks after dose escalation or later, Mayo scores will also be 
obtained.
Synopsis, Patient 
population; Section 
4.1, Inclusion 
Criterion 10.h.iii
Section 9.3.1.5, 
Optional Evaluations
(renumbered from 
9.3.1.3)
The ileocolonoscopy must have occurred within 4 weeks prior to the initiation of, or 
during, the screening process.
For patients in the Dose Escalation Group, investigators may perform optional 
ileocolonoscopy during screening, unless ileocolonoscopy was performed within 4 
weeks prior to screening, and again at Week 24 or later (allowable window of +1 week). 
For patients who cross over from the Reference Group to the Dose Escalation Group, 
investigators may perform optional ileocolonoscopy within 2 weeks prior to the first 
10 mg/kg infliximab dose and at least 24 weeks after dose escalation (allowable window 
of +1 week).
Time and Events 
Schedule, Footnote 
“e”
Optional repeat ileocolonoscopy may be performed at least 24 weeks after dose escalation 
or later; refer to Section 9.3.1.5 for further details.
Time and Events 
Schedule, 
Ileocolonoscopy
“X” mark from at week 24 through 56 for Ileocolonoscopy
Time and Events 
Schedule, Mayo score 
(only for UC patients 
in Dose Escalation 
Group having 
optional 
ileocolonoscopy)
“X” mark at week 16 from Week 24 through 56 for Mayo score (only for UC patients in 
Dose Escalation Group having optional ileocolonoscopy), with associated Footnote “o” 
added: For patients who discontinue treatment prior to Week 56 information needed 
for the PCDAI or partial Mayo scores with respect to questions such as stool 
frequency or quality, abdominal pain, and general well-being will be obtained from 
patient diary and/or recall.
Rationale: The time window for reporting serious adverse events was revised to be more consistent with the 
Sponsor’s standard post-trial reporting guidelines.
Section 12.3.1, All 
Adverse Events
Serious adverse events, including those spontaneously reported to the investigator within 
168 weeks after the last dose of infliximab, must be reported using the Serious Adverse 
Event Form.
Rationale: Clarification added to the Time and Events Schedule regarding assessments to be performed at the time 
of treatment discontinuation, or early study discontinuation.
Time and Events 
Schedule
Modified Column Heading: (Week) 56/End of Treatment; Week 64 
(Final Safety Visit) c /Early Study Discontinuation
Rationale:  Wording pertaining to the screening visit was corrected in the bullets for “New Malignancy” and “New
Autoimmune Disorder”. 
Section 12.1.1, 
Adverse Event 
Definitions and 
Classifications
…(including during the enrollment screening visit)
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
24
Approved, Date: 20 February 2018
Applicable 
Section(s)
Description of Change(s)
Rationale:  Text regarding sample storage for future research is not applicable and was corrected.
Section 16.2.5, Long-
Term Retention of 
Samples for 
Additional Future 
Research
Samples collected in this study may be stored according to local regulations for additional 
research.  However, no genetic analyses will be performed. The research may begin at any 
time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will 
not be labeled with personal identifiers. Patients may withdraw their consent for their 
samples to be stored for research. No samples will be stored for additional future 
research.
Rationale: Minor grammatical and formatting errors were noted and corrected in the protocol. These changes do 
not impact the conduct of the protocol and therefore are not listed here.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
25
Approved, Date: 20 February 2018
SYNOPSIS
Title
A Phase 4, Multicenter, Open-label Study of Serum Infliximab Concentrations and Efficacy and Safety of Dose 
Escalation in Pediatric Patients with Inflammatory Bowel Disease
Remicade® (infliximab)
Remicade® (infliximab), a recombinant immunoglobulin G (IgG) 1-κ human-murine chimeric monoclonal antibody,
is an antagonist of the cytokine tumor necrosis factor alpha (TNFα) that specifically binds and neutralizes both the 
soluble TNFα homotrimer and its membrane-bound precursor. Infliximab is indicated for treatment of several 
autoimmune diseases in which TNFα plays a major role.   
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate whether trough serum infliximab concentrations at the time of loss 
of clinical response will identify pediatric patients with inflammatory bowel disease (IBD) who would benefit 
(regain clinical response) from dose escalation above the currently approved dose (5 mg/kg every 8 weeks [q8wk]).  
Overall safety will be assessed throughout the duration of the study.
Secondary Objectives
Secondary objectives of this study are to:

Identify disease characteristics associated with maintenance of sustained clinical response in patients after dose 
escalation 

Evaluate the rate of serious adverse events in patients who receive an increased dose of infliximab due to loss 
of response (Dose Escalation Group) relative to the rate of serious adverse events in those patients in response 
who are maintained on infliximab 5 mg/kg q8wk (Reference Group)   
Hypothesis
In pediatric IBD patients with loss of response, trough serum infliximab concentrations will be associated with 
regaining of response after dose escalation.  
OVERVIEW OF STUDY DESIGN
This is a multicenter, prospective, open-label study in pediatric patients with IBD who are receiving infliximab 
therapy. The study will include 2 groups, a Dose Escalation Group (n=80) and a Reference Group (n=50). Both the 
Dose Escalation and Reference Groups will include 60% Crohn’s disease (CD) patients and 40% ulcerative colitis 
(UC) patients at enrollment, to ensure a clinically meaningful number of patients by IBD diagnosis. Patients in both 
groups will receive infliximab q8wk through Week 56, with a Final Safety Visit occurring 8 weeks after the last 
dose of infliximab. Patients in the Reference Group who lose clinical response may cross over to the Dose 
Escalation Group provided they meet all entry criteria for the Dose Escalation Group (as described under PATIENT 
POPULATION below). Investigators may discontinue patients who have not regained clinical response after receiving 
2 doses of 10 mg/kg infliximab.
After obtaining informed consent/assent, detailed demographic and medical history, including qualitative and 
quantitative signs and symptoms present at initiation of infliximab therapy and the time of response, will be 
collected on all patients meeting inclusion and exclusion criteria at the time of enrollment. Review of concomitant 
medications as well as safety and efficacy assessments (Pediatric Crohn’s Disease Activity Index [PCDAI] scores or
partial Mayo scores) will be conducted at every study visit through Week 56. Samples will be collected for 
measurement of serum concentrations of infliximab and antibodies to infliximab (ATI) at screening for patients in 
the Dose Escalation Group, prior to each infusion during the study for patients in each group, and at the time of loss 
of clinical response for patients in each group. If a UC patient in the Dose Escalation Group undergoes optional 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
26
Approved, Date: 20 February 2018
ileocolonoscopy, Mayo scores will also be obtained. The end of the study will occur on the date of the last visit of 
the last patient participating in the study.
An internal Safety Monitoring Committee will be established to monitor safety data on an ongoing basis to ensure 
the continuing safety of patients enrolled in this study.
PATIENT POPULATION
Patients must be male or female at least 6 years of age and less than 17 years of age at the time of enrollment. 
He/she must have a biopsy-confirmed diagnosis of CD or UC prior to study entry. In addition, group-specific 
inclusion criteria include the following:
Patients in the Dose Escalation Group:
a.
Must have completed the recommended infliximab induction dosing regimen of 5 mg/kg at weeks 0, 2, and 6 
and at least 1 maintenance dose of 5 mg/kg q8wk and have demonstrated a clinical response according to the 
criteria in Attachment 3 for CD patients or Attachment 4 for UC patients (the last 2 doses occurring at least 
48 days, but no more than 64 days, apart, with allowable dose range of 4.5 to 6 mg/kg); or, an induction 
regimen with doses >6 mg/kg and have received at least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses 
at least 48, but no more than 64, days apart with allowable dose range of 4.5 to 6 mg/kg) and have demonstrated 
clinical response for at least 28 days after the most recent (second or later) 5 mg/kg maintenance dose; or, 
maintenance doses >6 mg/kg within the past 6 months and at least 2 maintenance doses of 5 mg/kg q8wk (the 
last 2 doses occurring at least 48 days, but no more than 64 days, apart, with allowable dose range of 4.5 to 6 
mg/kg) and have demonstrated a clinical response for at least 28 days after the most recent (second or later) 5 
mg/kg maintenance dose
b.
Must have lost clinical response, according to the criteria in Attachment 3 for CD patients or Attachment 4 for 
UC patients, after the first or subsequent q8wk maintenance dose of infliximab 5 mg/kg, for patients who have 
completed the recommended infliximab induction dosing regimen (5 mg/kg at weeks 0, 2, and 6) or, after the 
most recent (second or later) q8wk maintenance dose of infliximab 5 mg/kg for patients with an induction 
regimen with  doses >6 mg/kg or for patients with previous maintenance doses >6 mg/kg 
c.
Must not have discontinued infliximab therapy (discontinuation defined as period of ≥6 months without 
receiving a dose)
d.
Must have received the last maintenance dose of infliximab at least 4 weeks but not more than 10 weeks prior to
screening 
e.
Must have an infliximab Ctrough < 7 µg/mL and ATI titers ≤ 12,800 at the time of loss of response
f.
Must have a PCDAI of > 30 points with both an abdominal pain and stool frequency sub-score of ≥ 5 (patients 
with CD)
g.
Must have a partial Mayo score of ≥ 5 points with both stool frequency and rectal bleeding sub-scores of ≥1
(patients with UC)
h.
Must meet one of the following criteria:
i.
Have serum CRP > 0.287 mg/dL
ii.
Have fecal calprotectin > 50 µg/g
iii.
Have evidence of active disease (ulcerations) on ileocolonoscopy. The ileocolonoscopy must have 
occurred within 6 weeks prior to the first 10 mg/kg dose.
Patients in the Reference Group:
a.
Must have completed the recommended infliximab induction dosing regimen of 5 mg/kg at weeks 0, 2, and 
6 and have achieved and maintained a stable clinical response* to infliximab after at least 1 maintenance 
dose of 5 mg/kg q8wk according to the criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients (the last 2 doses occurring at least 48 days, but no more than 64 days, apart, with allowable dose 
range of 4.5 to 6 mg/kg) ; or, an induction regimen with doses >6 mg/kg and have received at least 2 
maintenance doses of 5 mg/kg q8wk (the last 2 doses at least 48, but no more than 64, days apart with 
allowable dose range of 4.5 to 6 mg/kg) and have demonstrated clinical response for at least 28 days after 
the most recent (second or later) 5 mg/kg maintenance dose; or, maintenance doses >6 mg/kg within the 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
27
Approved, Date: 20 February 2018
past 6 months and at least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses occurring at least 48 
days, but no more than 64 days, apart, with allowable dose range of 4.5 to 6 mg/kg) and have demonstrated 
a clinical response for at least 28 days after the most recent (second or later) 5 mg/kg maintenance dose.
* 
Patients with a stable clinical response to infliximab are defined as those patients who have achieved 
clinical response according to criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients and who did not initiate or receive increased doses of 5-aminosalicylic acid (5-ASA), 
corticosteroids, immunomodulators or antibiotics for the treatment of IBD for 4 weeks prior to 
screening.
b.
Must not have discontinued infliximab therapy (discontinuation defined as period of ≥6 months without 
receiving a dose). 
Refer to the full protocol for a list of all entry criteria.
DOSAGE AND ADMINISTRATION
Upon meeting enrollment criteria for the Dose Escalation Group, patients will receive infliximab 10 mg/kg q8wk at 
Week 0. Patients will be eligible to receive 56 weeks of therapy with infliximab at the escalated dose with a Final 
Safety Visit at Week 64. 
Upon meeting enrollment criteria for the Reference Group, patients will receive 5 mg/kg q8wk. Those who lose 
clinical response during participation in the study will be eligible, if they meet the enrollment criteria for the Dose 
Escalation Group, to cross over to the Dose Escalation Group.
Patients in the Reference Group who lose response and cross over to the Dose Escalation Group must complete 
screening for the Dose Escalation Group and receive the first 10 mg/kg dose of infliximab within 40 weeks of 
enrollment into the study.
Patients who cross over from the Reference Group to the Dose Escalation Group will be eligible to receive a total of 
56 weeks of therapy with infliximab, which includes duration of therapy while in the Reference Group prior to dose 
escalation. 
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy will be evaluated using the PCDAI and partial Mayo score.
Primary Endpoint
The primary efficacy endpoint is clinical response at Week 16 after dose escalation, defined as:

CD patients:
A decrease from baseline in PCDAI of ≥ 15 points with total score of ≤30 points 

UC patients:
A decrease from baseline in partial Mayo score of ≥2 points and ≥30% and a decrease in 
the rectal bleeding sub-score by ≥ 1 point or achievement of an absolute sub-score of 
≤1point 
Secondary Endpoints
Major secondary efficacy endpoint:   Sustained clinical response through 56 weeks after dose escalation
Other secondary efficacy endpoints:
1.
For CD patients changes from baseline at Week 16 and at Week 56 in: 

Abdominal pain and loose/watery stool frequency sub-scores of the PCDAI 

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
2.    For UC patients changes from baseline at Week 16 and at Week 56 in:

Stool frequency and rectal bleeding sub-scores of the partial Mayo score 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
28
Approved, Date: 20 February 2018

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
3.   Correlates of Wong-Baker FACES scale with clinical remission and response at Week 16     
4.  The association between abdominal pain PCDAI sub-score and the Wong-Baker FACES scale for patients with 
CD
Secondary safety endpoint: The incidence of serious adverse events
SERUM INFLIXIMAB CONCENTRATIONS AND ANTIBODIES TO INFLIXIMAB
Venous blood samples will be collected for measurement of serum concentrations of infliximab and ATI titers. 
Serum infliximab concentrations will be determined using a validated, enzyme-linked immunosorbent assay. Serum
ATI titers will be determined using a validated, drug-tolerant electrochemiluminescence immunoassay (ECLIA) 
method. 
SAFETY EVALUATIONS
Safety evaluations during the study include adverse events, clinical laboratory tests, physical examinations including 
vital signs, and screening for tuberculosis.  
STATISTICAL METHODS
Sample Size Calculation
Both the Dose Escalation and Reference Groups will be composed of 60% CD patients and 40% UC patients. 
Accordingly, the proposed study will enroll 80 (48 CD and 32 UC) patients in the Dose Escalation Group and 50 (30 
CD and 20 UC) patients in the Reference Group, with the conservative assumption that approximately 10 patients 
(20%) in the Reference Group may dose escalate. 1,2 Thus, the final sample size in the Dose Escalation Group is 
estimated to be 90 patients, with 54 CD patients and 36 UC patients.  
The sample size estimation was calculated based on precision estimates for clinical response rates after dose 
escalation from 5 mg/kg q8w to 10 mg/kg q8w at Week 16, the primary efficacy endpoint. It is anticipated the 
dropout rate due to loss to follow up and other non-efficacy related reasons by Week 16 will be about 5% of 
patients, based on the Phase 3 pediatric infliximab trials in CD and UC patients.1,2 Adjusting for dropout rate, a 
sample size of 76 - 85 patients (without or with cross over) will provide precision estimates between ± 8.5 – 11.2% 
for expected response rates between 20 - 50%, based on a 2-sided 95% confidence interval (CI). 
A response rate of 5% was assumed for patients with loss of clinical response not receiving dose escalation. At a 
significance level of 0.05 (2-sided), the statistical power is greater than 90% to detect at least a 15% increase in 
clinical response after dose escalation, for the overall Dose Escalation Group (N=76 – 85, without or with cross 
over). For the CD subgroup (N = 46 - 51, without or with cross over), the power is between 84% - 90%.  For the UC 
subgroup (N = 30 - 34, without or with cross over), the power is between 70% - 74%.
When testing the association between infliximab concentration and regain of clinical response after dose escalation, 
using logistic regression to test the null hypothesis of no association between infliximab serum concentrations and 
clinical response, ie, β = 0 (α = 0.05, 2-sided), a sample size of 76 - 85 patients (without or with cross over) will 
provide statistical power between 66% and 85% to detect β of 0.916, assuming the response rate is between 20 –
50%. 
Statistical Analyses
For the primary analysis, the clinical response rate at 16 weeks after dose escalation and the surrounding 2-sided 
95% confidence interval will be estimated for the entire Dose Escalation Group, as well as for subgroups of CD and 
UC patients. For the patients who cross over from the Reference Group to the Dose Escalation Group, their clinical 
response at 16 weeks after dose escalation will be included in the primary endpoint analysis. For the Dose Escalation 
Group, including patients who cross over from the Reference Group, logistic regression will be performed to 
evaluate the relationship between serum infliximab concentration prior to dose escalation and clinical response at 
Week 16 after dose escalation.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
29
Approved, Date: 20 February 2018
Safety data will be summarized for both the Dose Escalation Group and the Reference Group.
References
1.
Hyams J, Crandall W, Kugathasan S, et al, and the REACH Study Group. Induction and maintenance infliximab therapy for the treatment 
of moderate-to-severe Crohn’s disease in children. Gastroenterol. 2007;132:863–873.
2.
Hyams J, Damaraju L, Blank M, et al, for the C0168T72 Study Group. Induction and maintenance therapy with infliximab for children 
with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10:391–399.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
30
Approved, Date: 20 February 2018
TIME AND EVENTS SCHEDULE
Study Procedures a, b
Screening
(Day -28)
Week
Week 64 
(Final Safety Visit) c /
Early Study 
Discontinuation
0
8
16
24
32
40
48
56/ End of 
Treatment
Informed consent/assent d
X
Distribute patient PCDAI or partial Mayo 
diary and study cards
X
Medical history and demographics
X
Review of inclusion/exclusion criteria
X
X
Prior medication review e
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
Ileocolonoscopy f
X
X---------------------------------------------
Physical examination g
X
X
X
Vital signs and Weight 
X
X
X
X
X
X
X
X
X
X
Height 
X
X
X
X
Stool culture for enteric pathogens, including 
Clostridium difficile toxins h
X
Fecal calprotectin h, i, j
X
Tuberculosis evaluation k
X
X
X
X
X
X
X
X
X
X
QFT-TB Gold test (or tuberculin skin test in 
countries where the QFT-TB Gold test is not 
approved/registered or is not required per 
local guidelines)
X
Chest radiograph l
X
Hepatitis B testing
X
Hepatitis C testing
X
Varicella antibody titers m
X
Measles antibody titers m
X
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
31
Approved, Date: 20 February 2018
Study Procedures a, b
Screening
(Day -28)
Week
Week 64 
(Final Safety Visit) c /
Early Study 
Discontinuation
0
8
16
24
32
40
48
56/ End of 
Treatment
Urine pregnancy test n
X
X
X
X
X
X
X
X
X
X
Hematology and chemistry 
X
X
X
X
X
X
Hematocrit 
X o
X o
X o
X o
Albumin
X o
X o
X o
X o
ESR
X j, p
X p
X p
X p
X p
X p
X p
X p
X p
CRP
X j
X
X
X
X
X
X
X
X
Infliximab concentration i, q
X j
X
X
X
X
X
X
X
X
X
Antibodies to infliximab q
X j
X
X
X
X
X
X
X
X
X
ANA and anti-dsDNA antibodies
X
X
PCDAI score or partial Mayo score r
Xw
Xw
X
X
X
X
X
X
X s
FACES (Wong-Baker pain scale) t
X
X
X
Stool Frequency u
X
X
X
Mayo score (only for UC patients in Dose 
Escalation Group having optional 
ileocolonoscopy)
X
X--------------------------------------------
Adverse event review
X
X
X
X
X
X
X
X
X
X v
Infliximab administration
X
X
X
X
X
X
X
X
a
All assessments are to be completed prior to infliximab administration.
b
If a patient discontinues study participation, he/she will be requested to return for a follow-up safety visit 8 weeks following the final administration of infliximab. 
During the follow-up safety evaluation, the procedures and evaluations indicated at Week 64 will be performed, prior to withdrawal of consent. If a patient 
withdraws consent, no further study procedures are to be performed.  
c
The Final Safety Visit for those patients completing the treatment portion of the study is to occur 8 weeks after the last administration of infliximab at Week 56.
d
Pre-screening stool sample consent may be obtained prior to the screening visit per local or site requirements.
e
The name, dose, frequency, route of administration, the start and stop dates, and duration of any therapy taken by the patient for CD or UC at any time in the past 
(eg, 5-ASAs; corticosteroids; immunomodulators, including thiopurines; biologics) will be recorded in the case report form. For biologics, brand (trade) names will 
be recorded. In addition, any other prestudy therapies administered up to 30 days before the first dose of infliximab at Week 0 must be recorded at screening.
f
An ileocolonoscopy is an optional evaluation for patients in the Dose Escalation Group and for patients crossing over to the Dose Escalation Group; it is not 
applicable to patients in the Reference Group. Optional repeat ileocolonoscopy may be performed during screening or as standard care within 6 weeks prior to the 
first infliximab 10 mg/kg dose and again at least 24 weeks after dose escalation or later; refer to Section 9.3.1.5 for further details.
g
Complete physical examinations (including skin and genitourinary examination) are to be conducted. 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
32
Approved, Date: 20 February 2018
h
Sample to be collected at or up to 24 hours prior to screening visit (with completion of appropriate stool sample consent), however, if not done, patient/caregiver may 
collect at home and return to the site within 24 hours of collection. The following medications should be avoided for 48 hours prior to the sample collection: 
antacids, barium, bismuth, antidiarrheal medication, and oily laxatives. Please refer to the Covance laboratory manual for further instructions.
i
For patients undergoing screening for the Dose Escalation Group, those who do not meet entry criteria based on infliximab concentration and/or fecal calprotectin 
and/or CRP levels may have repeat infliximab concentration and/or fecal calprotectin and/or CRP levels performed during the screening process, provided that all 
entry criteria are met within 14 days prior to administration of the first 10 mg/kg dose of infliximab.
j
At screening, to be performed for patients in the Dose Escalation Group or for patients in the Reference Group prior to crossing over to the Dose Escalation Group. 
k
See Section 9.5.5 for TB evaluations. If TB is suspected at any time, follow-up is required as described in Section 9.5.5.
l
Chest radiographs (both posterior-anterior and lateral views) must be performed as part of the screening process in all cases when either the tuberculin skin test 
and/or QFT-TB Gold test results for TB are positive or proof of negative chest radiograph performed prior to initiation of infliximab cannot be obtained.
m
Varicella and measles titers do not need to be obtained if proof of age-appropriate immunization or proof of prior infection is obtained. 
n
For female patients of childbearing potential only.
o
For CD patients only. Hematocrit and albumin laboratory studies must be performed at each of these visits in order to calculate PCDAI. 
p
ESR is to be collected for CD patients only at each dosing visits for calculation of PCDAI.
q
Infliximab concentration and ATI titers will be performed for both the Dose Escalation and Reference groups prior to each infusion and at the time of loss of 
response.  Prior to crossing over to the Dose Escalation Group, patients in the Reference Group who lose clinical response must meet all inclusion criteria for the 
Dose Escalation Group, including Ctrough < 7 g/mL and ATI titers ≤ 12,800 (see Section 4.1 inclusion criterion #10).  
r
The PCDAI or partial Mayo diaries will be completed by patients during the screening period. For calculation of PCDAI at Screening and/or Week 0 for CD patients 
in the Dose Escalation Group the hematocrit, ESR, and albumin values obtained during screening will be used. For calculation of PCDAI prior to the first 10 mg/kg 
dose for CD patients crossing over from the Reference Group to the Dose Escalation Group, the hematocrit, ESR, and albumin obtained within 2 weeks prior to the 
administration of the first 10 mg/kg dose will be used. The PCDAI or partial Mayo score should be calculated prior to infliximab administration at Week 0 for the 
Dose Escalation Group or prior to the administration of the first 10 mg/kg dose for patients crossing over from the Reference Group.
s
For patients who discontinue treatment prior to Week 56 information needed for the PCDAI or partial Mayo scores with respect to questions such as stool frequency 
or quality, abdominal pain, and general well-being will be obtained from patient diary and/or recall.
t
For cross over patients, the Wong-Baker FACES pain scale will be administered prior to the administration of the first and the third dose of 10 mg/kg of infliximab.  
u
For cross over patients stool frequency data will be collected prior to the administration of the first and the third dose of 10 mg/kg of infliximab. 
v
Required follow-up for adverse events after the Final Safety Visit is described in Section 12.3.
w
The Week 0 PCDAI or partial Mayo score should be the highest of any values obtained during a period of up to 28 days prior to, or including, Week 0.
Note:   (1) The maximum acceptable visit window for all visits after the Screening visit is ±7 days. Patients must meet all enrollment criteria for the Week 0 visit prior 
to the administration of infliximab.
(2) At an infusion visit, blood samples should be collected prior to infliximab administration. The same venipuncture can be used to collect serum samples for 
measuring infliximab concentration, ATI, blood draws for safety and efficacy, as well as the infusion of infliximab.
Key:
5-ASA = 5- aminosalicylic acid; ANA = antinuclear antibody; anti-dsDNA = anti-double stranded DNA antibody; ATI = antibody-to-infliximab; CD = Crohn’s 
disease; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; TB = tuberculosis; TNF = tumor necrosis factor; PCDAI = pediatric Crohn's disease 
activity index; q8wk = every 8 weeks; QFT-TB = QuantiFERON-TB (test); UC = ulcerative colitis.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
33
Approved, Date: 20 February 2018
ABBREVIATIONS
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
6-TG
6-thioguanine
ACCENT
A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen 
ACT 1
Active Ulcerative Colitis Trial 1
ACT 2
Active Ulcerative Colitis Trial 2
ADAPT
A Phase 4, Multicenter, Open-label Study of Serum Infliximab Concentrations and Efficacy and 
Safety of Dose Escalation in Pediatric Patients with Inflammatory Bowel Disease
ALT
alanine aminotransferase
ANA
antinuclear antibody
Anti-dsDNA
anti-double stranded DNA antibody
Anti-HBc
total hepatitis B core antibody
Anti-HBs
hepatitis B surface antibody
AST
aspartate aminotransferase
ATI
antibodies to infliximab
AZA
Azathioprine
BCG
Bacille Calmette-Guerin
BUN
blood urea nitrogen
CD
Crohn’s disease
CI
confidence interval
CRF
case report form (paper or electronic as appropriate for this study)
CRP
C-reactive protein
DCF
data clarification form
DEVELOP
An Inflammatory Bowel DisEase Multicenter, ProspectiVE, LOng-term Registry of Pediatric 
Patients
DNA
deoxyribonucleic acid
ECLIA
electrochemiluminescence immunoassay
eDC
electronic data capture
EU
European Union
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HIV
human immunodeficiency virus
HSTCL
hepatosplenic T-cell lymphoma
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin
IRB
Institutional Review Board
ITT
intention-to-treat (population)
IUD
intrauterine device
IUS
intrauterine system
IV
Intravenous
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intention-to-treat (population)
MMF
mycophenolate mofetil 
MTX
Methotrexate
PCDAI
Pediatric Crohn's Disease Activity Index
PGA
Physician’s Global Assessment
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
34
Approved, Date: 20 February 2018
PPD
purified protein derivative
PQC
product quality complaint
q8wk
every 8 weeks
QFT-TB
quantiFERON-TB
RBC
red blood cell
REACH
A Randomized, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of Anti-TNFα
Chimeric Monoclonal Antibody (Infliximab, REMICADE®) in Pediatric Patients with Moderate 
to Severe Crohn's Disease
SAP
Statistical Analysis Plan
SI
International System of Units
SUSAR
suspected unexpected serious adverse reaction
TB
Tuberculosis
TNF
tumor necrosis factor
UC
ulcerative colitis
US
United States
WBC
white blood cell
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
35
Approved, Date: 20 February 2018
1.
INTRODUCTION
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.
Remicade® (infliximab), a recombinant immunoglobulin G (IgG) 1-κ human-murine chimeric 
monoclonal antibody, is an antagonist of the cytokine tumor necrosis factor alpha (TNFα) that 
specifically binds and neutralizes both the soluble TNFα homotrimer and its membrane-bound 
precursor. Infliximab is indicated for treatment of several autoimmune diseases in which TNFα 
plays a major role, including adult patients with Crohn’s disease (CD), ulcerative colitis (UC), 
rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or plaque psoriasis as well as 
pediatric patients with CD or UC. Infliximab is administered via intravenous (IV) infusion.  For 
the most comprehensive nonclinical and clinical information regarding infliximab refer to the
most current local label. 
Following the 23 Sep 2011 approval for infliximab for the treatment of pediatric patients with 
moderate to severe UC, the United States (US) Food and Drug Administration (FDA) requested 
that the sponsor obtain further data on the safety and efficacy of dose escalation in pediatric 
patients with inflammatory bowel disease (IBD) who have lost an initial response to infliximab. 
Accordingly, the current study was designed with specific input from the FDA to evaluate 
whether trough concentrations at the time of loss of clinical response could be used to identify 
pediatric patients with CD or UC who have low infliximab exposures and would benefit from a 
dose increase above that currently approved without increasing the risk of serious adverse events. 
In addition, the correlation between trough serum infliximab concentrations and antibodies to
infliximab (ATI) will be evaluated.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate whether trough serum infliximab 
concentrations at the time of loss of clinical response will identify pediatric patients with IBD 
who would benefit (regain clinical response) from dose escalation above the currently approved 
dose (5 mg/kg every 8 weeks [q8wk]).  
Overall safety will be assessed throughout the duration of the study.
Secondary Objectives
Secondary objectives of this study are to:

