An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Inflammatory Bowel Diseases

Intervention / Treatment
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* Drug: Infliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a biopsy-confirmed diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) prior to study entry Must meet concomitant medication stability criteria as specified in protocol Is considered eligible according to the tuberculosis (TB) Screening criteria specified in protocol 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 administration of infliximab at Week 0 Must have screening laboratory test results as specfied in the protocol Must be up to date with all immunizations in agreement with current local immunization guidelines for immunosuppressed participants prior to Screening Must not have discontinued infliximab therapy Exclusion Criteria: Must not require, or must not have required, within the 2 months prior to Screening, surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intraabdominal or pancreatic abscess requiring surgical drainage, or other conditions possibly confounding the evaluation of benefit from infliximab treatment Must not have presence or history of colonic or small bowel obstruction within 6 months prior to Screening, confirmed by objective radiographic or endoscopic evidence of a stricture with resulting obstruction (example, dilation of the colon or small bowel proximal to the stricture on barium radiograph or an inability to traverse the stricture at endoscopy) Must not have local manifestations of CD, such as fistulae, strictures, abscesses, or other disease complications for which surgery might be indicated. Enterocutaneuous fistulae for which surgery is not indicated, are allowed Must not have presence of a stoma Must not have documented short bowel syndrome (more than 100 centimeter in total of small bowel resected)

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Group<br>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. | Drug: Infliximab<br>* 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.<br>* Other names: Remicade;|
| Experimental: Reference Group<br>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. | Drug: Infliximab<br>* 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.<br>* Other names: Remicade;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response at Week 16 After Dose Escalation as Evaluated by Pediatric Crohn's Disease Activity Index (PCDAI) in Crohn's Disease (CD) Participants | Clinical response was defined as Crohn's disease (CD) participants with decrease from baseline in PCDAI of greater than or equal to (>=) 15 points with total score of less than or equal to (<=) 30 points. PCDAI includes three history items (abdominal pain, number of liquid stools, general wellbeing), five physical examination items (abdominal examination, perirectal disease, extraintestinal manifestations, weight, height), and three laboratory tests (hematocrit, albumin, erythrocyte sedimentation rate). Items are scored on a three-point scale (zero, 5, or 10 points) except for hematocrit and erythrocyte sedimentation rate which are scored as zero, 2.5 or 5 points. PCDAI scores can range from zero to 125 with higher scores indicating more active disease. Data for this OM was planned to be analyzed for Dose escalation (DE) group only. | Week 16 | 
| Clinical Response at Week 16 After Dose Escalation as Evaluated by Mayo Score in Ulcerative Colitis (UC) Participants | Clinical Response as per Mayo score was defined as decrease from baseline in partial Mayo score of >= 2 points and >= 30 percent (%) and decrease in rectal bleeding sub-score by >= 1 point or achievement of an absolute sub-score of less than or equal to (<=) 1 point (for UC participants). A Partial Mayo Score which is Mayo score without endoscopy ranges from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment [PGA]) with each ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe). Data for this OM was planned to be analyzed for the DE group only. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Clinical Response Through 56 Weeks After Dose Escalation | Sustained clinical response at Week 56 was defined as achieving clinical response per the primary OM definitions at Week 16 and maintaining clinical response at 1 year after dose escalation (Week 56). Clinical response was defined as a decrease from baseline in PCDAI of >= 15 points with total score of =< 30 points (for CD participants) and a decrease from baseline in partial Mayo score of >=2 points and >=30% and a decrease in rectal bleeding sub-score by >= 1 point or achievement of an absolute sub-score of =< point (for UC participants). Data for this OM was planned to be analyzed for the DE group only. | Up to Week 56 | 
| Change From Baseline in Abdominal Pain and Loose/Watery Stool Frequency Sub-scores of the PCDAI at Week 16 and Week 56 in CD Participants | Abdominal and loose/watery stool frequency was evaluated by using the relevant sub-scores of the PCDAI. PCDAI includes three history items (abdominal pain, number of liquid stools, general wellbeing), five physical examination items (abdominal examination, perirectal disease, extraintestinal manifestations, weight, height), and three laboratory tests (hematocrit, albumin, erythrocyte sedimentation rate). Items are scored on a three-point scale (zero, 5, or 10 points) except for hematocrit and erythrocyte sedimentation rate which are scored as zero, 2.5 or 5 points. PCDAI scores can range from zero to 125 with higher scores indicating more active disease. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 and Week 56 | 