Identify disease characteristics associated with maintenance of sustained clinical response in 
patients after dose escalation  
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
36
Approved, Date: 20 February 2018

Evaluate the rate of serious adverse events in patients who receive an increased dose of 
infliximab due to loss of response (Dose Escalation Group) relative to the rate of serious 
adverse events in those patients in response who are maintained on infliximab 5 mg/kg 
q8wk (Reference Group)
2.2.
Hypothesis
In pediatric IBD patients with loss of response, trough serum infliximab concentrations will be 
associated with regaining of response after dose escalation.  
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, prospective, open-label study in pediatric patients with IBD who are 
receiving infliximab therapy (see Figure 1). The study will include 2 groups, enrolled based on 
entry criteria that include assessment of clinical response or loss of clinical response according to 
the criteria in Attachment 3 or 4, respectively, and as described below:
Dose Escalation Group (n=80):
Pediatric patients with IBD who have received a) the 
recommended infliximab induction dosing regimen of 
5 mg/kg at weeks 0, 2, and 6, have achieved clinical response 
and subsequently lost clinical response after at least 
1 maintenance dose of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, 
with allowable dose range of 4.5 to 6 mg/kg); or, 
b) an induction regimen with doses >6 mg/kg and have 
received at least 2 maintenance doses of 5 mg/kg q8wk (the 
last 2 doses at least 48, but no more than 64, days apart with 
allowable dose range of 4.5 to 6 mg/kg)
and have 
demonstrated clinical response for at least 28 days after the
most recent (second or later) 5 mg/kg maintenance dose; or, 
c) maintenance doses >6 mg/kg within the past 6 months and
at least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, 
with allowable dose range of 4.5 to 6 mg/kg) and have 
demonstrated a clinical response for at least 28 days after the
most recent (second or later) 5 mg/kg maintenance dose. 
These patients will dose escalate to 10 mg/kg q8wk at Week 
0.
Reference Group (n=50): 
Pediatric patients with IBD who have received a) the 
recommended infliximab induction dosing regimen
of
5 mg/kg at weeks 0, 2, and 6, and have achieved and 
maintained a stable clinical response* to infliximab after at 
least 1 maintenance dose of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, 
with allowable dose range of 4.5 to 6 mg/kg); or b) an 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
37
Approved, Date: 20 February 2018
induction regimen with doses >6 mg/kg and have received at 
least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses at 
least 48, but no more than 64, days apart with allowable dose 
range of 4.5 to 6 mg/kg) and have demonstrated clinical 
response for at least 28 days after the most recent (second or 
later) 5 mg/kg maintenance dose; or, 
c) maintenance doses >6 mg/kg within the past 6 months and
at least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, 
with allowable dose range of 4.5 to 6 mg/kg) and have 
demonstrated a clinical response for at least 28 days after the
most recent (second or later) 5 mg/kg maintenance dose. 
* Patients with a stable clinical response to infliximab are 
defined as those patients who have achieved clinical 
response according to criteria in Attachment 3 for CD 
patients or Attachment 4 for UC patients and who did not 
initiate or receive increased doses of 5-aminosalicylic acid 
(5-ASA), 
corticosteroids, 
immunomodulators 
or 
antibiotics for the treatment of IBD for 4 weeks prior to 
screening.
Patients in the Reference Group who lose clinical response 
may cross over the Dose Escalation Group, provided they 
meet entry criteria including having Ctrough < 7 g/mL and ATI 
titers ≤ 12,800 (see Section 4.1, inclusion criterion #10 for the
Dose Escalation Group). 
Although the Dose Escalation and Reference Groups will not be comparable in terms of disease 
activity, the Reference Group will provide safety information, serum infliximab concentration 
data, and ATI titer data in a contemporaneous IBD cohort undergoing infliximab therapy. Both 
the Dose Escalation and Reference Groups will include 60% CD patients and 40% UC patients at 
enrollment, to ensure a clinically meaningful number of patients by IBD diagnosis. 
Patients in both groups will receive infliximab q8wk through Week 56, with the Final Safety 
Visit occurring 8 weeks after the last dose of infliximab. Investigators may discontinue patients 
who have not regained clinical response after receiving 2 doses of 10 mg/kg infliximab
administered 8 weeks apart.  
After obtaining informed consent/assent, detailed demographic and medical history, including 
qualitative and quantitative signs and symptoms present at initiation of infliximab therapy and 
the time of response, will be collected on all patients meeting inclusion and exclusion criteria at 
the time of enrollment. Review of concomitant medications as well as safety and efficacy 
assessments (Pediatric Crohn’s Disease Activity Index [PCDAI] scores or partial Mayo scores) 
will be conducted at every study visit through Week 56. Samples will be collected for 
measurement of serum concentrations of infliximab and ATI titers at screening for patients in the 
Dose Escalation Group, prior to each infusion during the study for patients in each group, and at 
the time of loss of clinical response for patients in each group. If a UC patient in the Dose 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
38
Approved, Date: 20 February 2018
Escalation Group undergoes optional ileocolonoscopy, Mayo scores will also be obtained. Refer 
to the Time and Events Schedule for all procedures to be performed over the course of the study. 
The end of the study will occur on the date of the last visit of the last patient participating in the 
study.
Figure 1:
Dose escalation study diagram
3.2.
Study Design Rationale
3.2.1.
Trough Serum Infliximab Concentrations and Dose Escalation 
Infliximab is highly effective for the treatment of pediatric IBD; however, 40% to 50% of 
patients may lose response to this agent within 1 year after the initiation of therapy, requiring 
dose escalation in order to regain response.8,9  Loss of response may be explained by:

Inadequate drug concentration (due to either inadequate dosing or rapid clearance), or

Immunogenicity of infliximab (ie, the development of high-titer ATI), or

Emergence of inflammatory processes independent of TNF.
Higher infliximab concentrations in the setting of low or undetectable levels of ATI have been 
associated with higher rates of clinical remission, lower serum C-reactive protein (CRP) 
concentrations, as well as endoscopic improvement in adult patients with both CD and UC.4,11,15
The Phase 3 infliximab program in adult patients with IBD provides exposure-response data that 
confirm a positive correlation between infliximab concentrations and clinical outcomes. 
Specifically, the Phase 3 clinical trial of infliximab in adult patients with CD, assessed the 
relationship between efficacy and exposure to infliximab, demonstrating a positive correlation 
between response status and median pre-infusion infliximab concentrations (ACCENT 1).5
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
39
Approved, Date: 20 February 2018
Furthermore, examining the relationship between sustained clinical response rates at Week 54 in 
relation to trough levels at Week 14 stratified by quintiles demonstrates that response rates 
diminish above levels of 6.8 µg/mL (Figure 2).  
Figure 2:
Sustained response to 5 mg/kg infliximab maintenance treatment by quintile of Week 14 serum 
infliximab concentrations in adult Crohn’s disease patients (ACCENT 1)
Similar analyses of data from the Phase 3 clinical trials of infliximab in adult patients with UC
(ACT 1 and ACT 2),1 demonstrate that infliximab concentrations above 6.8 µg/mL at Week 30 
were associated with diminished proportions of patients achieving clinical response, mucosal 
healing, and clinical remission at Week 30.
The Phase 3 infliximab pediatric IBD program also demonstrated a positive relationship between 
infliximab concentrations and clinical response. In the Phase 3 pediatric CD study, REACH, 
patients with higher pre-infusion infliximab concentrations at Week 54 had greater 
improvements in change from baseline in PCDAI. The sponsor’s Phase 3 study of pediatric 
patients with UC (Study C0168T72) demonstrated that at Week 8, higher serum infliximab 
concentrations were associated with greater proportions of patients achieving efficacy endpoints 
(clinical response, 92.9%; mucosal healing, 92.9%; clinical remission, 64.3%) versus those with 
lower serum concentrations (53.9%, 53.9%, 30.8%, respectively).2 These studies, however, did 
not identify specific trough concentrations associated with sustained clinical response. Data from 
the Immunogenicity Substudy in DEVELOP demonstrated that among pediatric IBD patients 
receiving 5 mg/kg infliximab q8wk, > 50% had undetectable infliximab concentrations and 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
40
Approved, Date: 20 February 2018
> 90% had infliximab concentrations < 7 µg/mL at the time of loss of response (data on file,
Figure 3).  
Figure 3:
Infliximab concentration (ug/mL) at the time of loss of response in pediatric inflammatory 
bowel disease patients in the DEVELOP registry (n=39)
The similarity of infliximab pharmacokinetic properties between pediatric and adult patients with 
IBD has been well documented.2,6 Based on the established exposure-response relationships 
demonstrated in adult patients with CD and UC, the documented pharmacokinetic comparability 
between adult and pediatric patients with IBD, and the data from the DEVELOP registry, 
pediatric IBD patients with loss of clinical response while on infliximab 5 mg/kg q8wk with 
serum infliximab concentrations < 7.0 µg/mL will most likely benefit from dose escalation.
3.2.2.
Antibodies to Infliximab and Dose Escalation  
The presence of ATI is associated with lower infliximab concentrations due to more rapid 
elimination of infliximab from serum secondary to the development of drug-anti-drug antibody
complexes. Since serum infliximab concentration correlates with efficacy outcomes, the 
development of ATI in patients who initially respond to infliximab could potentially decrease the 
effectiveness of the drug. Indeed, Yanai et al (2014) reported that patients with subtherapeutic 
infliximab concentrations with high ATI titers had significantly higher rates of failure of early 
response to dose intensification as well as shorter duration of sustained response once it was 
regained, compared with patients with low ATI titers.17 Finally, the association between the 
development of ATI and infusion reactions has also been documented.3,12  
In the DEVELOP registry, 667 patients have participated to date in the Immunogenicity 
Substudy, 
in 
which 
ATI 
titers 
have 
been 
evaluated 
using 
the 
drug-tolerant
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
41
Approved, Date: 20 February 2018
electrochemiluminescence immunoassay (ECLIA) method. A total of 24 patients in the 
Immunogenicity Substudy had infusion reactions, 6 of whom had serious infusion reactions. Of 
these 24 patients with infusion reactions, 29% (n=7) had ATI titers > 12,800 (data on file). 
Also, within the Immunogenicity Substudy, 24 patients had ATI titers > 12,800, including the 
7 patients with infusion reactions noted above. Of the 24 patients with ATI titers > 12,800, 71% 
did not have an infusion reaction, and 29% had infusion reactions. Based on data cited above, 
pediatric IBD patients with loss of clinical response while receiving infliximab 5 mg/kg q8wk 
with ATI titers ≤ 12,800 (using the ECLIA method) will most likely benefit from dose 
escalation, with consideration of the potential risk of infusion reactions. 
3.2.3.
Other Study Design Features
Infliximab will be administered open-label in order to meet the objectives of this study. The 
efficacy assessments chosen for this study, the PCDAI score and partial Mayo score, are 
validated, well-documented indices that measure clinical efficacy10,11,16 Although the Dose 
Escalation and Reference Groups will not be comparable in terms of disease activity, the 
Reference Group will provide safety information, serum infliximab concentration data, and ATI 
titer data in a contemporaneous IBD cohort undergoing infliximab therapy.  
4.
PATIENT POPULATION
Screening for eligible patients will be performed within 28 days before the Week 0
administration of infliximab.
Pediatric patients with IBD undergoing infliximab therapy according to the local guidelines 
specified in the most current local label who meet the following inclusion and exclusion criteria 
are eligible to participate in the study. 
If there is a question about the inclusion or exclusion criteria below, the investigator should 
consult with the appropriate sponsor representative before enrolling a patient in the study. 
4.1.
Inclusion Criteria
Each potential patient must satisfy all of the following criteria to be enrolled in the study:
1.
Must be male or female at least 6 years of age and less than 17 years of age at the time 
of enrollment 
2.
Must have a biopsy-confirmed diagnosis of CD or UC prior to study entry
3.
Must meet concomitant medication stability criteria (see Section 8)
4.
Is considered eligible according to the following tuberculosis (TB) screening criteria:
a. Have no history of latent or active TB prior to screening 
b. Have no signs or symptoms suggestive of active TB upon medical history and/or 
physical examination
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
42
Approved, Date: 20 February 2018
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 prior to or 
simultaneously with the first on-study administration of infliximab at Week 0
d.
Within 6 weeks prior to the first on-study administration of infliximab at Week 0, 
have a negative QuantiFERON-TB (QFT-TB) Gold test (see Attachment 1.1), or 
have a newly identified positive QFT-TB Gold test result in which active TB has 
been ruled out and for which appropriate treatment for latent TB has been initiated 
either prior to or simultaneously with the first on-study administration of infliximab 
at Week 0
e.
If the QFT-TB Gold test is not approved/registered in that country or is not required 
per local guidelines, a negative tuberculin skin test or a newly identified positive 
tuberculin skin test result in which active TB has been ruled out and for which 
appropriate treatment for latent TB has been initiated either prior to or 
simultaneously with the first on-study administration of infliximab at Week 0 is 
additionally required (see Attachment 1.2)
f.
Indeterminate QFT-TB Gold results should have the test repeated. In the event that 
the second QFT-TB Gold test result is also indeterminate, the patient should be 
excluded from the study.  
g.
Unless country or site guidelines do not recommend a chest radiograph as a 
necessary screening process prior to initiation of anti-TNF therapies, a chest 
radiograph (both posterior-anterior and lateral views) must have been performed 
within 3 months prior to infliximab initiation or during the pre-study infliximab 
treatment and read by a qualified radiologist; the results of which must show no 
evidence of current active TB or old inactive TB. Chest radiographs (both 
posterior-anterior and lateral views) must be performed as part of the screening 
process in all cases when either the tuberculin skin test and/or QFT-TB Gold test 
results for TB are positive or proof of previously performed negative chest 
radiograph cannot be obtained.
5.
Must have negative stool results for enteric pathogens. Stool studies must include a
stool culture and Clostridium difficile toxin assay. These must have been performed
during screening or the current episode of disease exacerbation as long as the stool
studies were performed within 4 months prior to the first on-study administration of 
infliximab at Week 0.
6.
Must have screening laboratory test results as follows:
a. Hemoglobin:
≥ 7.5 g/dL
b. White blood cells (WBC): ≥ 2.5 x 103 cells/µL (SI:  ≥ 2.5 x109 cells/L) 
c. Neutrophils:
≥ 1.5 x 103 cells/ µL (SI:  ≥ 1.5 x109 cells/L) 
d. Platelets:
≥ 100 x 103 cells/ µL (SI:  ≥ 100 x109 cells/L)
e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 
not exceeding 2.0 times the upper limit of normal. If patients have ALT or AST 
levels between the ULN and 2x the ULN, clinically appropriate evaluations must be 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
43
Approved, Date: 20 February 2018
performed (and documented in the record) prior to enrollment to rule out etiologies 
that would contraindicate treatment with infliximab.
f.
Serum creatinine not to exceed:
-
6 to 10 years of age: 
0.7 mg/dL (SI: 62 µmol/L)
-
11 to 12 years of age: 1.0 mg/dL (SI: 88 µmol/L)
-
≥ 13 years of age:  
1.2 mg/dL (SI: 106 µmol/L)
7.
Must be up to date with all immunizations in agreement with current local 
immunization guidelines for immunosuppressed patients prior to screening
8.
Must have acceptable evidence of immunity to measles and varicella prior to the 
administration of infliximab at Week 0, including any of the following:  
a. Documentation of age-appropriate vaccination for varicella and/or measles (that 
includes two doses of each vaccine), or
b. Verification of past varicella and/or measles infection by a healthcare provider 
(school or occupational clinic nurse, nurse practitioner, physician assistant, or 
physician), or
c. In the absence of (a) or (b) for varicella and/or measles, must have documentation of
positive protective antibody titers (performed prior to or during screening) to 
varicella and/or measles.
9.
If at increased risk for colon cancer, the patient must have either had a colonoscopy to 
assess the presence of dysplasia within 1 year prior to the first administration of 
infliximab at Week 0 or a colonoscopy to assess the presence of malignancy at the 
Screening Visit
Note: All patients who have had extensive colitis for ≥ 8 years, or disease limited to the 
left side of the colon for ≥ 10 years, are considered at increased risk. For patients with a 
pathology finding of “indefinite dysplasia with reactive atypia” on colonoscopy, the 
investigator should discuss the case with the medical monitor to determine eligibility.
10.
Group-specific inclusion criteria are noted below:
Patients in the Dose Escalation Group:
a. Must have completed the recommended infliximab induction dosing regimen of 
5 mg/kg at weeks 0, 2, and 6, and at least 1 maintenance dose of 5 mg/kg q8wk (the 
last 2 doses occurring at least 48 days, but no more than 64 days, apart, with 
allowable dose range of 4.5 to 6 mg/kg) and have demonstrated a clinical response 
according to the criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients
b. Patients who have received an induction regimen with doses greater than 6 mg/kg 
must have received at least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, with allowable dose 
range of 4.5 to 6 mg/kg) and have demonstrated a clinical response for at least 28 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
44
Approved, Date: 20 February 2018
days after the most recent (second or later) 5 mg/kg maintenance dose according to 
the criteria in Attachment 3 for CD patients or Attachment 4 for UC patients            
c. Patients who have received maintenance doses greater than 6 mg/kg within the past 
6 months must have received at least 2 maintenance doses of 5 mg/kg q8wk (the last 
2 doses occurring at least 48 days, but no more than 64 days, apart, with allowable 
dose range of 4.5 to 6 mg/kg) and have demonstrated a clinical response for at least 
28 days after the most recent (second or later) 5 mg/kg maintenance dose according 
to the criteria in Attachment 3 for CD patients or Attachment 4 for UC patients
d. Must have lost clinical response, according to the criteria in Attachment 3 for CD 
patients or Attachment 4 for UC patients, after the first or subsequent q8wk 
maintenance dose of infliximab 5 mg/kg for patients who have completed the 
recommended infliximab induction dosing regimen (5 mg/kg at weeks 0, 2, and 6) 
or, after the most recent (second or later) q8wk maintenance dose of infliximab 5 
mg/kg for patients with an induction regimen with  doses >6 mg/kg or for patients 
with previous maintenance doses >6 mg/kg
e. Must not have discontinued infliximab therapy (discontinuation defined as period of 
≥6 months without receiving a dose).
f.
Must have received the last maintenance dose of infliximab at least 4 weeks but not 
more than 10 weeks prior to screening 
g. Must have an infliximab Ctrough < 7 g/mL and ATI titers ≤ 12,800 at the time of loss 
of response*
h. Must have a PCDAI of > 30 points with both an abdominal pain and stool frequency 
sub-score of ≥ 5 (patients with CD)
i.
Must have a partial Mayo score of ≥ 5 points with both stool frequency and rectal 
bleeding sub-scores of ≥ 1 (patients with UC)
j.
Must meet one of the following criteria:*