| Change From Baseline in Abdominal Pain Using the Wong-Baker FACES Scale at Week 16 and Week 56 in CD Participants | Change from baseline in abdominal pain using the Wong-Baker FACES scale at Week 16 and Week 56 in CD participants was reported. 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. 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 participant must choose the face that best describes how they are feeling. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 and Week 56 | 
| Change From Baseline in Absolute Stool Frequency Based on PCDAI Score at Week 16 and Week 56 in CD Participants | Change from baseline in Absolute stool frequency at Week 16 and Week 56 in CD participants were reported. PCDAI includes three history items (abdominal pain, number of liquid stools, general wellbeing), five physical examination items (abdominal examination, perirectal disease, extraintestinal manifestations, weight, height), and three laboratory tests (hematocrit, albumin, erythrocyte sedimentation rate). Items are scored on a three-point scale (zero, 5, or 10 points) except for hematocrit and erythrocyte sedimentation rate which are scored as zero, 2.5 or 5 points. PCDAI scores can range from zero to 125 with higher scores indicating more active disease. An absolute stool frequency subscore of =<1 point was indicative of mild disease. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 and Week 56 | 
| Change From Baseline in Stool Frequency Sub-Score of the Partial Mayo Score at Week 16 and Week 56 in UC Participants | Change from baseline in Stool frequency sub-score of the partial Mayo score at Week 16 and Week 56 in UC participants were reported. A Partial Mayo Score which is Mayo score without endoscopy ranges from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe). An absolute stool frequency subscore of <=1 point was indicative of mild disease. Higher scores indicate more severe disease. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 and Week 56 | 
| Change From Baseline in Rectal Bleeding Sub-Scores of the Partial Mayo Score at Week 16 and Week 56 in UC Participants | Change from baseline in rectal bleeding sub-scores of the partial Mayo score at Week 16 and Week 56 in UC participants were reported. A Partial Mayo Score which is Mayo score without endoscopy ranges from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe). An absolute rectal bleeding subscore of <=1 point was indicative of mild disease. Higher scores indicate more severe disease. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 and Week 56 | 
| Change From Baseline in Abdominal Pain Using the Wong-Baker FACES Scale at Week 16 and Week 56 in UC Participants | Change from baseline in Abdominal pain using the Wong-Baker FACES scale at Week 16 and Week 56 in UC participants were reported. 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. 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 participant must choose the face that best describes how they are feeling. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 And Week 56 | 
| Change From Baseline in Absolute Stool Frequency at Week 16 and Week 56 in UC Participants | Change from baseline in absolute stool frequency at Week 16 and Week 56 in UC participants were reported. Data for this OM was planned to be analyzed for the DE group only. | Baseline, Week 16 And Week 56 | 
| Correlation of Wong-Baker FACES Scale With Clinical Remission and Response at Week 16 | 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. The scale shows a series of faces ranging from a happy face at 0, No hurt to a crying face at 10 Hurts worst. Data for this OM was planned to be analyzed for the DE group only. Statistical test of the hypothesis (regression model) was not performed due to insufficient data being collected to permit analysis. | Week 16 | 
| Relationship Between Abdominal Pain PCDAI Sub-Score And the Wong-Baker Faces Scale For CD Participants | PCDAI is validated clinical tool used to assess disease severity in pediatric CD participants. PCDAI collects information on disease-related variables:Total number of liquid stools, abdominal pain, and general well-being (scored by participants or participant's legal representative);Extra-intestinal manifestations;Physical examinations of abdominal mass, perirectal disease;Weight change, height change or, height velocity;Hematocrit;erythrocyte sedimentation rate; albumin. PCDAI score is calculated as sum of individual component scores and ranges from 0-100 points. Wong-Baker FACES Pain Scale combines pictures and numbers to allow pain to be rated by children over age of 3. Scale shows a series of faces ranging from a happy face at 0, No hurt to crying face at 10 Hurts worst. Data for this OM was planned to be analyzed for the DE group only. Statistical test of the hypothesis (regression model) was not performed due to insufficient data being collected to permit analysis. | Week 16 and 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric Inflammatory Bowel Disease, Infliximab, Pediatric Participants, Pediatric Ulcerative Colitis, Pediatric Crohn's Disease, Dose Escalation