Have serum CRP > 0.287 mg/dL

Have fecal calprotectin > 50 µg/g

Have evidence of active disease (ulcerations) on ileocolonoscopy. The
ileocolonoscopy must have occurred within 6 weeks prior to first 10 mg/kg 
dose.
*  For patients undergoing screening for the Dose Escalation Group, those who do not meet entry 
criteria based on infliximab concentration and/or fecal calprotectin and/or CRP levels may have 
repeat infliximab concentration and/or fecal calprotectin and/or CRP levels performed during the 
screening process, provided that all entry criteria are met within 14 days prior to administration of 
the first 10 mg/kg dose of infliximab.
Patients in the Reference Group:
a. Must have completed the recommended infliximab induction dosing regimen of 
5 mg/kg at weeks 0, 2, and 6, and have maintained a stable clinical response*
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
45
Approved, Date: 20 February 2018
according to the criteria in Attachment 3 for CD patients or Attachment 4 for UC 
patients after at least 1 maintenance dose of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, with allowable dose 
range of 4.5 to 6 mg/kg)
*
Patients with a stable clinical response to infliximab are defined as those 
patients who have achieved clinical response according to criteria in 
Attachment 3 for CD patients or Attachment 4 for UC patients and who did 
not initiate or receive increased doses of 5-aminosalicylic acid (5-ASA), 
corticosteroids, immunomodulators or antibiotics for the treatment of IBD for 
4 weeks prior to screening.
b.  Patients who have received an induction regimen with doses greater than 6 mg/kg 
must have received at least 2 maintenance doses of 5 mg/kg q8wk (the last 2 doses 
occurring at least 48 days, but no more than 64 days, apart, with allowable dose 
range of 4.5 to 6 mg/kg) and have demonstrated a clinical response for at least 28 
days after the most recent (second or later) 5 mg/kg maintenance dose according to 
the criteria in Attachment 3 for CD patients or Attachment 4 for UC patients            
c.  Patients who have received maintenance doses greater than 6 mg/kg within the past 
6 months must have received at least 2 maintenance doses of 5 mg/kg q8wk (the last 
2 doses occurring at least 48 days, but no more than 64 days, apart, with allowable 
dose range of 4.5 to 6 mg/kg) and have demonstrated a clinical response for at least 
28 days after the most recent (second or later) 5 mg/kg maintenance dose according 
to the criteria in Attachment 3 for CD patients or Attachment 4 for UC patients
d.  Must not have discontinued infliximab therapy (discontinuation defined as period of 
≥6 months without receiving a dose).
11.
Prior to enrollment, a female must be either:
a. Not of childbearing potential: premenarchal; permanently sterilized (eg, bilateral 
tubal occlusion [which includes tubal ligation procedures as consistent with local 
regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or 
otherwise be incapable of pregnancy, or
b. Of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for 
patients participating in clinical studies: eg, established use of oral, injected or 
implanted hormonal methods of contraception; placement of an intrauterine device 
(IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the 
vasectomized partner should be the sole partner for that patient); true abstinence 
(when this is in line with the preferred and usual lifestyle of the patient)
c. Note: If the patient’s childbearing potential changes after start the start of the study 
(eg, female who is not heterosexually active becomes active, premenarchal female 
experiences menarche) the patient must begin a highly effective method of birth 
control, as described above  
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
46
Approved, Date: 20 February 2018
12.
A female patient of childbearing potential must have a negative urinary pregnancy test 
at both screening and Week 0 
13.
A female patient must agree not to donate eggs (ova, oocytes) for the purposes of 
assisted reproduction for a period of 6 months after last dose of study medication
14.
A male patient who is sexually active with a female of childbearing potential and has 
not had a vasectomy must agree to use a double barrier method of birth control eg, 
either condom with spermicidal foam/gel/film/cream/suppository or partner with 
occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository, and all men must also not donate sperm during the 
study and for 6 months after receiving the last dose of infliximab
15.
Each patient’s legally acceptable representative must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for 
the study and are willing to participate in the study. Assent is also required of children 
capable of understanding the nature of the study as described in Section 16.2.3. If a 
patient turns 18 years of age after enrollment in the study, he/she must be re-consented.
16.
Must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol
4.2.
Exclusion Criteria
Any potential patient who meets any of the following criteria will be excluded from participating 
in the study. 
A patient is not eligible for enrollment if he/she has any of the following disease 
characteristics:
1.
Must not require, or must not have required, within the 2 months prior to screening, 
surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-
abdominal or pancreatic abscess requiring surgical drainage, or other conditions
possibly confounding the evaluation of benefit from infliximab treatment
2.
Must not have presence or history of colonic or small bowel obstruction within 
6 months prior to screening or radiographic or endoscopic evidence of a stricture with
resulting obstruction (eg, dilation of the colon or small bowel proximal to the stricture 
on barium radiograph or an inability to traverse the stricture at endoscopy)
3.
Must not have local manifestations of CD, such as fistulae, strictures, abscesses, or other 
disease complications for which surgery might be indicated.  Enterocutaneous fistulae 
for which surgery is not indicated, are allowed.  
4.
Must not have presence of a stoma
5.
Must not have documented short bowel syndrome (more than 100 cm in total of small 
bowel resected)  
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
47
Approved, Date: 20 February 2018
6.
Must not have UC limited to the rectum only or to < 20 cm of the colon
7.
Must not have severe extensive colitis as evidenced by:
a.
Investigator judgment that the patient is likely to require a colectomy within 
12 weeks of baseline
      OR
b. Symptom complex at screening or baseline visits that includes at least 4 of the 
following:
1) Diarrhea with ≥ 6 bowel movements/day with macroscopic blood in stool
2) Focal severe or rebound abdominal tenderness
3) Persistent fever (≥ 37.5°C)
4) Tachycardia (> 90 beats/minute)
5) Anemia (hemoglobin < 8.5 g/dL)
8.
Patients with UC must not have a history of extensive colonic resection (eg, less than
30 cm of colon remaining) that would prevent adequate evaluation of the effect of 
infliximab on clinical disease activity
9.
Must not have a history of dysplasia or adenomatous colonic polyps that were not 
removed
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
48
Approved, Date: 20 February 2018
A patient is not eligible for enrollment if he/she:
10.
Is currently receiving any of the following concomitant medications:
a. Immunomodulatory agents other than 6-mercaptopurine (6-MP), azathioprine
(AZA), or methotrexate (MTX; including, but not limited to, 6-thioguanine [6-TG], 
cyclosporine, mycophenolate mofetil [MMF], tacrolimus, and sirolimus)
b. Immunomodulatory biologic agents (including, but not limited to, anakinra, 
etanercept, certolizumab, adalimumab, rituximab, natalizumab, visilizumab,  
ustekinumab, and vedolizumab)
c. Thalidomide or related agents
d. Investigational (non-marketed) agents
e. Oral corticosteroids at a dose > 50 mg of prednisone or its equivalent per day
f.
Require routine use (≥ 2 times per week) of antimotility agents for control of 
diarrhea (ie, diphenoxylate hydrochloride with atropine sulfate, loperamide, or other 
opioids)
Note: While 5-ASAs and/or corticosteroids (≤50 mg of prednisone or its equivalent per 
day) are permitted:
–
A patient in the Dose Escalation Group must be on a stable dose of these 
medications for 2 weeks prior to screening, or he/she is ineligible for enrollment.  
–
A patient in the Reference Group who is crossing over to the Dose Escalation Group 
must be on a stable dose of these medications for 2 weeks before dose escalation, or 
he/she is ineligible for dose escalation.  
11.
Has previously received:
a. Natalizumab within 12 months of first infliximab administration
b. Agents that deplete B or T cells (eg, rituximab, alemtuzumab, or visilizumab) within 
12 months of first infliximab administration, or continue to manifest depletion of B 
or T cells more than 12 months after completion of therapy with lymphocyte 
depleting agents
c. Cyclosporine, tacrolimus, sirolimus, or MMF within 8 weeks prior to first 
administration of infliximab at Week 0
d. Any immunosuppressant biologic drug (approved or investigational) within 4 weeks 
prior to first administration of infliximab or within 5 half-lives of the investigational 
agent, whichever is longer, or is currently enrolled in an interventional study
e. Apheresis (ie, Adacolumn apheresis) within 2 weeks prior to first administration of 
infliximab at Week 0
f.
Has used an invasive investigational medical device within 4 weeks prior to first 
administration of infliximab
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
49
Approved, Date: 20 February 2018
A patient is not eligible for enrollment if he/she has any of the following infections or 
predisposition to infections:
12.
Must not have a history of active granulomatous infection, histoplasmosis, or 
coccidioidomycosis, prior to screening
13.  
Must not have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of 
screening 
14.  
Must not have a chest radiograph within 3 months prior to the first administration of 
study agent that shows an abnormality suggestive of a malignancy or current active 
infection, including TB
15.
Must not have a nontuberculous mycobacterial or opportunistic infection (eg, 
cytomegalovirus, pneumocystosis, aspergillosis)
16.
Must not have a persistently indeterminate (≥ 2) QFT-TB Gold test results; indeterminate 
results should be handled as outlined in Section 9.1  
17.
Must not have a history of, or ongoing, chronic or recurrent infectious disease,
including but not limited to, chronic renal infection, chronic chest infection (eg, 
bronchiectasis), sinusitis, recurrent urinary tract infection (eg, recurrent pyelonephritis,
chronic cystitis), an open, draining, or infected skin wound, or an ulcer
18.
Must not have immune deficiency syndrome (eg, severe combined immunodeficiency
syndrome, T-cell deficiency syndromes, B-cell deficiency syndromes, or chronic
granulomatous disease)
19.
Must not have a known history of infection with human immunodeficiency virus (HIV)
20.
Must not be seropositive for antibodies to hepatitis C virus
21.
Each patient must undergo screening for hepatitis B virus (HBV). At a minimum, this 
includes testing for HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), 
and anti-HBc (total HBV core antibody); additional details are provided in 
Attachment 2.  
a.
A patient who tests negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs-) is eligible for this study.
b. A patient who tests positive for surface antigen (HBsAg+) is not eligible for this 
study, regardless of the results of other hepatitis B tests.
c.
A patient who tests negative for surface antigen (HBsAg-) and tests positive for total 
core antibody (anti-HBc+) and surface antibody (anti-HBs+) is eligible for this 
study.
d. A patient who tests positive only for surface antibody (anti-HBs+) is eligible for this 
study.
e.
A patient who tests positive only for core antibody (anti-HBc+) must undergo 
further testing for hepatitis B deoxyribonucleic acid (HBV DNA test). If the HBV 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
50
Approved, Date: 20 February 2018
DNA test is positive, the patient is not eligible for this study. If the HBV DNA test 
is negative, the patient is eligible for this study. If the HBV DNA test cannot be 
performed, the patient is not eligible for the study.  
Note: For patients who are not eligible for this study due to HBV test results, 
consultation with a physician with expertise in the treatment of HBV infection is 
recommended.
22.
Must not have received, or is expected to receive, any live virus or bacterial
vaccination within 8 weeks (or longer as indicated in the package insert/summary of 
product characteristics of the relevant vaccine) prior to the first administration of 
infliximab
23.
Must not have had a serious infection (eg, hepatitis, pneumonia, or pyelonephritis), have
been hospitalized for an infection, or have been treated with parenteral antibiotics for an 
infection within 2 months prior to first administration of infliximab. Less serious 
infections (eg, acute upper respiratory tract infection, simple urinary tract infection) 
need not be considered exclusionary at the discretion of the investigator.
A patient is not eligible for enrollment if he/she has a history of malignancies or an 
increased potential for malignancy as described below:
24.
Must not have presence of, or history of, any malignancy
25.
Must not have a presence or history of lymphoproliferative disease including
lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease,
such as lymphadenopathy of unusual size or location (eg, nodes in the posterior triangle 
of the neck, infraclavicular, epitrochlear, or periaortic areas), or clinically significant 
hepatomegaly or splenomegaly
A patient is not eligible for enrollment if he/she has the following coexisting conditions or 
past medical history:
26.
Must not have known allergies, a known hypersensitivity to human immunoglobulin
proteins or other components of infliximab, or intolerance to infliximab or its excipients
(refer to the most recent local label)
27.
Must not have had a fever of unknown origin for longer than 3 weeks duration within 
3 months prior to screening, unless thought likely to be associated with IBD
28.
Must not have a concomitant diagnosis or history of congestive heart failure
29.
Must not have a history of moderate or severe progressive, or uncontrolled liver or renal 
insufficiency; or significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, 
neurologic, hematologic, psychiatric, or metabolic disturbances
30.
Must not have a concomitant diagnosis or history of systemic lupus erythematosus
31.
Must not have a transplanted organ (with the exception of a corneal transplant
performed > 3 months prior to the first administration of infliximab at Week 0)
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
51
Approved, Date: 20 February 2018
32.
Must not have a concomitant diagnosis or history of demyelinating disease, such as
multiple sclerosis or optic neuritis
33.
Must not have a current or prior history of substance abuse (drug or alcohol)
Other reasons for which a patient is not eligible for this study include the following:
34.
Must not have poor tolerability of venipuncture or lack of adequate venous access for
required blood sampling
35.
Must not be pregnant, nursing, or planning pregnancy or fathering a child
36.
Must not have any condition for which, in the opinion of the investigator, participation 
would not be in the best interest of the patient (eg, compromise the well-being) or that 
could prevent, limit, or confound the protocol-specified assessments
37.
Must not be an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as 
well as family members of the employees or the investigator
38.
The patient and/or parent/guardian are not able to adhere to the protocol requirements
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a patient's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of infliximab is given such that he or she no longer meets 
all eligibility criteria, then the patient 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 patients 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.
Must not receive a live virus or live bacterial vaccination during the study or within 
6 months after the last administration of infliximab
2.
Must not receive a BCG vaccination during the study or within 12 months after the
last administration of infliximab
3.
Must agree not to plan a pregnancy or father a child within 6 months following the
last administration of infliximab
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
52
Approved, Date: 20 February 2018
4.
If sexually active, female patients must be practicing a highly effective method of 
birth control
(eg, prescription 
oral contraceptives, 
contraceptive injections, 
contraceptive patch,
intrauterine device, double-barrier method [eg, condoms, 
diaphragm, or cervical cap, with spermicidal foam, cream, or gel], or male partner 
sterilization) as local regulations permit, during the study and for 6 months after
receiving the last administration of infliximab
5.
If sexually active, males must use a double barrier method of birth control and not
donate sperm
during
the
study
and
for
6
months
after
receiving
the
last
administration of infliximab
6.
Must not be enrolled in any of the following while participating in the study:
a.
Any interventional clinical trial with an investigational agent (ie, non-marketed 
agent) 
b. Any interventional clinical trial, observational study, and/or registry with 
inclusion/exclusion criteria that prohibit concurrent enrollment in other studies
5.
TREATMENT ALLOCATION AND BLINDING
This is an open-label study. A patient will be allocated to the Dose Escalation Group or the 
Reference Group depending on response to his or her current treatment regimen as described in 
inclusion criterion #10.
6.
DOSAGE AND ADMINISTRATION
Upon meeting enrollment criteria for the Dose Escalation Group (see inclusion criterion #10), 
patients will receive infliximab 10 mg/kg q8wk (Figure 1) at Week 0. Patients will be eligible to 
receive 56 weeks of therapy with infliximab at the escalated dose with a Final Safety Visit at 
Week 64. Investigators may discontinue patients in the Dose Escalation Group who have not 
regained clinical response after receiving 2 doses of 10 mg/kg infliximab, administered 8 weeks 
apart.
Upon meeting enrollment criteria for the Reference Group (see inclusion criterion #10), patients 
will receive 5 mg/kg q8wk. Those who lose clinical response during participation in the study 
will be eligible, if they meet the enrollment criteria for the Dose Escalation Group, to cross over 
to the Dose Escalation Group.
Patients in the Reference Group who lose response and cross over to the Dose Escalation Group 
must complete screening for the Dose Escalation Group and receive the first 10 mg/kg dose of 
infliximab within 40 weeks of enrollment into the study.
Patients who cross over from the Reference Group to the Dose Escalation Group will be eligible 
to receive a total of 56 weeks of therapy with infliximab, which includes duration of therapy 
while in the Reference Group prior to dose escalation. 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
53
Approved, Date: 20 February 2018
7.
TREATMENT COMPLIANCE
Infliximab will be administered as an IV infusion by qualified study-site personnel and the 
details of each administration will be recorded in the CRF (including date, start and stop times of 
the IV infusion, and volume infused).
8.
PRESTUDY AND CONCOMITANT THERAPY
The name, dose, frequency, route of administration, the start and stop dates, and duration of any 
therapy taken by the patient for CD or UC at any time in the past (eg, 5-ASAs; corticosteroids; 
immunomodulators, including thiopurines; biologics; antibiotics) is to be recorded in the case 
report form (CRF). For biologics, brand (trade) names will be recorded.
In addition, any other prestudy therapies administered up to 30 days before the first 
administration of infliximab at Week 0 must be recorded at screening.
Concomitant therapies must be recorded throughout the study beginning at screening through the 
Final Safety Visit. Concomitant therapies should also be recorded beyond the Final Safety Visit
only in conjunction with new or worsening adverse events or serious adverse events that meet 
the criteria outlined in Section 12.3.2.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from infliximab must be recorded in the CRF. Recorded 
information will include the name of the therapy, treatment period, and its indication. 
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a patient into the study.
The following concomitant medications for IBD are allowed in this study: 5-ASAs, 
corticosteroids, immunomodulators (ie, 6-MP, AZA, MTX), and antibiotics. 
For patients in the Dose Escalation Group:

For patients receiving concomitant therapy with 5-ASAs, and/or corticosteroids, and/or 
immunomodulators, and/or antibiotics the dosage of these medications must be stable for 2 
weeks before screening 

Between Week 0 and Week 16, concomitant IBD medications (ie, 5-ASAs, and/or 
corticosteroids, and/or immunomodulators, and/or antibiotics) should not be initiated or their 
dose increased

For UC patients receiving 5-ASAs at baseline, the dose must remain stable for 16 weeks 
after dose escalation  

For patients receiving immunomodulators (ie, 6-MP, AZA, or MTX), corticosteroids or 
antibiotics at baseline, the immunomodulators and antibiotics may be tapered or may be 
discontinued at any time during the study, and corticosteroids may be tapered beginning at 
Week 0
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
54
Approved, Date: 20 February 2018
For patients in the Reference Group who cross over to the Dose Escalation Group:

Patients receiving concomitant therapy with 5-ASAs, and/or corticosteroids, and/or 
immunomodulators, and/or antibiotics, the dosage of these medications must be stable for 2 
weeks before receiving the 10 mg/kg dose 

For 16 weeks after dose escalation, concomitant IBD medications (ie, 5-ASAs, and/or 
corticosteroids, and/or immunomodulators, and/or antibiotics) should not be initiated or their 
dose increased 

For UC patients receiving 5-ASAs at the time of dose escalation, the dose must remain 
stable for 16 weeks after dose escalation

For patients receiving immunomodulators (ie, 6-MP, AZA, or MTX), corticosteroids, or 
antibiotics at the time of dose escalation, the immunomodulators and antibiotics may be 
tapered or may be discontinued at any time during the study, and corticosteroids may be 
tapered beginning at the time of dose escalation
Medications that are prohibited after enrollment are defined in Section 4.2, exclusion criteria #10
and #11.
For patients in both the Dose Escalation and the Reference Group:
Treatment with and tapering of corticosteroids (including budesonide) is at the discretion of the 
investigator. For those patients whom the investigator determines it is appropriate to taper the 
use of corticosteroids and budesonide, the following tapering schedule is recommended:
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 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
Patients receiving budesonide should have their daily dose tapered by 3 mg every 3 weeks until 
0 mg/day. Cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients with 
CD and UC who were treated with AZA. Postmarketing cases of HSTCL have also been 
reported in adolescent and young adult patients with CD and UC who have received infliximab 
and other anti-TNF therapies with concomitant AZA or 6-MP therapy. Some of these patients 
had limited exposure to infliximab and other anti-TNF therapies. Investigators should carefully 
assess the potential risks and benefits of infliximab use in combination with the 
immunomodulators AZA or 6-MP in both the Dose Escalation and Reference Groups prior to 
initiating or continuing the use of these immunomodulators. Investigators are encouraged to 
individualize patient therapy and are permitted to discontinue immunomodulators during 
screening or at any time during the study.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
55
Approved, Date: 20 February 2018
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.
Screening Procedures
Screening procedures will be performed as indicated in the Time and Events Schedule. 
At the Screening Visit, written informed consent must be obtained from the patient’s parent or 
legal guardian, and assent must be obtained from the patient. Informed consent and assent must 
be obtained for this study by the principal investigator or designee prior to conducting any 
protocol-specific procedure. Pre-screening stool sample consent may be obtained prior to the 
screening visit per local or site requirements.
Patients must undergo testing for TB (see Attachment 1.1 [QFT-TB test] or Attachment 1.2
[tuberculin skin test]) 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
(see Section 9.5.5). The patient should be asked about past testing for TB, including chest 
radiograph results and responses to tuberculin skin or other TB testing. Patient eligibility for 
enrollment based on TB test results is described in inclusion criterion #4.
Each patient must undergo screening for HBV. At a minimum, this includes testing for HBsAg, 
anti-HBs, and anti-HBc; additional details are provided in Attachment 2.  
At screening and subsequent visits, PCDAI and Mayo diary cards will be distributed for patients 
to use over the course of the study. Patients (or their legally-acceptable representatives) will be 
instructed to complete the diary cards daily and will be reminded to bring the diary cards to each 
visit for data collection and review by the investigator/study coordinator. Information needed for 
the PCDAI or partial Mayo scores with respect to questions such as stool frequency or quality, 
abdominal pain, and general well-being will be obtained from the patient diary and/or recall at 
Week 0 and subsequent visits. CD patients (or their legally acceptable representatives) will be 
instructed to ensure that liquid stools reported on the PCDAI are indeed loose or watery.
Female patients of childbearing potential must have a negative urine pregnancy test at screening 
and a negative urine test at Week 0. Sexually active patients must consent to use a highly 
effective method of contraception and continue to use contraception for the duration of the study. 
The method(s) of contraception used by each patient must be documented.
An assessment of all screening laboratory test results, including serum infliximab concentration 
and ATI titers; clinical data; and concomitant medication data will be reviewed by the principal 
investigator or designee to confirm that the patient satisfies all inclusion criteria and does not 
violate any exclusion criteria. If a patient needs to be rescreened, this should be discussed with 
the sponsor and/or the sponsor’s designee.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
56
Approved, Date: 20 February 2018
9.2.
Study Procedures
The Time and Events Schedule summarizes the frequency and timing of assessments applicable 
to this study.
All visit-specific assessments should be completed before administration of infliximab. The 
maximum acceptable visit window for all visits after the screening visit is ± 7 days. Patients 
must meet all enrollment criteria prior to the first on-study administration of infliximab at Week
0. 
The total blood volume to be collected from each patient will be approximately 124.5 mL over 
the course of the study; however, repeat or unscheduled samples may be taken for safety reasons 
or for technical issues with the samples.
While the Final Safety Visit is to occur at Week 64, investigators may recontact the patient’s 
legal representative or the patient (if of age of consent) to obtain long-term follow-up 
information to determine the patient's safety or survival status (refer to Section 16.2.3).
Patients will be instructed that infliximab will not be made available to them by the sponsor after 
they have completed or discontinued from the study, and that they should return to their primary 
physicians to determine standard of care.
9.3.
Clinical Assessments
9.3.1.
Evaluations 
The disease activity assessments listed below should be performed for both Reference and Dose 
Escalation Group patients.
9.3.1.1.
Pediatric Crohn’s Disease Activity Index (PCDAI)
The PCDAI is a validated clinical tool used to assess disease severity in pediatric patients with 
CD.10 This assessment should be performed for all study visits at which infliximab is 
administered (Week 0 - Week 56/End of Treatment). The PCDAI collects information on the 
following disease-related variables: 

Total number of liquid stools, abdominal pain, and general well-being (scored by the patient 
or patient’s legal representative); 

Extra-intestinal manifestations; 

Physical examinations of abdominal mass and, perirectal disease; 

Weight change and height change or, height velocity; and 

Hematocrit, erythrocyte sedimentation rate (ESR), and albumin. 
The PCDAI score is calculated as the sum of the individual component scores and ranges from 0 
to 100 points.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
57
Approved, Date: 20 February 2018
For calculation of PCDAI at Week 0 for CD patients in the Dose Escalation Group the 
hematocrit, ESR, and albumin values obtained during screening will be used. For calculation of 
PCDAI prior to the first 10 mg/kg dose for CD patients crossing over from the Reference Group 
to the Dose Escalation Group, the hematocrit, ESR, and albumin obtained within 2 weeks prior 
to the administration of the first 10 mg/kg dose will be used. The PCDAI should be calculated 
prior to infliximab administration at Week 0 for the Dose Escalation Group or prior to the 
administration of the first 10 mg/kg dose for patients crossing over from the Reference Group.
9.3.1.2.
Mayo and Partial Mayo Score
The Mayo score is a validated clinical tool used to assess disease activity in patients with UC.11
This assessment should be performed for all study visits at which infliximab is administered 
(Week 0 - Week 56/End of Treatment).
Mayo UC activity scores are as follows:

Clinical remission: 
a score of ≤ 2 points, with no individual sub-score > 1

Mildly active disease: 
a score of 3 to 5 points

Moderately active disease: 
a score of 6 to 10 points

Severe disease: 
a score of 11 to 12
Mayo scores are calculated using the following:
1) Stool frequency and rectal bleeding data from the most recent consecutive 3-day period 
prior to the visit excluding the day(s) that medications for constipation, diarrhea, or 
irregularity were taken, the day(s) of a procedure or preparation for a procedure that 
would affect bowel frequency and/or blood content of the stool, the 48 hours after the use 
of anti-motility agent(s), and the 72 hours after a colonoscopy; 
2) The Physician’s Global Assessment (PGA); and 
3) The results of a sigmoidoscopy or colonoscopy. 
Partial Mayo scores (which exclude endoscopic data11) range from 0 – 9 and are categorized as 
follows: 

Inactive disease:
a score of 0 – 2

Mild disease:
a score of 3 – 4 

Severe disease:
a score of 5 – 9
9.3.1.3.
Wong-Baker FACES Pain Scale
The Wong-Baker FACES Pain Scale is a pain scale that combines pictures and numbers to allow 
pain to be rated by children over the age of 3.4 The scale shows a series of faces ranging from a 
happy face at 0, "No hurt" to a crying face at 10 "Hurts worst". The patient must choose the face 
that best describes how they are feeling.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
58
Approved, Date: 20 February 2018
The Wong-Baker FACES Pain Scale should be completed prior to infliximab administration at 
Week 0, Week 16 and Week 56 visits for the Dose Escalation Group and Reference Group, or 
prior to the administration of the first and third 10 mg/kg dose for patients crossing over from the 
Reference Group. In addition, all patients who discontinue treatment will complete the Wong-
Baker FACES pain scale at the time of treatment discontinuation visit.
9.3.1.4.
Stool Frequency (Absolute Value)
Absolute stool frequency values will be recorded from patients’ recall prior to infliximab 
administration at Week 0, Week 16 and Week 56 visits for the Dose Escalation Group and 
Reference group or prior to the administration of the first and third 10 mg/kg dose for patients 
crossing over from the Reference Group. In addition, stool frequency information should be 
obtained from all patients who discontinue treatment at the time of treatment discontinuation 
visit.
9.3.1.5.
Optional Evaluations
For patients in the Dose Escalation Group, investigators may perform optional ileocolonoscopy 
during screening or as standard care within 6 weeks prior to the first infliximab 10 mg/kg dose,
and again at Week 24 or later. For patients who cross over from the Reference Group to the Dose 
Escalation Group, investigators may perform optional ileocolonoscopy within 2 weeks prior to 
the first 10 mg/kg infliximab dose and at least 24 weeks after dose escalation.
9.3.2.
Endpoints
Primary Endpoint
The primary efficacy endpoint is clinical response at Week 16 after dose escalation, defined as:
CD patients:
A decrease from baseline in PCDAI of ≥ 15 points with total score of 
≤30 points 
UC patients:
A decrease from baseline in partial Mayo score of ≥2 points and ≥30% 
and a decrease in the rectal bleeding sub-score by ≥ 1 point or 
achievement of an absolute sub-score of ≤1 point 
Secondary Endpoints
Major secondary efficacy endpoint:   Sustained clinical response through 56 weeks after dose 
escalation
Other pharmacokinetic and clinical remission secondary endpoint:  The relationship between 
trough infliximab levels and clinical remission at Week 16 will be analyzed with the Reference 
Group and the Dose Escalation Group patients in a combined analysis
Other secondary efficacy endpoints:
1. For CD patients changes from baseline at Week 16 and at Week 56 in:

Abdominal pain and loose/watery stool frequency sub-scores of the PCDAI
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
59
Approved, Date: 20 February 2018

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
2. For UC patients changes from baseline at Week 16 and at Week 56 in:

Stool frequency and rectal bleeding sub-scores of the partial Mayo score

Abdominal pain using the Wong- Baker FACES scale 

Absolute stool frequency 
3. Correlates of Wong-Baker FACES scale with clinical remission and response at Week 16
4. The association between abdominal pain PCDAI sub-score and the Wong-Baker FACES
scale for CD patients
Secondary safety endpoint: The incidence of serious adverse events
9.4.
Serum Infliximab Concentrations and Antibodies to Infliximab
Venous blood samples will be collected for measurement of serum concentrations of infliximab 
and ATI titers at the times shown in the Time and Events Schedule. Serum infliximab 
concentrations will be determined using a validated, enzyme-linked immunosorbent assay. 
Serum ATI titers will be determined using a validated, drug-tolerant ECLIA method. All samples 
will by assayed by the sponsor or its designee. All samples collected for detection of ATI titers 
will also be evaluated for serum infliximab concentration to enable interpretation of the antibody 
data.
Samples collected for analysis may additionally be used for additional evaluations, to evaluate 
safety or efficacy aspects that address concerns arising during or after the study period. Genetic 
analyses will not be performed on these samples. Patient confidentiality will be maintained. 
9.5.
Safety Evaluations
Details regarding an internal Safety Monitoring Committee are provided in Section 11.7.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
9.5.1.
Adverse Events
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, surrogate, 
or the patient'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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
60
Approved, Date: 20 February 2018
9.5.2.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. The laboratory reports must 
be filed with the source documents.
The following tests will be performed:  

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-percent reticulocytes
-red blood cell (RBC) count
-WBC count with differential

Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-uric acid
-chloride
-calcium
-bicarbonate
-phosphate
-blood urea nitrogen (BUN)
-albumin
-creatinine
-total protein
-glucose
-magnesium
-AST
-ALT
-gamma-glutamyltransferase (GGT)
-total, direct, indirect bilirubin

Urine pregnancy testing for female patients of childbearing potential

QFT-TB Gold test (or tuberculin skin test in countries where the QFT-TB Gold test is not 
approved/registered or is not required per local guidelines)

Stool culture for enteric pathogens, including Clostridium difficile toxins. The following 
medications should be avoided for 48 hours prior to the sample collection: antacids, barium, 
bismuth, antidiarrheal medication, and oily laxatives. 

Stool fecal calprotectin

Serology for Hepatitis B

Serology for Hepatitis C

Serology for varicella and measles antibody titers

Determination of antinuclear antibody (ANA) and anti-double stranded DNA antibody
(anti-dsDNA antibody) status

ESR for CD patients only

CRP

Infliximab concentration and antibody to infliximab titers
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
61
Approved, Date: 20 February 2018

Abnormal liver function tests. If laboratory testing for a patient who is enrolled in the 
study and receiving study drug reveals an increase of serum aminotransferases (ALT or 
AST) to >3 x ULN and an increase of bilirubin to >2 x ULN, study agent administration 
should be suspended immediately. In addition, laboratory tests for ALT, AST, alkaline 
phosphatase, and total bilirubin should be confirmed by a retest within 24 hours if possible, 
but no later than 72 hours after notification of test results. See Attachment 5 (Liver Safety: 
Suggested Actions and Follow-up Assessments) for additional information on monitoring 
and assessment of abnormal liver function tests.
During the study, all abnormal laboratory values will require further explanation from the 
investigator. Clinically significant abnormal laboratory values should be repeated until they 
return to normal or are otherwise explained by the investigator.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
9.5.3.
Physical Examination and Vital Signs
Complete physical examinations (including skin and genitourinary examination) are to be 
conducted. 
Vital signs assessed in this study will include heart rate, blood pressure, temperature, height, and 
weight.
9.5.4.
Screening Chest Radiograph
Unless country or site guidelines do not recommend a chest radiograph as a necessary screening 
process prior to initiation of anti-TNF therapies, a chest radiograph (both posterior-anterior and 
lateral views) must have been performed within 3 months prior to infliximab initiation or during 
the pre-study infliximab treatment and read by a qualified radiologist; the results of which must 
show no evidence of current active TB or old inactive TB. 
Chest radiographs (both posterior-anterior and lateral views) must be performed as part of the 
screening process in all cases when either the tuberculin skin test and/or QFT-TB Gold test 
results for TB are positive or proof of negative chest radiograph performed prior to initiation of 
infliximab cannot be obtained.
9.5.5.
Early Detection of Active Tuberculosis
To aid in the early detection of TB reactivation or new TB infection during study participation, 
patients must be evaluated for signs and symptoms of active TB at scheduled or unscheduled 
visits (refer to Time and Events Schedule) or by telephone contact approximately every 8 to 
12 weeks. The following series of questions is suggested for use during the evaluation:
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
62
Approved, Date: 20 February 2018

“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 patient may have TB reactivation or new TB infection, 
infliximab administration should be interrupted and an immediate and thorough investigation 
should be undertaken, including, where possible, consultation with a physician specializing in 
TB. Investigators should be aware that TB reactivation in immunocompromised patients may 
present as disseminated disease or with extrapulmonary features. Patients with evidence of active 
TB must immediately discontinue infliximab and should be referred for appropriate treatment.
Patients who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QFT-TB Gold test, a repeat tuberculin 
skin test in countries in which the QFT-TB Gold test is not approved/registered/required or the 
tuberculin skin test is mandated by local health authorities, and, if possible, referral to a 
physician specializing in TB to determine the patient’s risk of developing active TB and whether 
treatment for latent TB is warranted. Infliximab administration should be interrupted during the 
investigation. A positive QFT-TB Gold test result should be considered detection of latent TB. If 
the result is indeterminate, the test should be repeated as outlined in Section 9.1. If 
recommended, treatment for latent TB must be initiated prior to or simultaneously with the 
administration of further infliximab. Patients who discontinue treatment for latent TB 
prematurely or who are noncompliant with therapy must immediately discontinue further 
administration of infliximab, and will be required to return to the study site 8 weeks after the last 
administration of infliximab, at which time the Week 64 procedures are to be performed.
Patients with recent exposure to TB, a history of a positive purified protein derivative (PPD) test, 
negative active TB evaluation and indeterminate QFT-TB TB Gold test should have an annual 
chest radiograph.
10.
PATIENT COMPLETION/WITHDRAWAL
10.1.
Completion 
A patient will be considered to have completed the treatment and safety follow-up portions of the 
study if he/she has completed study assessments through Week 64. 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
63
Approved, Date: 20 February 2018
10.2.
Discontinuation of Study Treatment
If treatment with infliximab must be discontinued before the end of the treatment period, this will 
not result in automatic withdrawal of the patient from the study. Treatment with infliximab 
should be permanently discontinued if any of the following occur:

The investigator believes that for safety reasons (eg, an adverse event) it is in the best 
interest of the patient to discontinue infliximab

The patient becomes pregnant

Reaction resulting in bronchospasm (both new onset infliximab-related and severe 
exacerbation of pre-existing asthma) with and without wheezing, and/or dyspnea requiring 
ventilatory support, and/or symptomatic hypotension with an absolute systolic blood 
pressure below the patient’s gender and age- or height-specific normal value or a greater
than 40 mmHg decrease in systolic blood pressure that occurs following an infliximab
administration

Reaction resulting in myalgia and/or arthralgia with fever and/or rash (suggestive of serum
sickness and not representative of signs and symptoms of other recognized clinical
syndromes) occurring 1 to 14 days after an infliximab infusion. These may be accompanied 
by other events including pruritus, facial, hand, or lip edema, dysphagia, urticaria, sore 
throat, and/or headache.

Opportunistic infection

Malignancy

Congestive heart failure

Demyelinating disease

The patient is deemed ineligible according to the following TB screening criteria:

A diagnosis of active TB is made

A patient 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 patient undergoing continued evaluation has a chest radiograph with evidence of 
current active TB and/or a positive QFT-TB Gold test result and/or a positive tuberculin 
skin test result in countries in which the QFT-TB
Gold test is not 
approved/registered/required and/or an indeterminate QFT-TB Gold test result on repeat 
testing with an additional TB risk factor as determined by the medical monitor and 
investigator

A patient receiving treatment for latent TB discontinues this treatment prematurely or is 
noncompliant with the therapy

Crohn’s disease-related bowel surgery with the exception of abscess drainage and seton 
placement

If, in the opinion of the patient and the investigator, a UC patient requires a colectomy 
(partial or total)
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
64
Approved, Date: 20 February 2018

The patient (or the patient’s legal representative) withdraws consent for administration of 
infliximab

The initiation of medications as specified in Section 4.2, exclusion criteria #10a-d and #11

Severe hepatic function abnormalities, as described in Section 9.5 and Attachment 5
If a patient discontinues participation in the study, he/she will be required to return for a Final 
Safety Visit 8 weeks following the final administration of infliximab. At that time, the 
procedures and evaluations indicated in the Time and Events Schedule at Week 64 will be 
performed. All procedures and evaluations must be conducted prior to withdrawal of consent.
10.3.
Withdrawal From the Study
A patient will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Sponsor decision
If a patient is lost to follow-up, every reasonable effort must be made by the study site personnel
to contact the patient and determine the reason for discontinuation/withdrawal. The measures
taken to follow up must be documented.
When a patient withdraws before completing the study, the reason for withdrawal is to be
documented in the CRF and in the source document. Patients who withdraw will not be replaced. 
Infliximab assigned to the withdrawn patient may not be assigned to another patient.
11.
STATISTICAL METHODS
Statistical analysis will be conducted by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP).
11.1.
Patient Information
The modified intention-to-treat (mITT) population will be used as the primary analysis dataset 
for the primary endpoint. The mITT population includes all patients enrolled in the Dose 
Escalation Group who receive at least one 10 mg/kg dose of infliximab after enrollment, 
including those who cross over from the Reference Group to Dose Escalation Group.
The per-protocol population will include all patients who enrolled in the Dose Escalation Group
including those who cross over from the Reference Group to the Dose Escalation Group, receive
at least two 10 mg/kg doses of infliximab, and do not have major protocol deviations. Patients 
who met the following criteria will be excluded from the per-protocol analysis:
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
65
Approved, Date: 20 February 2018

Patients who meet loss of clinical response criteria who did not receive two 10 mg/kg doses,
or 

Patients who did not meet loss of clinical response criteria but who did receive at least one 
10 mg/kg dose.
The per-protocol population will be used as a sensitivity analysis for the primary endpoint.  For 
patients who cross over from the Reference Group to the Dose Escalation Group, the data prior 
to and after crossover will be summarized for this subgroup, and these data will also be included 
in the corresponding Dose Escalation and Reference Groups. 
The safety population will include all patients who received infliximab after enrollment. The 
treatment group is based on the treatment dose the patients actually received.
Patients’ demographic and baseline disease characteristics will be summarized using descriptive 
statistics, for all patients, and by CD and UC subgroups. The baseline measurement is defined as 
the measurement collected at Week 0 prior to the infliximab dose or collected at the Screening 
Visit if not collected at Week 0.
11.2.
Sample Size Determination
Both the Dose Escalation and Reference Groups will be composed of 60% CD patients and 40% 
UC patients. Accordingly, the proposed study will enroll 80 (48 CD and 32 UC) patients in the 
Dose Escalation Group and 50 (30 CD and 20 UC) patients in the Reference Group, with the 
conservative assumption that approximately 10 patients (20%) in the Reference Group may dose 
escalate.8,9 Thus, the final sample size in the Dose Escalation Group is estimated to be 
90 patients, with 54 CD patients and 36 UC patients (Figure 4).  
The sample size estimation was calculated based on precision estimates for clinical response 
rates after dose escalation from 5 mg/kg q8w to 10 mg/kg q8w at Week 16, the primary efficacy 
endpoint.
It is anticipated the dropout rate due to loss of follow up and other non-efficacy related reasons 
by Week 16 will be about 5% of patients), based on the Phase 3 pediatric infliximab trials in CD 
and UC patients.8,9 As indicated in Table 1, adjusting for dropout rate, a sample size of 76 - 85 
patients (without or with cross over) will provide precision estimates between ± 8.5 – 11.2% for 
expected response rates between 20 - 50%, based on a 2-sided 95% confidence interval (CI). The 
anticipated range for clinical response is based on the response rates for adult patients 
undergoing infliximab dose escalation.13,14
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
66
Approved, Date: 20 February 2018
There are currently no data available on pediatric patients with loss of response on 5 mg/kg q8w 
not receiving dose escalation. For the purposes of a conservative sample size calculation, a
response rate of 5% was assumed for patients with loss of clinical response not receiving dose 
escalation, although it would be predicted that the actual response rate would be negligible 
(< 1%). At a significance level of 0.05 (2-sided), the statistical power is greater than 90% to 
detect at least a 15% increase in clinical response after dose escalation, for the overall Dose 
Escalation Group (N=76 – 85, without or with cross over). For the CD subgroup (N = 46 - 51, 
without or with cross over), the power is between 84% - 90%.  For the UC subgroup (N = 30 -
34, without or with cross over), the power is between 70% - 74%.
When testing the association between infliximab concentration and regain of clinical response 
after dose escalation, using logistic regression to test the null hypothesis of no association 
between infliximab serum concentrations and clinical response, ie, β = 0 (α = 0.05, 2-sided), a 
sample size of 76 - 85 patients (without or with cross over) will provide statistical power 
between 66% and 85% to detect β of 0.916, assuming the response rate is between 20 – 50%. 
Figure 4:
Sample size details by diagnosis with crossover assumptions
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
67
Approved, Date: 20 February 2018
Table 1:
Precision estimation for anticipated clinical response rates, adjusting for 5% non-
efficacy related dropout rate prior to Week 16
Treatment group
Sample Size
Clinical Response Rate
20%
30%
40%
50%
Dose Escalation Group with 
Reference Group crossover
85
±8.5%
±9.7%
±10.4%
±10.6%
Dose Escalation Group without 
Reference Group crossover
76
±9.0%
±10.3%
±11.0%
±11.2%
CD patients (Dose 
Escalation Group with 
Reference Group crossover)
51
±11.0%
±12.6%
±13.4%
±13.7%
UC patients (Dose 
Escalation Group with 
Reference Group crossover)
34
±13.4%
±15.4%
±16.5%
±16.8%
Key: CD = Crohn’s disease; UC = ulcerative colitis
In DEVELOP, the most common serious adverse event category has been gastrointestinal 
disorders, with an event rate of approximately 10.6 events per 100 patient-years among patients 
exposed to infliximab as the only biologic medication (data on file). The sample size of 80 - 90 
dose escalation patients will provide a 95% CI of ± 6.4 - 6.7% around an event rate of 10.6% (ie, 
± 6.4 - 6.7% estimated precision). The sample size of 40 - 50 patients in the Reference Group of 
the proposed study will provide a 95% CI of ± 8.5 - 9.5% around an event rate of 10.6% 
(ie, ± 8.5 - 9.5% estimated precision).
11.3.
Efficacy Analyses
11.3.1.
Analyses for the Primary Endpoint
11.3.1.1.
Analyses
The primary endpoint is clinical response at Week 16, defined as:

CD patients:
A decrease from baseline in PCDAI of ≥ 15 points with total score of 
≤30 points 

UC patients:
A decrease from baseline in partial Mayo score of ≥2 points and ≥30% 
and a decrease in the rectal bleeding sub-score by ≥ 1 point or 
achievement of an absolute sub-score of ≤1 point 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
68
Approved, Date: 20 February 2018
The following analyses are planned:
Analysis of clinical response rates at Week 16
For the primary analysis, the clinical response rate at 16 weeks after dose escalation and the 
surrounding 2-sided 95% CI will be estimated for the entire Dose Escalation Group. Assuming a 
response rate of 5% for patients with loss of clinical response not receiving dose escalation, the 
proposed study will demonstrate the efficacy of dose escalation if the lower limit of the 95% CI 
for the proportion of patients in clinical response at Week 16 is > 5%. For the patients who cross
over from the Reference Group to the Dose Escalation Group, clinical response at 16 weeks after 
dose escalation will be included in the primary endpoint analysis. The clinical response rate at 16 
weeks after dose escalation and the surrounding 95% CI (2-sided) will also be estimated for 
subgroups of CD and UC patients.
Analyses of the relationship between trough serum infliximab concentrations and clinical 
response at Week 16
Logistic regression will be performed to evaluate the relationship between serum infliximab 
concentration prior to dose escalation and clinical response at Week 16 after dose escalation in 
the Dose Escalation Group, including patients who cross over from the Reference Group.
The entire distribution of trough serum infliximab concentrations prior to the first 10 mg/kg
infliximab dose will serve as the independent variable in these analyses, in which trough serum 
infliximab concentrations will be treated as a continuous variable. In additional analyses, trough 
serum infliximab concentrations prior to dose escalation will be treated as a categorical variable, 
where the association between the infliximab concentration cutoff value prior to dose escalation 
(eg, cutoffs of 3, 3.5, or 4 µg/mL or by quartiles) and clinical response will be evaluated. 
Inflammatory bowel disease diagnosis (CD or UC) will be included as a covariate in the logistic 
regression analysis.
The effect of potential confounding factors will be assessed, as appropriate, in the logistic 
regression analysis. The possible covariates may include age, sex, disease duration, duration of 
infliximab treatment prior to infliximab dose increase, antibodies to infliximab, and 
immunomodulator use.
Details of the analysis will be provided in the SAP.
11.3.1.2.
Missing Data Handling for the Primary Endpoint Analyses
In the primary analysis of the primary endpoint, if a patient discontinues from the study prior to 
Week 16 due to ‘loss of efficacy’ or worsening of disease, the patient will be considered a non-
responder. If a patient has missing data at Week 16 for other non-efficacy related reasons that are 
likely to be random (eg, loss of follow up), multiple imputations will be used to handle data 
missing at random. The details of multiple imputations will be provided in the SAP.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
69
Approved, Date: 20 February 2018
Sensitivity analyses will be conducted using ‘worst case’ non-responder imputation (ie, patients 
with missing data at Week 16 will be treated as non-responders). Completer analysis without 
imputation will also be performed as a sensitivity analysis.  Logistic regression analysis will be 
performed using response data without imputation.
11.3.2.
Analyses for the Secondary Endpoints
The major secondary efficacy endpoint is sustained clinical response at Week 56, defined as 
achieving clinical response per the primary endpoint definitions at Week 16 and maintaining 
clinical response at 1 year after dose escalation (Week 56). The proportions of patients achieving 
sustained clinical response will be summarized. Infliximab concentrations and ATI status over 
time will be summarized by sustained clinical response status at Week 56. Logistic regression 
methods will be used, as appropriate, to evaluate the association between sustained response and 
trough serum infliximab concentration and the impact of potential confounding factors may be 
assessed.
The other secondary efficacy endpoints include:
1. For CD patients changes from baseline at Week 16 and at Week 56 in:

Abdominal pain and loose/watery stool frequency sub-scores of the PCDAI

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
2. For UC patients changes from baseline at Week 16 and at Week 56 in:

Stool frequency and rectal bleeding sub-scores of the partial Mayo score

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
Descriptive statistics and 95% CIs will be provided for these endpoints. A Wilcoxon signed rank 
test or paired t-test will be used, when appropriate, to evaluate within patient change on these 
disease signs and symptoms measurements from baseline at Week 16 and at Week 56. 
Descriptive statistics will be used to summarize these measurements over time. The analysis will 
be performed for both the Dose Escalation and Reference groups.
The Sponsor will analyze how the Wong-Baker FACES scale correlates with clinical 
remission/response by performing a logistical regression to evaluate the association between 
Wong-Baker FACES scale and clinical response at Week 16.   
In a secondary analysis, an ordinary regression model will be used to evaluate the association 
between abdominal pain PCDAI sub-score and the Wong-Baker FACES scale for CD patients.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
70
Approved, Date: 20 February 2018
Analyses for the secondary safety endpoint are described in Section 11.5.
11.3.3.
Other Planned Efficacy Analyses
Descriptive summaries of clinical disease status (ie, PCDAI and partial Mayo scores) will 
include number of patients, mean, median, standard deviation, minimum and maximum values 
for continuous variables and frequency and percentage for categorical variables. PCDAI or 
partial Mayo scores over time and change from baseline will be summarized for the Dose 
Escalation and Reference groups, and by CD and UC subgroups. 
For patients who cross over from the Reference Group to the Dose Escalation Group, the clinical 
disease status prior to and after crossover will be summarized. Graphic methods will be used, as 
appropriate, to display parameter estimates over time.
11.4.
Serum Infliximab Concentrations and Antibodies to Infliximab
Serum infliximab concentrations and ATI titers will be listed for all patients with available data. 
If the data do not allow for accurate assessment of serum infliximab concentrations (eg, 
incomplete administration of infliximab, missing information of dosing, and sampling times), 
they will be excluded from the analyses.
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All patients and samples excluded from the analyses will be 
clearly documented in the study report.
The proportion of ATI positive patients will be summarized for the Dose Escalation Group and 
the Reference Group. The partial PCDAI and partial Mayo scores will be summarized by ATI 
status.  Infliximab concentrations will also be summarized for the Dose Escalation Group and the 
Reference Group.
The relationship between trough infliximab levels and clinical remission at Week 16 will be 
analyzed with the Reference Group and the Dose Escalation Group patients in a combined 
analysis. 
For patients who cross over from the Reference Group to the Dose Escalation Group, the 
infliximab concentration and ATI status prior to and after cross over will be summarized.
11.5.
Safety Analyses
Safety analysis will be performed on the safety population, where the treatment group is based 
on the dose the patients actually received.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
71
Approved, Date: 20 February 2018
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 treatment-emergent adverse events 
will be included in the analysis. Non-treatment-emergent adverse events will be presented in
listings. For each adverse event, the percentage of patients who experience at least 1 occurrence 
of the given event will be summarized by treatment group. 
As one of the secondary objectives of the study, adverse event and serious adverse event rates 
will be summarized for both the Dose Escalation and Reference and Groups, to evaluate the rate 
of serious adverse events in the Dose Escalation Group relative to the rate in the Reference 
Group. Adverse event and serious adverse event incidences per 100 patient-years of follow up 
will be summarized in a similar manner. For events of special interest, eg, serious infections, the 
95% CI of event rates will be estimated for the Dose Escalation and the Reference Groups. 
Because the Dose Escalation and Reference Groups are not comparable in terms of disease 
activity, logistic regression or Cox proportional hazard models will be used to compare serious 
adverse events rates between these 2 groups, adjusting for potential confounding factors, such as 
disease severity, with the acknowledgment that these models will not be able to fully adjust for 
confounding by indication.
Averse events prior to and after crossover will be summarized for patients who cross over from 
the Reference Group to the Dose Escalation Group. The safety profile of these patients before 
and after dose escalation will provide additional data for the comparison of the incidence of 
serious adverse events between dosing regimens. Adverse events will also be summarized by CD 
and UC subgroups.
In addition, gastrointestinal and non-gastrointestinal adverse events will be summarized for the 
Dose Escalation and Reference Groups.  
Summaries, listings, or patient narratives may be provided, as appropriate, for those patients who 
die, who discontinue treatment due to an adverse event, or who experience a severe or a serious 
adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for the Dose Escalation Group and the Reference Group 
for each laboratory measurement at baseline and at each scheduled time point as appropriate.
Analyses for CD and UC subgroups will be performed. Frequency tabulations of the changes 
from baseline will be presented in pre- versus posttreatment cross-tabulations (with classes for 
below, within, and above normal ranges). A listing of patients with any laboratory results outside 
the reference ranges will be provided. A listing of patients with any markedly abnormal 
laboratory results will also be provided.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
72
Approved, Date: 20 February 2018
Vital Signs
Descriptive statistics will be used to summarize heart rate, blood pressure, temperature, height, 
and weight at baseline and changes from baseline over the course of the study as appropriate. 
The percentage of patients with values beyond clinically important limits will be summarized.
11.6.
Interim Analysis
There will be no interim analyses performed. 
11.7.
Safety Monitoring Committee
An internal Safety Monitoring Committee will be established to monitor the safety data on an
ongoing basis to ensure the continuing safety of the patients enrolled in this study. The
committee will meet periodically to review the safety data (ie, adverse events and laboratory 
results). After the review, the Safety Monitoring Committee will make recommendations 
regarding the continuation of the study. The details will be provided in a separate charter. The 
Safety Monitoring Committee will consist of a clinician and a statistician, at a minimum. The 
Safety Monitoring Committee’s responsibilities, authorities, and procedures will be documented 
in its charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of patients, 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 patient 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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
73
Approved, Date: 20 February 2018
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
European Union (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 patient was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Adverse Events of Special Interest

Serious Infections: A serious infection is an infection diagnosed by a physician based on 
results of culture, microscopy, serology, biopsy, or imaging, or based on clinical judgment, 
that also meets the definition of a serious adverse event.

Tuberculosis: Any diagnosis of active or latent TB occurring in patients participating in the 
study must be reported by the investigator. 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.

New Malignancy: Any diagnosis of a malignancy in patients participating in the registry 
must be reported by the investigator. After the initial report of a malignancy (including 
during the screening visit), only new malignancies (defined as a malignancy that was not 
diagnosed prior to the time of the last visit/telephone contact in the study) are to be reported 
thereafter. These include lymphoproliferative disease including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of 
unusual size or location (eg, nodes in the posterior triangle of the neck, intraclavicular, 
epitrochlear, or periaortic areas), or splenomegaly.  
Although not considered an adverse event of special interest, investigators should report any 
occurrence of a premalignant condition.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
74
Approved, Date: 20 February 2018

Dysplasia of the Colon: The presence of dysplasia in the colon will be determined on the 
basis of biopsies obtained by colonoscopy and interpreted by a local pathologist. The 
determination of the need to conduct a colonoscopy or obtain biopsies will be made by the 
treating physician.  

New Autoimmune Disease: Autoimmune diseases (including lupus-like syndrome, 
psoriasis, multiple sclerosis, or other demyelinating diseases) that are diagnosed during 
participation in the study should be reported. Following the recording of an autoimmune 
disease (including during the screening visit), only new autoimmune disease (defined as an 
autoimmune disease not diagnosed prior to the time of the last visit/telephone contact in the 
study) must be reported thereafter.

Opportunistic Infection: Opportunistic infections due to bacterial, mycobacterial, invasive 
fungal, viral, or parasitic organisms including, but not limited to aspergillosis, 
blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, 
pneumocystosis, and tuberculosis must be reported.
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 infliximab, the expectedness of an adverse 
event will be determined by whether or not it is listed in the current local label. For a non-
sponsor therapy with a marketing authorization, the expectedness of an adverse event will be 
determined by whether or not it is listed in the package insert/summary of product 
characteristics.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
75
Approved, Date: 20 February 2018
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the patient (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest following administration of infliximab that may require expedited 
reporting and/or safety evaluation include, but are not limited to:

Overdose of infliximab

Suspected abuse/misuse of infliximab

Inadvertent or accidental exposure to infliximab

Any failure of expected pharmacologic action (ie, lack of effect) of infliximab

Unexpected therapeutic or clinical benefit from use of infliximab

Medication error involving a sponsor product (with or without patient exposure to 
infliximab, eg, name confusion)
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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
76
Approved, Date: 20 February 2018
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 patient'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 8 weeks after the last 
dose of infliximab, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to infliximab, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). 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.
Patients (or their designees) 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 patient 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

Patient number
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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
77
Approved, Date: 20 February 2018
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 patient's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than infliximab or to factors unrelated to study 
conduct

It becomes unlikely that any additional information can be obtained (patient 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 patient's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a patient in a study whether or not the event is expected or associated with 
infliximab, is considered a serious adverse event.
12.3.3.
Adverse Events of Special Interest 
Any newly identified adverse event of special interest occurring after the first administration of 
infliximab in patients participating in this clinical study must be reported by the investigator 
using the appropriate adverse event of special interest notification form within 24 hours of the 
event.
Note: These events are to be considered serious only if they meet the definition of a serious 
adverse event.
The sponsor is conducting a separate research study to learn more about HSTCL in patients with 
inflammatory bowel disease. Any patient who develops HSTCL during the course of this study 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
78
Approved, Date: 20 February 2018
may be contacted to determine if he/she is interested in participating in the HSTCL research 
study.
12.3.4.
Pregnancy
All initial reports of pregnancy in female patients or partners of male patients 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. If a patient becomes 
pregnant during the study, treatment with infliximab should be discontinued. The patient will be 
required to return for a follow-up safety visit 8 weeks after the last administration of infliximab.
Because the effect of infliximab on sperm is unknown, pregnancies in partners of male patients 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
Additional follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of patients, 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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
79
Approved, Date: 20 February 2018
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
INFLIXIMAB INFORMATION
14.1.
Physical Description of Infliximab
Infliximab will be supplied as a sterile, white, lyophilized powder in a single-use 20 mL vial. 
Each vial contains 100 mg infliximab. Infliximab will be reconstituted with 10 mL of Sterile 
Water for Injection, resulting in a concentration of 10 mg/mL infliximab for administration. Each 
mL of the solution contains 10 mg of infliximab, 50 mg of sucrose, 0.61 mg of dibasic sodium 
phosphate dihydrate, 0.22 mg of monobasic sodium phosphate monohydrate, and 0.05 mg of 
polysorbate 80.
The maximum dose of infliximab per infusion is 1 g.
14.2.
Packaging
The investigational supplies will be uniquely packaged to assure that they are appropriately 
managed throughout the supply chain process.
14.3.
Labeling
Infliximab labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
The vials of infliximab must be stored in a secured refrigerator at 2°C to 8°C.
The physical stability of reconstituted infliximab has been demonstrated for at least 24 hours 
when stored at 25°C. However, because the infliximab formulation does not contain a 
preservative, it is recommended that the administration of the solution for infusion is started as 
soon as possible but within 3 hours of reconstitution and dilution. 
Each vial must be reconstituted with Sterile Water for Injection using a syringe equipped with a 
21-gauge or smaller needle (eg, 22-, 23-, or 25-gauge). The lyophilized powder should be 
completely dissolved within 5 minutes. Dissolution of the powder is accomplished by careful 
rotation of the vial. DO NOT SHAKE! Foaming of the solution on reconstitution is not unusual. 
Following reconstitution, the solution must be allowed to sit for 5 minutes to allow foaming to 
subside. The solution should be colorless to light yellow and opalescent. A few translucent 
particles may develop, as infliximab is a protein. DO NOT USE THE SOLUTION IF OPAQUE 
PARTICLES, DISCOLORATION, OR OTHER FOREIGN PARTICLES ARE PRESENT. 
The reconstituted solution must be combined from the appropriate number of vials and diluted in 
normal saline to a final volume of 250 mL. It is recommended that the infliximab infusion be 
started as soon as possible but within 3 hours after it has been reconstituted and diluted. Aseptic 
procedures must be used during the preparation and administration of the study material. The 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
80
Approved, Date: 20 February 2018
infusion must be administered over a period of not less than 2 hours and must use an infusion set 
with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less).  
The vials do not contain antibacterial preservatives. Therefore, any unused portion of the 
infusion solution should not be stored for reuse.
Additional details for the preparation and administration of infliximab are provided in the site 
investigational product manual.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all infliximab received at the site is inventoried 
and accounted for throughout the study. 
All infliximab infusions administered to the patient must be documented on the drug 
accountability form. Infliximab will be stored and disposed of according to the sponsor's 
instructions. Study-site personnel must not combine contents of infliximab containers.
Infliximab 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 infliximab must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused 
infliximab will be documented on the drug return form. When the study site is an authorized 
destruction unit and infliximab 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. 
Infliximab should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Infliximab will be supplied only to 
patients participating in the study. Infliximab may not be relabeled or reassigned for use by other 
patients. The investigator agrees neither to dispense infliximab 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:

Site investigational product manual

Laboratory manual

PCDAI and partial Mayo diaries with user instructions

CDC Growth Charts

Wong-Baker FACES Pain Scale 

Stool frequency questionnaire
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
81
Approved, Date: 20 February 2018

Interactive web response system (IWRS) Manual 

Electronic Data Capture (eDC) Manual

Sample ICF
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential patients will be fully informed of the risks and requirements of the study and, during the 
study, patients will be given any new information that may affect their decision to continue 
participation. They will be told that their consent/assent 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 patients who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent/assent voluntarily will 
be enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each patient, his or her parent(s) (preferably both parents, if available) 
or a legally acceptable representative(s), as required by local regulations, must give written consent 
(permission) according to local requirements after the nature of the study has been fully explained 
and before the performance of any study-related assessments. Assent must be obtained from 
children (minors) capable of understanding the nature of the study, depending on the institutional 
policies. For the purposes of this study, all references to patients who have provided consent (and 
assent as applicable) refers to the patient and his or her parent(s) or the patient's legal guardian(s) 
or legally acceptable representative(s) who have provided consent according to this process. 
Minors who assent to a study and later withdraw that assent should not be maintained in the study 
against their will, even if their parents still want them to participate.
The total blood volume to be collected is considered to be within the normal range allowed for this 
patient population over this time frame.7
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 patients. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study patients are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
82
Approved, Date: 20 February 2018
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 patients)

Local label (or equivalent information) and amendments/addenda

Sponsor-approved patient recruiting materials

Information on compensation for study-related injuries or payment to patients 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 patients

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 patients, data or study conduct), the ICF, applicable recruiting materials, and 
patient 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 patients, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to patients

If applicable, new or revised patient recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to patients for participation 
in the study, if applicable

New edition(s) of the local label

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 
infliximab

New information that may adversely affect the safety of the patients or the conduct of the 
study
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
83
Approved, Date: 20 February 2018

Deviations from or changes to the protocol to eliminate immediate hazards to the patients

Report of deaths of patients 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 patients, 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. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for patients, data, or study conduct).
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/Assent
Each patient (or a legally acceptable representative) must give written consent/assent according 
to local requirements after the nature of the study has been fully explained. The ICF(s) must be 
signed before performance of any study-related activity. The ICF(s) and assent forms that is/are 
used must be approved by both the sponsor and by the reviewing IEC/IRB and be in a language 
that the patient 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 patients or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Patients 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 patient will receive for the treatment of 
his or her disease. Patients 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 patient 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 patient, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the patient or legally acceptable 
representative is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the patient for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent disease-
related treatments, or to obtain information about his or her survival status.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
84
Approved, Date: 20 February 2018
The patient or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the patient'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 patient.
If the patient 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 
patient or legally acceptable representative is obtained.
Children (minors) or patients who are unable to comprehend the information provided can be 
enrolled only after obtaining consent of a legally acceptable representative. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, depending on 
the institutional policies. Written assent should be obtained from patients who are able to write. A 
separate assent form written in language the patient can understand should be developed for 
adolescents. After having obtained the assent, a copy of the assent form must be given to the 
patient, and to the patient's parent and/or legally acceptable representative.
If a patient participating in this study turns 18 years of age after enrollment, the patient must be re-
consented.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from patients 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 patients confidential.
The informed consent/assent obtained from the patient (or his or her legally acceptable 
representative) includes explicit consent/assent 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.
Written informed consent must be obtained from the patient’s parent or legal guardian, and 
assent must be obtained from the patient. Informed consent and assent must be obtained for this 
study by the principal investigator or designee prior to conducting any protocol-specific 
procedure.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
85
Approved, Date: 20 February 2018
The patient 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.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
No samples will be stored for additional 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, 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 patients, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
86
Approved, Date: 20 February 2018
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of infliximab to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, patient 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 patient:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Patient Identification, Enrollment, and Screening Logs
The investigator agrees to complete a patient identification and enrollment log to permit easy 
identification of each patient during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
87
Approved, Date: 20 February 2018
The patient identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure patient confidentiality, no copy will be made. All 
reports and communications relating to the study will identify patients by patient identification
and date of birth. In cases where the patient is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a patient screening log, which reports on all patients who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: patient identification, eligibility, and study identification; study discussion 
and date of signed study and (if applicable) pre-screening stool sample collection informed 
consents; 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; infliximab administration information; and date of study 
completion and reason for early discontinuation of infliximab or withdrawal from the study, if 
applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a patient should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by patient interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each patient in printed or electronic format. 
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the patient's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
88
Approved, Date: 20 February 2018
English. Study site personnel must complete the CRF as soon as possible after a patient visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All patient measurements (eg, pain scale information or other questionnaires) will be completed 
by the same individual who made the initial baseline determinations whenever possible. The 
investigator must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. The investigator or study-site personnel must adjust the CRF (if applicable) 
and complete the query.
Corrections to paper CRFs must be made in such a way that the original entry is not obscured. 
Correction fluid or tape must NOT be used. The correct data must be inserted, dated, and 
initialed by the investigator or an authorized member of the study-site personnel. If multi-part 
pressure-sensitive CRFs are used, the study-site personnel must not write on separated parts of 
the CRFs left at the study site once the original has been sent to the sponsor. Completed CRFs 
will be continuously submitted according to the sponsor's instructions and reviewed by the 
sponsor to determine their acceptability. If necessary, Data Correction/Clarification Forms 
(DCFs) will be generated and transmitted to the study site. The investigator or an authorized 
member of the study-site personnel must complete, sign, and date the DCFs.
If corrections to a paper CRF are needed after removal of the original CRF copy from the study
site, a DCF will be used.
If corrections to an electronic CRF are needed after the initial entry into the CRF, this can be 
done in 3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, 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 paper CRFs for accuracy and completeness during 
on-site monitoring visits and after their return to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. The data will be entered into the study database 
and verified for accuracy and consistency with the data sources.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
89
Approved, Date: 20 February 2018
The sponsor will review electronic CRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate. After upload of the data into the study database they 
will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each patient, 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.
For CRFs completed on pressure-sensitive paper, a copy is to be retained in the archives of the 
sponsor. A second copy must be archived by the investigator.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques to monitor this study, including 
central, remote, and/or on-site monitoring.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
90
Approved, Date: 20 February 2018
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the CRF are known to the sponsor and study-site 
personnel and are accessible for verification by the sponsor study-site contact. If electronic 
records are maintained at the study site, the method of verification must be discussed with the 
study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last patient participating in the study. 
The final data from the study site will be sent to the sponsor (or designee) after completion of the 
final patient 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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
91
Approved, Date: 20 February 2018
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 patients by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Patient
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 infliximab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including research data, generated as a result of this study, 
are considered confidential and remain the sole property of the sponsor. The investigator agrees 
to maintain this information in confidence and use this information only to accomplish this 
study, and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of infliximab, 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 CRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of 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 patient identifiers will not be used in 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
92
Approved, Date: 20 February 2018
publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
93
Approved, Date: 20 February 2018
REFERENCES
1.
Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and 
efficacy in adult patients with ulcerative colitis, Gastroenterol. 2014;147:1296-1307.
2.
Adedokun OJ, Xu Z, Padgett l, et al. Pharmacokinetics of infliximab in children with moderate-to-severe 
ulcerative colitis: results from a randomized, multicenter, open-label, Phase 3 study. Inflamm Bowel Dis. 
2013;19:2753–2762. 
3.
Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factor-alpha binding capacity and anti-infliximab 
antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in 
Crohn’s disease. Am J Gastroenterol. 2008;103:944-948.
4.
Cohen LL, Lemanek K, Blount RL, et al.   Evidence-based assessment of pediatric pain.  J Ped Psych.  2008; 
33:939–955.
5.
Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of C-
reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of 
the ACCENT I trial. Gut. 2014;doi:10.1136/gutjnl-2012-304094.
6.
Fasanmade AA, Adedokun OJ, Blank M, et al. Pharmacokinetic properties of infliximab in children and adults 
with Crohn's disease: a retrospective analysis of data from 2 Phase 3 clinical trials. Clin Ther. 2011;33:946-
964.
7.
Howie S. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ. 
2011;89:46-53.
8.
Hyams J, Crandall W, Kugathasan S, et al, and the REACH Study Group. Induction and maintenance 
infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterol. 
2007;132:863–873.
9.
Hyams J, Damaraju L, Blank M, et al, for the C0168T72 Study Group. Induction and maintenance therapy 
with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 
2012;10:391–399.
10.
Hyams J, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn's disease activity 
index. J Pediatr Gastroenterol Nutr. 1991;12:439-447.
11.
Lewis JD, Chuai S, Nessel L, et al. Use of the noninvasive components of the Mayo score to assess clinical 
response in ulcerative colitis. Inflamm Bowel Dis. 2008;14:1660–1666.
12.
Miele E, Markowitz JE, Mamula P, et al. Human antichimeric antibody in children and young adults with 
inflammatory bowel disease receiving infliximab. J Pediatr Gastroenterol Nutr. 2004;38:502-508.
13.
Pariente B, Pineton de Chambrun G, Krzysiek R, et al. Trough levels and antibodies to infliximab may not 
predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. Inflamm 
Bowel Dis. 2012;18:1199–1206.
14.
Regueiro M, Siemanowski B, Kip KE, et al. Infliximab dose intensification in Crohn's disease. Inflamm Bowel 
Dis. 2007;13:1093-1099.
15.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately 
active ulcerative colitis: a randomized study. N Engl J Med. 1987;317:1625–1629.
16.
Turner D, Seow CH, Greenberg GR, et al. A systematic prospective comparison of noninvasive disease activity 
indices in ulcerative colitis. Clin Gastroenterolo Hepatol. 2009;7:1081–1088.
17.
Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and anti-drug antibodies are associated with outcome of 
interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522-530.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
94
Approved, Date: 20 February 2018
ATTACHMENT 1:
TUBERCULOSIS TESTING
Attachment 1.1: QuantiFERON®-TB Gold Testing
The QuantiFERON®-TB Gold test is one of the interferon-(IFN-) based blood assays for TB screening (Cellestis, 
2009). 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 has been 
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 central laboratory.  The central laboratory will perform an ELISA to quantify the 
amount of IFN-present in the plasma using spectrophotometry and computer software analysis.
The central 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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
95
Approved, Date: 20 February 2018
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, US 
guidelines must be followed.
In countries in which the QuantiFERON®-TB Gold test is not considered approved/registered, a tuberculin skin test 
is additionally required.
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;361:1168-73.
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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
96
Approved, Date: 20 February 2018
Attachment 1.2: 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 the US and many other countries, the most conservative definition of positivity for the tuberculin skin test is 
reserved for immunocompromised patients, and this definition is to be applied in this study to maximize the 
likelihood of detecting latent TB, even though the subjects may not be immunocompromised at baseline.
In the US and Canada, an induration of 5 mm or greater in response to the intradermal tuberculin skin test is 
considered to be a positive result and evidence for either latent or active TB.
In countries outside the US and Canada, country-specific guidelines for immunocompromised patients should be 
consulted for the interpretation of tuberculin skin test results.  If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed. 
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable antituberculous 
treatment regimens for latent TB.  If no local country guidelines for immunocompromised patients exist, US 
guidelines must be followed.
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.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
97
Approved, Date: 20 February 2018
ATTACHMENT 2:
HEPATITIS B VIRUS (HBV) SCREENING WITH HBV DNA 
TESTING
Patients must undergo screening for hepatitis B virus (HBV). At a minimum, this includes testing 
for HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), and anti-HBc total (HBV 
core antibody total): 

Patients who test negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs-) are eligible for this study.

Patients who test negative for surface antigen (HBsAg-) and test positive for core 
antibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study.

Patients who test positive only for surface antibody (anti-HBs+) are eligible for this 
study.

Patients who test positive for surface antigen (HBsAg+) are NOT eligible for this study, 
regardless of the results of other hepatitis B tests.

Patients who test positive only for core antibody (anti-HBc+) must undergo further 
testing for the presence of hepatitis B virus deoxyribonucleic acid (HBV DNA test). If 
the HBV DNA test is positive, the patient is NOT eligible for this study. If the HBV 
DNA test is negative, the patient is eligible for this study. In the event the HBV DNA 
test cannot be performed, the patient is NOT eligible for this study. 
For patients who are not eligible for this study due to HBV test results, consultation with a 
physician with expertise in the treatment of hepatitis B virus infection is recommended. 
Eligibility based on hepatitis C and B virus test results
Eligible
Not Eligible
HBsAg-, anti-HBc-, anti-HBs-
HBsAg+ 
(regardless of the results of other HB tests)
Anti-HBc+, Anti-HBs+
Seropositive for antibodies to hepatitis C virus
Anti-HBs+
Patients only positive for core antibody (anti-HBc+) require further testing for HBV DNA
HBV DNA-
HBV DNA+
HBV DNA test cannot be performed
Legend:
HBV 
       (hepatitis B virus)
anti-HBs      (HBV surface antibody)
HBsAg        (HBV surface antigen) 
anti-HBc     (HBV core antibody)
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
98
Approved, Date: 20 February 2018
ATTACHMENT 3:
DEFINITION OF INITIAL RESPONSE AND LOSS OF RESPONSE 
TO INFLIXIMAB THERAPY FOR PATIENTS WITH CROHN’S DISEASE
The criteria for initial response and response followed by loss of response are described below.
Initial response to current therapy with infliximab
Based on available medical records or at screening have or had at least 1 of the following evidences of response, 
as assessed by a treating physician:

Improvement in stool frequency

Improvement in rectal bleeding

Improvement in daily abdominal pain/discomfort

Weight gain or voluntary weight stable/loss

Improvement in perirectal disease

Improvement in extra-intestinal manifestations
These signs and symptoms of Crohn’s disease are offered only as a benchmark of the minimally acceptable criteria 
required to designate a patient as having had an adequate initial response to infliximab therapy. This benchmark 
acknowledges that the PCDAI is not routinely recorded in clinical practice.
Response followed by loss of response to current therapy with infliximab
Subjects must satisfy criteria A and B.
A.
Initially responded to infliximab therapy (as per the criteria above)
AND
B.
At screening have at least 1 of the following signs or symptoms related to recurrence of Crohn’s disease, as 
assessed by a treating physician:

Worsening in stool frequency

Worsening in rectal bleeding

Worsening in abdominal pain/discomfort

Involuntary weight stable or weight loss

Occurrence of or worsening in perirectal disease 

Occurrence of or worsening in extra-intestinal manifestations
These signs and symptoms of Crohn’s disease are offered only as a benchmark of the minimally acceptable criteria 
required to designate a patient as having lost response to infliximab. This benchmark acknowledges that the PCDAI 
is not routinely recorded in clinical practice.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
99
Approved, Date: 20 February 2018
ATTACHMENT 4:
DEFINITION OF INITIAL RESPONSE AND LOSS OF RESPONSE 
TO INFLIXIMAB THERAPY FOR PATIENTS WITH ULCERATIVE COLITIS
The criteria for initial response and response followed by loss of response are described below.
Initial response to current therapy with infliximab
Based on available records or at screening have or had at least 1 of the following evidences of response, as 
assessed by a treating physician:

Improvement in stool frequency

Improvement in rectal bleeding

Improvement in daily abdominal discomfort  
These signs and symptoms of ulcerative colitis are offered only as a benchmark of the minimally acceptable criteria 
required to designate a patient as having had an adequate initial response to infliximab therapy. This benchmark 
acknowledges that the Mayo Severity Index is not routinely recorded in clinical practice.
Response followed by loss of response to current therapy with infliximab
Subjects must satisfy criteria A and B.
C.
Initially responded to infliximab therapy (as per the criteria above)
AND
D.
At screening have at least 1 of the following signs or symptoms related to recurrence of ulcerative colitis, as 
assessed by a treating physician:

Worsening in stool frequency

Worsening in rectal bleeding

Worsening in daily abdominal discomfort  
These signs and symptoms of ulcerative colitis are offered only as a benchmark of the minimally acceptable criteria 
required to designate a patient as having lost response to infliximab. This benchmark acknowledges that the Mayo 
Severity Index is not routinely recorded in clinical practice.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
100
Approved, Date: 20 February 2018
ATTACHMENT 5:
LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS
Guideline Algorithm for Monitoring, Assessment, and Evaluation of Abnormal Liver Tests
in Participants with No Underlying Liver Disease and Normal Baseline ALT, AST, 
Alkaline Phosphatase, and Bilirubin
**SEE NEXT PAGE FOR TESTS AND EVALUATIONS TO BE OBTAINED
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
101
Approved, Date: 20 February 2018
The complete work-up below (items 1-5) should be performed in every situation where “**” 
appears above.  Items 6-7 are optional, to be considered on case-by-case basis. All studies should be 
reported with appropriate source documentation.
The study medical monitor should be notified when the abnormalities are detected and provided 
with an update of the results of the diagnostic work-up.
The following definition of patterns of Drug-Induced Liver Injury (DILI) is used when directing 
the work-up for potential DILI based on elevations of common liver tests (LT):
Histopathology
LT
Ratio
(ALT/ULN)/(Alk Phos/ULN)
Hepatocellular 
ALT ≥3 × ULN
≥5
Cholestatic
ALT ≥3 × ULN 
≤2
Mixed
ALT ≥3 × ULN and AP ≥2 × ULN
>2 to <5
1.
Obtain detailed history of present illness (abnormal LT’s) including (if not already obtained 
at baseline) height, weight, body mass index (BMI).  Assess for abdominal pain, nausea, 
vomiting, scleral icterus, jaundice, dark urine, pruritus, rash, fever, and lymphadenopathy.  
Assess for history of prior abnormal liver tests, liver disease including viral hepatitis, 
obesity, metabolic syndrome, congestive heart failure (CHF), occupational exposure to 
hepatotoxins, diabetes mellitus (DM), gallstone disease or family history of gallstone or 
liver disease. Specifically record history of alcohol use, other meds including 
acetaminophen, non-steroidal anti-inflammatory drugs (NSAID), over the counter (OTC) 
herbal supplements, vitamins,  nutritional supplements, traditional Chinese  medicines, and 
street drugs; and document whether or not there has been any recent change in any other 
prescription drugs and start-stop dates. Obtain travel history to endemic areas for hepatitis 
A, hepatitis E. Ask for history of any prior blood transfusions and when they were 
performed.  Perform physical exam, obtain vital signs and BMI, and document presence or 
absence of scleral icterus, palpable liver including size, degree of firmness or tenderness, 
palpable spleen including size, ascites, and stigmata of chronic liver disease (spider 
angiomata, gynecomastia, palmar erythema, testicular atrophy).  Allow free text in case 
report form for other relevant history and physical information.
2.
Mandatory liver ultrasound with consideration of further imaging (eg, computerized 
tomography 
[CT], 
magnetic 
resonance 
imaging 
[MRI], 
magnetic 
resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography 
(ERCP), Doppler studies of hepatic vessels, etc., if indicated based on ultrasound findings or 
clinical situation).
3.
If total bilirubin (Tbili) is >2xULN, request fractionation to document the fraction that is 
direct bilirubin and to rule out indirect hyperbilirubinemia indicative of Gilbert’s syndrome, 
hemolysis or other causes of indirect hyperbilirubinemia. Complete blood count (CBC) with 
white blood count (WBC) and eosinophil count platelet count, international normalized ratio 
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
102
Approved, Date: 20 February 2018
(INR), and total protein and albumin (compute globulin fraction) should also be 
documented.  If INR is abnormal, prothrombin time (PT), partial thromboplastin time (PTT) 
should be obtained and these values should be followed until normal, along with 
documentation of whether parenteral vitamin K was given along with the effect of such 
treatment on INR.
4.
If initial LTs and ultrasound do not suggest Gilbert’s syndrome,  biliary tract disease or 
obstruction, viral hepatitis serology should be obtained including anti-hepatitis A virus 
immunoglobin M (anti-HAV IgM), anti-HAV total,  hepatitis B surface antigen (HBsAg), 
anti-HBs,  anti-HB core total,  anti-HB core IgM, anti-hepatitis C virus (anti-HCV),  anti-
hepatitis E virus IgM (anti-HEV IgM) (even if has not traveled to an endemic area for 
hepatitis E), Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) screen.

If patient is immunosuppressed, test for HCV RNA and HEV RNA.

If HBsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV DNA to 
detect active HepB, especially in patients who are immunosuppressed.

If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive 
test, HBV DNA should be obtained to detect reactivation of hepatitis B.
5.
Assuming that the history, physical, and initial imaging and laboratory has not revealed a 
cause of elevated LTs, screen for other causes of liver disease including: Total protein and 
albumin (estimate globulin fraction and obtain quantitative immunoglobulins if elevated), 
antinuclear antibody (ANA), anti-liver kidney microsomal antibody type 1 (anti-LKM1), 
anti-liver-kidney microsomal antibodies (anti-LKM antibodies), anti-smooth muscle 
antibodies (ASMA), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). If 
the pattern of laboratory abnormalities is not hepatocellular, but cholestatic or a mixed 
pattern (see definitions in table above), then gamma-glutamyl transferase (GGT), anti-
mitochondrial antibody (AMA) and anti-neutrophil cytoplasmic antibody (pANCA) should 
also be tested.  If there is an indication by history or elevated baseline LTs that there may be 
an underlying chronic liver disease possibly exacerbated by exposure to the study 
intervention in the clinical trial or making the participant more susceptible to DILI, test 
iron/Total iron binding capacity (TIBC) and ferritin (hemochromatosis), and alpha-1-
antitrypsin level.  If patient is <50 years of age, ceruloplasmin should also be tested to 
screen for Wilson’s disease.  If patient is sick enough to be hospitalized and is under age 50, 
a slit lamp examination to detect Kayser-Fleischer rings and a 24-hour urine collection for 
copper should be measured. Consider serum ethanol and/or acetaminophen level and urine 
drug screen as clinically appropriate.
6.
A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology 
and if immunosuppressive therapy is contemplated.
A liver biopsy may be considered:

if there is unrelenting rise in liver biochemistries or signs of worsening liver function 
despite stopping the suspected offending agent.

if peak ALT level has not fallen by >50% at 30-60 days after onset in cases of 
hepatocellular DILI, or if peak Alk P has not fallen by >50% at 180 days in cases of 
cholestatic DILI despite stopping the suspected offending agent.

in cases of DILI where continued use or re-exposure to the implicated agent is expected.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
103
Approved, Date: 20 February 2018

if liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence 
of chronic liver diseases and chronic DILI.
7.
If pertinent, copies of hospital discharge summary, radiology, pathology and autopsy reports 
should be obtained.
NCT02566889


Remicade® (infliximab)
Clinical Protocol C0168IBD4020 Amendment 3
104
Approved, Date: 20 February 2018
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Andrew Greenspan, MD
Institution:
Janssen Scientific Affairs, LLC
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT02566889


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Andrew Greenspan
20Feb2018, 18:36:37 PM, UTC
Document Approval
NCT02566889

SAP_001.pdf: 
1
Approved Date: 23 July 2019
Janssen Research & Development 
Statistical Analysis Plan
A Phase 4, Multicenter, Open-label Study of Serum Infliximab Concentrations and 
Efficacy and Safety of Dose Escalation in Pediatric Patients with Inflammatory Bowel 
Disease
ADAPT
Protocol C0168IBD4020 ADAPT; Phase 4
Remicade ®  (infliximab)
Status:
Approved
Date:
23 July 2019
Prepared by:
Janssen Scientific Affairs, LLC.  
Document No.: EDMS-ERI-192458966
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.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
1
Approved Date: 23 July 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 1
ABBREVIATIONS ........................................................................................................................................ 2
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Study Objectives .............................................................................................................................. 7
1.2.
Study Design.................................................................................................................................... 7
1.3.
Statistical Hypotheses for the Primary Objectives ........................................................................... 9
1.4.
Sample Size Justification ................................................................................................................. 9
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11
2.1.
Visit Windows................................................................................................................................. 11
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 11
2.3.
Analysis Population........................................................................................................................ 12
2.4.
Definition of Subgroups.................................................................................................................. 12
2.4.1.
CD and UC subgroups................................................................................................................ 12
2.5.
Other General Definitions............................................................................................................... 12
2.5.1.
Baseline Measurement............................................................................................................... 12
2.5.2.
Study Day and Study Duration ................................................................................................... 12
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 12
4.
SUBJECT INFORMATION................................................................................................................ 13
4.1.
Demographics and Baseline Characteristics ................................................................................. 13
4.2.
Disposition Information................................................................................................................... 13
4.3.
Protocol Deviations ........................................................................................................................ 13
4.4.
Prior and Concomitant Medications ............................................................................................... 13
5.
EFFICACY ......................................................................................................................................... 14
5.1.
Analysis Specifications................................................................................................................... 14
5.1.1.
Data Handling Rules................................................................................................................... 14
5.2.
Primary and Secondary Efficacy Endpoint(s) ................................................................................ 15
5.2.1.
Primary Efficacy Endpoint(s) ...................................................................................................... 15
5.2.2.
Secondary Efficacy Variables..................................................................................................... 15
5.2.3.
Data Presentation....................................................................................................................... 16
5.3.
Serum Infliximab Concentrations and Antibodies to Infliximab...................................................... 16
6.
SAFETY............................................................................................................................................. 16
6.1.
Adverse Events .............................................................................................................................. 16
6.2.
Clinical Laboratory Tests................................................................................................................ 17
REFERENCES............................................................................................................................................ 19
ATTACHMENT ........................................................................................................................................... 20
ATTACHMENT 1
PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX ................................................ 20
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
2
Approved Date: 23 July 2019
ABBREVIATIONS
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
6-TG
6-thioguanine
ADAPT
A Phase 4, Multicenter, Open-label Study of Serum Infliximab Concentrations and Efficacy and 
Safety of Dose Escalation in Pediatric Patients with Inflammatory Bowel Disease
AE
adverse event
ALT
alanine aminotransferase
ANA
antinuclear antibody
Anti-dsDNA
anti-double stranded DNA antibody
AST
aspartate aminotransferase
ATI
antibodies to infliximab
ATC
Anatomical Therapeutic Chemical
BCG
Bacille Calmette-Guerin
BUN
blood urea nitrogen
CD
Crohn’s disease
CI
confidence interval
CRF
case report form (paper or electronic as appropriate for this study)
CRP
c-reactive protein
DEVELOP
An Inflammatory Bowel DisEase Multicenter, ProspectiVE, LOng-term Registry of Pediatric 
Patients
DNA
deoxyribonucleic acid
ESR
erythrocyte sedimentation rate
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
ITT
intention-to-treat (population)
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intention-to-treat (population)
MMF
mycophenolate mofetil
MTX
Methotrexate
PCDAI
Pediatric Crohn's Disease Activity Index
PGA
Physician’s Global Assessment
PT
Preferred Term
q8wk
every 8 weeks
QFT-TB
quantiFERON-TB
RBC
red blood cell
REACH
A Randomized, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of Anti-TNFα
Chimeric Monoclonal Antibody (Infliximab, REMICADE®) in Pediatric Patients with Moderate 
to Severe Crohn's Disease
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SI
System of Units
SOC
System Organ Class
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TNF
tumor necrosis factor
UC
ulcerative colitis
US
United States
WBC
white blood cell
WHO-DD
World Health Organization-Drug Dictionary
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
3
Approved Date: 23 July 2019
TIME AND EVENTS SCHEDULE
Study Procedures a, b
Screening
(Day -14)
Week
Week 64
(Final Safety Visit) c
/Early Study
Discontinuation
0
8
16
24
32
40
48
56/ End of
Treatment
Informed consent/assent
X
Distribute patient PCDAI or partial Mayo 
diary and study cards
X
Medical history and demographics
X
Review of inclusion/exclusion criteria
X
X
Prior medication review d
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
Ileocolonoscopy e
X
X---------------------------------------------
Physical examination (including skin 
examination) f
X
X
X
Vital signs and Weight
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
Stool culture for enteric pathogens, including
Clostridium difficile toxinsg
X
Fecal calprotectin h, i
X
Tuberculosis evaluation j
X
X
X
X
X
X
X
X
X
X
QFT-TB Gold test (or tuberculin skin test in 
countries where the QFT-TB Gold test is not 
approved/registered or is not required per 
local guidelines)
X
Chest radiograph k
X
Hepatitis B testing
X
Hepatitis C testing
X
Varicella antibody titers l
X
Measles antibody titers l
X
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
4
Approved Date: 23 July 2019
Study Procedures a, b
Screening
(Day -14)
Week
Week 64
(Final Safety Visit) c
/Early Study
Discontinuation
0
8
16
24
32
40
48
56/ End of
Treatment
Urine pregnancy test m
X
X
X
X
X
X
X
X
X
X
Hematology and chemistry
X
X
X
X
X
X
Hematocrit
X n
X n
X n
X n
Albumin
X n
X n
X n
X n
ESR
X i, n
X n
X n
X n
X n
X n
X n
X n
X n
CRP
X i
X
X
X
X
X
X
X
X
Infliximab concentration o
X i
X
X
X
X
X
X
X
X
X
Antibodies to infliximab n
X i
X
X
X
X
X
X
X
X
X
ANA and anti-dsDNA antibodies
X
X
PCDAI score or partial Mayo score p
X
X
X
X
X
X
X
Xq
FACES (Wong-Baker pain scale) r
X
X
X
Stool Frequency r
X
X
X
Mayo score (only for UC patients in Dose 
Escalation Group having optional 
ileocolonoscopy)
X
X--------------------------------------------
Adverse event review
X
X
X
X
X
X
X
X
X
X t
Infliximab administration
X
X
X
X
X
X
X
X
a.
All assessments are to be completed prior to infliximab administration.
b.
If a patient discontinues study participation, he/she will be requested to return for a follow-up safety visit 8 weeks following the final administration of infliximab.
During the follow-up safety evaluation, the procedures and evaluations indicated at Week 64 will be performed, prior to withdrawal of consent. If a patient withdraws 
consent, no further study procedures are to be performed.
c.
The Final Safety Visit for those patients completing the treatment portion of the study is to occur 8 weeks after the last administration of infliximab at Week 56. 
d.
The name, dose, frequency, route of administration, the start and stop dates, and duration of any therapy taken by the patient for CD or UC at any time in the past (e.g.,
5-ASAs; corticosteroids; immunomodulators, including thiopurines; biologics) will be recorded in the case report form. For biologics, brand (trade) names will be 
recorded. In addition, any other prestudy therapies administered up to 30 days before the first dose of infliximab at Week 0 must be recorded at screening. 
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
5
Approved Date: 23 July 2019
e.
An ileocolonoscopy is an optional evaluation for patients in the Dose Escalation Group and for patients crossing over to the Dose Escalation Group; it is not 
applicable to patients in the Reference Group. Optional repeat ileocolonoscopy may be performed at least 24 weeks after dose escalation or later; refer to 
protocol Section 9.3.1.5 for further details.
f.
Complete physical examinations (including skin and genitourinary examination) are to be conducted.
g.
Sample to be collected at screening visit, however, if not done, patient/caregiver may collect at home and return to the site within 24 hours of collection. Please refer 
to the Covance laboratory manual for further instructions.
h.
For patients undergoing screening for the Dose Escalation Group, those who do not meet entry criteria based on fecal calprotectin and/or CRP levels may have repeat 
fecal calprotectin and/or CRP levels performed during the screening process, provided that all entry criteria are met within 14 days prior to administration of the first
10 mg/kg dose of infliximab.
i.
At screening, only to be performed for patients in the Dose Escalation Group or for patients in the Reference Group prior to crossing over to the Dose Escalation
Group.
j.
See Protocol Section 9.5.5 for TB evaluations. If TB is suspected at any time, follow-up is required as described in Protocol Section 9.5.5.
k.
Unless country or site guidelines do not recommend a chest radiograph as a necessary screening process prior to initiation of anti-TNF therapies, a chest radiograph
(both posterior-anterior and lateral views) must have been performed within 3 months prior to infliximab administration at Week 0 and read by a qualified
radiologist; the results of which must show no evidence of current active TB or old inactive TB. Chest radiographs (both posterior-anterior and lateral views) must be 
performed as part of the screening process in all cases when either the tuberculin skin test and/or QFT-TB Gold test results for TB are positive.
l.
Varicella and measles titers do not need to be obtained if proof of age-appropriate immunization or proof of prior infection is obtained. 
m.  For female patients of childbearing potential only.
n.
For CD patients only. Note that at these visits, routine hematology and chemistry laboratory studies are not obtained; therefore, hematocrit and albumin laboratory 
studies must be performed in order to calculate PCDAI. In addition, ESR is to be collected for CD patients only at each of these visits for calculation of PCDAI.
o.
Infliximab concentration and ATI titers will be performed for both the Dose Escalation and Reference groups prior to each infusion and at the time of loss of 
response.  Prior to crossing over to the Dose Escalation Group, patients in the Reference Group who lose clinical response must meet all inclusion criteria for the 
Dose Escalation group, including Ctrough < 7 μg/mL and ATI titers ≤ 12,800 (see Protocol Section 4.1 inclusion criterion #10).
p.
The PCDAI or partial Mayo diaries will be completed by patients during the screening period. For calculation of PCDAI at Week 0 for CD patients in the Dose 
Escalation Group the hematocrit, ESR, and albumin values obtained during screening will be used. For calculation of PCDAI prior to the first 10 mg/kg dose for CD 
patients crossing over from the Reference Group to the Dose Escalation Group, the hematocrit, ESR, and albumin obtained within 2 weeks prior to the administration 
of the first 10 mg/kg dose will be used. The PCDAI or partial Mayo score should be calculated prior to infliximab administration at Week 0 for the Dose Escalation 
Group or prior to the administration of the first 10 mg/kg dose for patients crossing over from the Reference Group.
q.
For patients who discontinue treatment prior to week 56 information needed for the PCDAI or partial Mayo scores with respect to questions such as stool frequency 
or quality, abdominal pain, and general well-being will be obtained from patient diary and/or recall.
r.
For cross over patients, the Wong-Baker FACES pain scale will be administered prior to the administration of the first and the third dose of 10 mg/kg of infliximab. 
s.
For cross over patients stool frequency data will be collected prior to the administration of the first and the third dose of 10 mg/kg of infliximab.
t.
Required follow-up for adverse events after the Final Safety Visit is described in Protocol Section 12.3.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
6
Approved Date: 23 July 2019
Note:
(1) The maximum acceptable visit window for all visits is ±7 days. Patients must meet all enrollment criteria for the Week 0 visit prior to the administration 
of infliximab.
(2) At an infusion visit, blood samples should be collected prior to infliximab administration. The same venipuncture can be used to collect serum samples 
for measuring infliximab concentration, ATI, blood draws for safety and efficacy, as well as the infusion of infliximab.
Key:
5-ASA = 5- aminosalicylic acid; ANA = antinuclear antibody; anti-dsDNA = anti-double stranded DNA antibody; ATI = antibody-to-infliximab; CD = Crohn’s 
disease; CRP = c-reactive protein; ESR = erythrocyte sedimentation rate; TB = tuberculosis; TNF = tumor necrosis factor; PCDAI = pediatric Crohn's disease 
activity index; q8wk = every 8 weeks; QFT-TB = QuantiFERON-TB (test); UC = ulcerative colitis.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
7
Approved Date: 23 July 2019
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses.
1.1.
Study Objectives
Primary Objectives

Evaluate whether trough serum infliximab concentrations at the time of loss of clinical
response will identify pediatric patients with inflammatory bowel disease (IBD) who would
benefit (regain clinical response) from dose escalation above the currently approved dose 
(5 mg/kg every 8 weeks [q8wk]).

Overall safety will be assessed throughout the duration of the study.
Secondary Objectives

Identify disease characteristics associated with maintenance of sustained clinical response in 
patients after dose escalation.

Evaluate the rate of serious adverse events (SAEs) in patients who receive an increased dose 
of infliximab due to loss of response (Dose Escalation Group) relative to the rate of SAEs in
those patients in response who are maintained on infliximab 5 mg/kg q8wk (Reference
Group).
1.2.
Study Design
This is a multicenter, prospective, open-label study in pediatric patients with IBD who are
receiving infliximab therapy. The study will include 2 groups, a Dose Escalation Group (n=80)
and a Reference Group (n=50). Although the Dose Escalation and Reference Groups will not be
comparable in terms of disease activity, the Reference Group will provide safety information,
serum infliximab concentration data, and antibodies to infliximab (ATI) titer data in a
contemporaneous IBD cohort undergoing infliximab therapy. 
Both the Dose Escalation and Reference Groups will include 60% Crohn’s disease (CD) patients
and 40% ulcerative colitis (UC patients) at enrollment, to ensure a clinically meaningful number
of patients by IBD diagnosis. Patients in both groups will receive infliximab q8wk through
Week 56, with a Final Safety Visit occurring 8 weeks after the last dose of infliximab. 
Patients in the Reference Group who lose clinical response may cross over to the Dose 
Escalation Group provided they meet all entry criteria for the Dose Escalation Group.
At the time of enrollment in the trial, patients must be receiving infliximab at a dose of
5
mg/kg q8wk (range 4.5 mg/kg to 6 mg/kg with a ± 7 day window for all 3 induction doses
and maintenance doses during the 6 months prior to infliximab administration at Week 0).
Upon meeting enrollment criteria for the Dose Escalation Group, patients will receive
infliximab 10 mg/kg q8wk (Figure 1) at Week 0. Patients will be eligible to receive 56 weeks of
therapy with infliximab at the escalated dose with a Final Safety Visit at Week 64.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
8
Approved Date: 23 July 2019
Investigators may discontinue patients in the Dose Escalation Group who have not regained
clinical response after receiving 2 doses of 10 mg/kg infliximab, administered 8 weeks apart.
Figure 1:
Dose escalation study diagram
Upon meeting enrollment criteria for the Reference Group, patients will continue to receive
5 mg/kg q8wk. Those who lose clinical response during participation in the study will be
eligible, if they meet the enrollment criteria for the Dose Escalation Group, to cross over to the
Dose Escalation Group.
Patients in the Reference Group who lose response and cross over to the Dose Escalation Group 
must complete screening for the Dose Escalation Group and receive the first 10 mg/kg dose of 
infliximab within 40 weeks of enrollment into the study. These patients will be eligible to receive
a total of 56 weeks of therapy with infliximab, which includes duration of therapy while in
the Reference Group prior to dose escalation.
After obtaining informed consent/assent, detailed demographic and medical history will be
collected on all patients meeting inclusion and exclusion criteria at the time of enrollment.
Review of concomitant medications as well as safety and efficacy assessments (Pediatric
Crohn’s Disease Activity Index [PCDAI] scores or partial Mayo scores) will be conducted at
every study visit through Week 56. Samples will be collected for measurement of serum 
concentrations of infliximab and antibodies to infliximab (ATI) at screening for patients in the 
Dose Escalation Group, prior to each infusion during the study for patients in each group, and at
the time of loss of clinical response for patients in each group. If a UC patient in the Dose
Escalation Group undergoes optional ileocolonoscopy at screening and at least 24 weeks after
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
9
Approved Date: 23 July 2019
dose escalation or later, Mayo scores will also be obtained. The end of the study will occur on 
the date of the last visit of the last patient participating in the study. Refer to the Time and Events 
Schedule for all procedures to be performed over the course of the study.
A patient will be considered to have completed the treatment and safety follow-up portions of the 
study if he/she has completed study assessments through Week 64. Patients may discontinue 
before the end of treatment period per legitimate reasons but is required to return for a Final 
Safety Visit 8 weeks after the final administration of infliximab. 
1.3.
Statistical Hypotheses for the Primary Objectives
In pediatric IBD patients with loss of response, trough serum infliximab concentrations will be 
associated with regain of response after dose escalation.  
1.4.
Sample Size Justification
Both the Dose Escalation and Reference Groups will be composed of 60% CD patients and 40% 
UC patients. Accordingly, the proposed study will enroll 80 (48 CD and 32 UC) patients in the 
Dose Escalation Group and 50 (30 CD and 20 UC) patients in the Reference Group, with the 
conservative assumption that approximately 10 patients (20%) in the Reference Group may dose 
escalate.1,2 Thus, the final sample size in the Dose Escalation Group is estimated to be 
90 patients, with 54 CD patients and 36 UC patients (Figure 2).   
Figure 2:
Sample size details by diagnosis with crossover assumptions
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
10
Approved Date: 23 July 2019
The sample size estimation was calculated based on precision estimates for clinical response 
rates after dose escalation from 5 mg/kg q8w to 10 mg/kg q8w at Week 16, the primary efficacy 
endpoint. It is anticipated the dropout rate due to loss of follow up and other non-efficacy
related reasons by Week 16 will be about 5% of patients), based on the Phase 3 pediatric
infliximab trials in CD and UC patients.1,2 As indicated in Table 1, adjusting for dropout rate, a
sample size of 76 - 85 patients (without or with cross over) will provide precision estimates
between ± 8.5 – 11.2% for expected response rates between 20 - 50%, based on a 2-sided 95%
confidence interval (CI). The anticipated range for clinical response is based on the response 
rates for adult patients undergoing infliximab dose escalation.3,4
Table 1:
Precision estimation for anticipated clinical response rates, adjusting for 5% non-efficacy 
related dropout rate prior to Week 16
Treatment group
Sample Size
Clinical Response Rate
20%
30%
40%
50%
Dose Escalation Group with
Reference Group crossover
85
±8.5%
±9.7%
±10.4%
±10.6%
Dose Escalation Group without
Reference Group crossover
76
±9.0%
±10.3%
±11.0%
±11.2%
CD patients (Dose
Escalation Group with
Reference Group crossover)
51
±11.0%
±12.6%
±13.4%
±13.7%
UC patients (Dose
Escalation Group with
Reference Group crossover)
34
±13.4%
±15.4%
±16.5%
±16.8%
Key: CD = Crohn’s disease; UC = ulcerative colitis
There are currently no data available on pediatric patients with loss of response on 5 mg/kg q8w 
not receiving dose escalation. For the purposes of a conservative sample size calculation, a 
response rate of 5% was assumed for patients with loss of clinical response not receiving dose 
escalation, although it would be predicted that the actual response rate would be negligible 
(< 1%). At a significance level of 0.05 (2-sided), the statistical power is greater than 90% to 
detect at least a 15% increase in clinical response after dose escalation, for the overall Dose 
Escalation Group (N=76 – 85, without or with cross over). For the CD subgroup (N = 46 - 51, 
without or with cross over), the power is between 84% - 90%. For the UC subgroup (N = 30 -
34, without or with cross over), the power is between 70% - 74%.
When testing the association between infliximab concentration and regain of clinical response 
after dose escalation, using logistic regression to test the null hypothesis of no association 
between infliximab serum concentrations and clinical response, i.e., β = 0 (α = 0.05, 2-sided), a 
sample size of 76 - 85 patients (without or with cross over) will provide statistical power 
between 66% and 85% to detect β of 0.916, assuming the response rate is between 20 – 50%.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
11
Approved Date: 23 July 2019
In DEVELOP, the most common serious adverse event category has been gastrointestinal 
disorders, with an event rate of approximately 10.6 events per 100 patient-years among patients 
exposed to infliximab as the only biologic medication (data on file). The sample size of 80 - 90 
dose escalation patients will provide a 95% CI of ± 6.4 - 6.7% around an event rate of 10.6%
(i.e., ± 6.4 - 6.7% estimated precision). The sample size of 40 - 50 patients in the Reference
Group of the proposed study will provide a 95% CI of ± 8.5 - 9.5% around an event rate
of 10.6% (i.e., ± 8.5 - 9.5% estimated precision).
1.5.
Randomization and Blinding
Not applicable.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
The Time and Events Schedule summarizes the frequency and timing of assessments applicable 
to this study.
All visit-specific assessments (Table 2) should be completed before administration of
infliximab. The maximum acceptable visit window for all visits is ± 7 days. Patients must meet
all enrollment criteria for the Week 0 visit prior to the administration of infliximab.   
Table 2:
Visit windows
Scheduled Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)a
Target Time Point
1
Screening
-14 to 0
-14 to 0
2
Week 0
1
1
3
Week 8
2-84
57
4
Week 16
85-140
113
5
Week 24
141-196
169
6
Week 32
197-252
225
7
Week 40
253-308
281
8
Week 48
309-364
337
9
Week 56
365-420
393
10
Week 64b
a
The first infliximab administration day in Week 0 is Study Day 1.
b     :  If a patient discontinues participation in the study, he/she will be required to return for a Final 
Safety Visit 8 weeks following the final administration of infliximab. At that time, the procedures and 
evaluations indicated in the Time and Events Schedule at Week 64 will be performed.
2.2.
Pooling Algorithm for Analysis Centers
Not applicable.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
12
Approved Date: 23 July 2019
2.3.
Analysis Population
The analysis population includes all patients who received at least one infusion of infliximab 
after enrollment. The treatment group is based on the treatment dose the patients actually 
received. Patients who cross over from Reference Group to the Dose Escalation Group will be 
included in the Dose Escalation Group. 
The analysis population will be used for: safety analysis, serum infliximab concentration and 
ATI listings, and planned efficacy Analysis.
2.4.
Definition of Subgroups 
2.4.1.
CD and UC subgroups
Both the Dose Escalation and Reference Groups will be composed of 60% CD patients and 40% 
UC patients. Planned Efficacy and Safety Analyses will be performed by subgroups of CD and 
UC patients. 

Safety endpoint: Adverse Events (AEs) and SAEs. 

Other safety endpoints: clinical laboratory tests
2.5.
Other General Definitions
2.5.1.
Baseline Measurement
The baseline measurement is defined as the measurement collected at Week 0 prior to the
infliximab dose or collected at the Screening Visit if not collected at Week 0. 
2.5.2.
Study Day and Study Duration
Study day 1 is defined as the first infliximab administration day in Week 0. For data recorded 
on/after the date of first infliximab administration, study day is computed as: 

Date of data collected – date of study day 1 + 1
For data recorded prior to the first infliximab administration, study day is computed as: 

Date of data collected – date of study day 1
Study end will be defined as the date of completion/discontinuation/withdrawal visit. 

Study duration (days) = date of study end – date of study day 1 +1 
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analyses will be performed. An internal Safety Monitoring Committee will be 
established to monitor safety data on an ongoing basis to ensure the continuing safety of patients 
enrolled in this study. 
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
13
Approved Date: 23 July 2019
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized using descriptive statistics for the
all enrolled subjects by treatment group. The continuous variables will be summarized 
descriptively by number of patients with non-missing values (n), mean, standard deviation (SD), 
median, minimum, maximum, 1st and 3rd quartiles. For the categorical variables, number of 
patients with non-missing values (n), number of patients and percentage within each category 
will be summarized.
The following demographics and baseline characteristics will be summarized:

age at enrollment

Years since IBD diagnosis at enrollment

Gender 

Race 

Ethnicity 

Baseline body weight, height and BMI

Type of IBD [CD, UC]
Duration of IBD/CD/UC Diagnosis (Years) at enrollment=
(Informed consent date –IBD/CD/UC Diagnosis Date + 1)/365.25
4.2.
Disposition Information
The early discontinuation of study agent and early termination from the study will be listed.  The 
number of patients who finished each scheduled visit will be summarized by treatment group.
4.3.
Protocol Deviations
All protocol deviations will be presented in listings. 
4.4.
Prior and Concomitant Medications
Prior medications are those medications with a stop date earlier than the individual study start 
date (Study Day 1). Concomitant medications are those with a start date no later than the 
individual study end date (study completion/withdrawal date) and a stop date no earlier than the 
Study Day 1. 
Medications, including 5-ASAs, corticosteroids, immunomodulators (including thiopurines), 
biologics and antibiotics) taken at baseline by the patient for CD or UC at any time in the past 
will be summarized by treatment groups for patients in the analysis population by number of 
patients and percentage. 
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
14
Approved Date: 23 July 2019
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Data Handling Rules 
Calculation of the PCDAI score: The PCDAI is a validated clinical tool used to assess disease
severity in pediatric patients with CD5 and is calculated as the sum of the individual component
scores and ranges from 0 to 100 points. 
The PCDAI (see Attachment 1) collects information on the following disease-related variables:
1. Total number of liquid stools, abdominal pain, and general well-being (scored by
the patient or patient’s legal representative);
2. Extra-intestinal manifestations;
3. Physical examinations of abdominal mass and, perirectal disease;
4. Weight change and height change or, height velocity; and
5. Hematocrit, erythrocyte sedimentation rate (ESR), and albumin.
For calculation of PCDAI at Week 0 for CD patients in the Dose Escalation Group the 
hematocrit, ESR, and albumin values obtained during screening will be used. For calculation of 
PCDAI prior to the first 10 mg/kg dose for CD patients crossing over from the Reference Group 
to the Dose Escalation Group, the hematocrit, ESR, and albumin obtained within 2 weeks prior 
to the administration of the first 10 mg/kg dose will be used. The PCDAI should be calculated 
prior to infliximab administration at Week 0 for the Dose Escalation Group or prior to the 
administration of the first 10 mg/kg dose for patients crossing over from the Reference Group.
The PCDAI will only be calculated for a visit if ≥3 of the 5 components are available at that 
visit. When at least 3 of the 5 components are available, any missing components will be 
imputed by carrying forward the last non-missing component. If the PCDAI score cannot be 
calculated (i.e., <3 components available) at a visit, the PCDAI score will be considered missing. 
Calculation of the Mayo and the partial Mayo score: The Mayo score is used to assess disease 
activity in patients with UC.6 Mayo UC activity scores are as follows:

Clinical remission: a score of ≤ 2 points, with no individual sub-score > 1

Mildly active disease: a score of 3 to 5 points 

Moderately active disease: a score of 6 to 10 points

Severe disease: a score of 11 to 12
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
15
Approved Date: 23 July 2019
Mayo scores are calculated using the following 3 components:
1)
Stool frequency and rectal bleeding data from the most recent consecutive 3-day
period prior to the visit excluding the day(s) that medications for constipation, 
diarrhea, or irregularity were taken, the day(s) of a procedure or preparation for a
procedure that would affect bowel frequency and/or blood content of the stool, the
48 hours after the use of anti-motility agent(s), and the 72 hours after a colonoscopy;
2)
The Physician’s Global Assessment (PGA); and
3) The results of a sigmoidoscopy or colonoscopy.
Partial Mayo scores (which exclude endoscopic data)6 range from 0 – 9
Mayo score/partial Mayo score will be missing if any component is missing. 
5.2.
Primary and Secondary Efficacy Endpoint(s)
5.2.1.
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is clinical response at Week 16 after dose escalation, defined as:

CD patients:
A decrease from baseline in PCDAI of ≥ 15 points with total score of ≤30
points 

UC patients:
Response is defined as meeting both criteria.
1) A decrease from baseline in partial Mayo score of ≥ 2 points and 
≥30% 
and
2) A decrease in the rectal bleeding sub-score by ≥ 1 point or the rectal 
bleeding sub-score is ≤ 1 point
5.2.2.
Secondary Efficacy Variables
1.
For CD patients changes from baseline at Week 16 in:

Abdominal pain and loose/watery stool frequency sub-scores of the PCDAI

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
2.
For UC patients changes from baseline at Week 16 in:

Stool frequency and rectal bleeding sub-scores of the partial Mayo score

Abdominal pain using the Wong-Baker FACES scale

Absolute stool frequency 
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
16
Approved Date: 23 July 2019
5.2.3.
Data Presentation 
Listings including primary, secondary efficacy endpoints, the Wong-Baker FACES Pain Scale , 
total scores of PCDAI and partial MAYO Scores and change from baseline over time for total 
PCDAI are provided for the dose escalation group in the analysis population.
5.3.
Serum Infliximab Concentrations and Antibodies to Infliximab
Venous blood samples will be collected for measurement of serum concentrations of infliximab 
and ATI titers at the times shown in the Time and Events Schedule. Serum infliximab 
concentrations and ATI titers will be summarized for all patients in the analysis population with 
available data. A listing for ATI titers will be provided as well. If the data do not allow for
accurate assessment of serum infliximab concentrations (e.g., incomplete administration of
infliximab, missing information of dosing and sampling times), they will be excluded from the
analyses. All concentrations below the lowest quantifiable concentration or missing data will be
labeled as such in the concentration database. All patients and samples excluded from the
analyses will be clearly documented in the study report.
6.
SAFETY
Safety evaluations during the study include adverse events (AEs), clinical laboratory tests. Safety 
analyses will be performed on the safety population, where the treatment group is based on the 
dose the patient actually received. Safety analyses will be based on observed data. 
6.1.
Adverse Events
The incidence of AEs will be summarized by treatment group and MedDRA SOC and PT 
through Week 64. Treatment-emergent adverse events (TEAEs) 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 TEAEs will be included in the analysis. The proportion of subjects 
who experienced at least 1 occurrence of the following TEAEs will be summarized by treatment 
group:

Any AEs

SAEs

AEs of special interest

Reasonably related AEs (associated with the use of the drug)
In addition, gastrointestinal and non-gastrointestinal adverse events will be summarized for the 
Dose Escalation and Reference Groups.  
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely on the AE eCRF page.
Adverse events will also be summarized by CD and UC subgroups.  
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
17
Approved Date: 23 July 2019
Summaries, listings, or patient narratives may be provided, as appropriate, for those patients who 
die, who discontinue treatment due to an adverse event, or who experience a severe or a serious 
adverse event.
6.2.
Clinical Laboratory Tests
Routine laboratory data for hematology and clinical chemistry will be collected according to the 
schedule in Time and Events Schedule. The laboratory data to be summarized are as follows: 

Hematology Panel

Hemoglobin

Hematocrit

WBC count with differential

Serum Chemistry Panel

alkaline phosphatase

albumin

ALT

AST

total, direct, indirect bilirubin
Reference ranges and markedly abnormal results will be used in the summary of laboratory data. 
Frequency tabulations of subjects with any post-baseline markedly abnormal laboratory value 
will be presented by CD/UC subgroup and reference/dose escalation treatments. A listing of 
patients with any markedly abnormal laboratory results will be provided. Markedly abnormal 
laboratory criteria are defined in Table 3.
For a laboratory value to be considered markedly abnormal, all the criteria listed for a parameter
in the following table must be met. For example, for a Hemoglobin value to be markedly 
abnormal, the Hemoglobin value must be < 100 and this value must be at least a 20 decrease 
from the baseline Hemoglobin value.
Summaries of laboratory data will be completed using all the available data at the time point of 
interest without imputing missing data.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
18
Approved Date: 23 July 2019
Table 3:
Markedly abnormal criteria for laboratory parameters
Hematology Test 
Criteria for Markedly Abnormal Status
Hemoglobin (g/L)
Decrease > 20.0 AND Value < 100.0
Hematocrit (%) 
Value < 0.27
Total WBC (x109/L)
Value < 2.0 OR Value > 20.0
Neutrophils, absolute (x109/L)
Percent decrease 33 AND Value < 1.5
Lymphocytes, absolute (x109/L)
Percent decrease 33 AND Value < 1.5
Eosinophils, absolute (x109/L)
Percent increase 100 AND Value > 1.3
Platelet count (x109/L)
Percent decrease 50 AND Value < 75
Chemistry Test
Criteria for Markedly Abnormal Status
Alkaline phosphatase (U/L)
Percent increase 100 AND Value > 500
ALT (U/L)
Percent increase 100 AND Value > 150
AST (U/L) 
Percent increase 100 AND Value > 150
Total bilirubin
(umol/L)
Percent increase 100 AND Value > 51.3
Sodium (mmol/L) 
(Increase 10 AND Value > 150) OR (Decrease 10 AND Value < 120)
Potassium (mmol/L) 
(Increase 0.8 AND Value > 5.5) OR (Decrease 0.8 AND Value < 3.0)
Chloride (mmol/L)
Value < 85 OR Value > 120
BUN/Urea (mmol/L)
Percent increase 66 AND Value > 14.28
Creatinine (umol/L) 
Percent increase 66 AND Value > 132.6
Albumin (g/L) 
Decrease 10.0 AND Value < 30.0
Total protein (g/L) 
Value < 45 OR Value > 100
Calcium (mmol/L) 
(Increase 0.37 AND Value > 2.62) OR (Decrease 0.37 AND Value < 1.87)
Note:  Increases and decreases above are relative to the baseline value.  Baseline is defined as the closest 
measurement taken prior to or at Week 0.  
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
19
Approved Date: 23 July 2019
REFERENCES
1.
Hyams J, Crandall W, Kugathasan S, et al, and the REACH Study Group. Induction and maintenance 
infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterol.
2007;132:863–873.
2.
Hyams J, Damaraju L, Blank M, et al, for the C0168T72 Study Group. Induction and maintenance therapy with
infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10:391–
399.
3.
Pariente B, Pineton de Chambrun G, Krzysiek R, et al. Trough levels and antibodies to infliximab may not 
predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. Inflamm 
Bowel Dis. 2012;18:1199–1206.
4.
Regueiro M, Siemanowski B, Kip KE, et al. Infliximab dose intensification in Crohn's disease. Inflamm Bowel
Dis. 2007;13:1093-1099.
5.
Hyams J, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn's disease activity 
index. J Pediatr Gastroenterol Nutr. 1991;12:439-447.
6.
Lewis JD, Chuai S, Nessel L, et al. Use of the noninvasive components of the Mayo score to assess clinical 
response in ulcerative colitis. Inflamm Bowel Dis. 2008;14:1660–1666.
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
20
Approved Date: 23 July 2019
ATTACHMENT
ATTACHMENT 1
PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX
HISTORY SCORE (Recall, 1 week) 
__________________________________________________________________________________
Abdominal Pain:
None
__________ (0 points)
Mild - Brief, does not interfere with activities
__________ (5)
Mod/Severe – daily, longer lasting, affects activities, nocturnal
__________ (10)
Total _____
Stools (per day):
0 – 1 liquid stools, no blood
__________ (0)
Up to 2 semi-formed with small blood or 2-5 liquid
__________ (5)
Gross bleeding or ≥ 6 liquid or nocturnal diarrhea
__________ (10)
Total _____
Subject Functioning- General well-being
No limitation of activities, well
__________ (0)
Occasional difficulty in maintaining age appropriate 
__________ (5)
activities, below par
Frequent limitation of activity, very poor
__________ (10)
Total _____   
History Score _____ (Max 30)
********************
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
21
Approved Date: 23 July 2019
LABORATORY SCORE
____________________________________________________________
HCT(%)
10 yrs:
33
____ (0)
Males 11-14:
35
____ (0)
28-32 ____ (2.5)
30-34 ____ (2.5)
< 28
____ (5)
< 30
____ (5)
Females 11-19 34
____ (0)
Males 15-19:
37
____ (0)
29-33 ____ (2.5)
32-36 ____ (2.5)
< 29
____ (5)
< 32
____ (5)
ESR (mm/hr)
< 20 
____ (0)
20-50 ____ (2.5)
> 50
____ (5)
Albumin (g/dL)
3.5
____ (0)
3.1-3.4 ____ (5)
3.0
____ (10)
Laboratory Score_____(Max 20)
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
22
Approved Date: 23 July 2019
GROWTH SCORE
________________________________________________________________________
Weight
Weight gain or voluntary weight stable/loss
_______ (0 points)
Involuntary weight stable, weight loss 1-9 %
_______ (5)
Weight Loss ≥ 10 %
_______ (10)
Total _____
Height
At diagnosis (Refer to percentile chart):
< 1 channel decrease
_______ (0)
1 and 2 channel decrease
_______ (5)
2 channel decrease
_______ (10)
OR
Total _____
Follow-up (Refer to growth velocity chart):
Height velocity
-1 SD
_______ (0)
Height velocity
< -1 SD and > -2 SD
_______ (5)
Height velocity
-2 SD
_______ (10)
Total _____
Growth Score _____ (Max 20)
********************
PHYSICAL EXAMINATION SCORE
__________________________________________________________________________
Abdomen
No tenderness, no mass
_______ (0)
Tenderness or mass without tenderness
_______ (5)
Tenderness, involuntary guarding, definite mass
_______ (10)
Total _____
Perirectal disease
None, asymptomatic tags
_______ (0)
1-2 indolent fistula, scant drainage, no tenderness
_______ (5)
Active fistula, drainage, tenderness or abscess
_______ (10)
Total _____
Physical Examination Score _____ (Max 20)
********************
NCT02566889


Remicade ® (infliximab)
Statistical Analysis Plan C0168IBD4020 ADAPT
23
Approved Date: 23 July 2019
NCT02566889