Top-down Infliximab Study in Kids With Crohn's Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a top-down treatment approach, prescribing infliximab (IFX) and azathioprine (AZA) at diagnose, yields better outcome in comparison to the usual step-up treatment approach, starting with prednison and AZA or exclusive enteral nutrition (EEN) and AZA, in moderate-to-severe pediatric Crohn's disease (CD) patients.

Detailed Description
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Objective: The purpose of this study is to determine whether a top-down treatment approach, prescribing IFX and AZA at diagnose, yields better outcome in comparison to the usual step-up treatment approach, starting with prednison and AZA or EEN and AZA, in moderate-to-severe pediatric CD patients. Sample size: We will include 100 (2 x 50) patients. With these numbers a difference of 60% and 85% (= 25) can be shown at a power of 80% (2-sided α 0.05). Study design: an international open-label randomised controlled trial Study population: Children (age 3-17 yrs) with new-onset, untreated, CD with moderate-to-severe disease activity (weighted Pediatric CD Index [wPCDAI] >40) Intervention: Patients will be randomised to either top-down or conventional step-up treatment. Treatment arm 1: Top-down IFX treatment will consist of a total of 5 IFX infusions of 5 mg/kg (IFX induction at week 0, 2 and 6, followed by 2 maintenance infusions every 8 weeks) combined with oral AZA 2-3 mg/kg once daily. AZA therapy will continue after the last IFX infusion to maintain remission. Treatment arm 2: Step-up treatment will consist of standard induction treatment by either oral prednisolone 1 mg/kg (maximum 40 mg) once daily for 4 weeks, followed by tapering in 6 weeks until stop, or EEN with polymeric feeding for 6-8 weeks after which normal foods are gradually reintroduced within 2-3 weeks. Either of these induction treatments will be combined with oral AZA 2-3 mg, once daily, as maintenance treatment. Main study parameters/endpoints: Clinical remission at 52 weeks without need for additional CD related therapy or surgery. Secondary endpoints include clinical response, remission and mucosal healing at week 10 and 52, growth, quality of life and adverse events.

Official Title
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Top-down Infliximab Study in Kids With Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Infliximab
* Drug: Prednisolone
* Other: Exclusive enteral nutrition
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children (age 3-17 years, both male and female, weight >10kg) with new-onset, untreated CD with moderate-to-severe disease activity assessed by a wPCDAI >40 will be eligible for inclusion after a diagnosis of CD was made based on the Porto criteria Exclusion Criteria: Patients with the following characteristics will be excluded: immediate need for surgery, symptomatic stenosis or stricture in the bowel due to scarring, active perianal fistulas, severe co-morbidity, severe infection such as sepsis or opportunistic infections, positive stool culture, positive Clostridium difficile assay, positive tuberculin test or a chest radiograph consistent with tuberculosis or malignancy, those already started with CD specific therapy, patients with a suspected or definitive pregnancy

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Top-down<br>Infliximab and azathioprine; patients will receive 5 infliximab infusions of 5 mg/kg (IFX induction at week 0, 2 and 6, followed by 2 maintenance infusions every 8 weeks). IFX will be discontinued after 5 IFX infusions. Patients will also receive oral azathioprine 2-3 mg/kg, once daily as maintenance treatment. | Drug: Infliximab<br> <br> * Other names: Inflectra;Drug: Azathioprine<br> <br> * Other names: Imuran;|
| Active Comparator: Step-up<br>Step-up treatment will consist of standard induction treatment by either oral prednisolone 1 mg/kg (maximum 40 mg) once daily for 4 weeks, followed by tapering in 6 weeks until stop, or EEN with polymeric feeding for 6-8 weeks after which normal foods are gradually reintroduced within 2-3 weeks. Either of these induction treatments will be combined with oral AZA 2-3 mg, once daily, as maintenance treatment. | Drug: Prednisolone<br> <br> Other: Exclusive enteral nutrition<br> <br> Drug: Azathioprine<br> <br> * Other names: Imuran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical remission without need for additional CD related therapy or surgery | Clinical remission is defined as a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) score of less than 12.5 points | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rates | Response is defined by a decrease in wPCDAI score above 17.5 points compared to baseline | 10 weeks | 
| Clinical remission rates | Remission is wPCDAI<12.5 | 10 and 52 weeks | 
| Mucosal healing | Assessed by endoscopy (SES-CD) and/or fecal calprotectin (<100microgram/gram) | 10 and 52 weeks | 
| Change in height Z-scores |  | 10 and 52 weeks | 
| Change in BMI Z-scores |  | 10 and 52 weeks | 
| Change bone age |  | 10 and 52 weeks | 
| Change in Tanner stage |  | 10 and 52 weeks | 
| Therapy failure rates over time | Therapy failure: primary non-response, loss of response according to wPCDAI and medication intolerance | 52 weeks | 
| Adverse events rates | Adverse events includes therapy side effects, disease complications (fistulas, abscesses, strictures, surgery, extra-intestinal manifestations) | 52 weeks, and 260 weeks | 
| Cumulative therapy use |  | 52 weeks, and 260 weeks | 
| Long-term yearly remission rates without need for additional CD related therapy or surgery | Clinical remission is defined as a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) score of less than 12.5 points | 260 weeks | 
| Long-term yearly number of flares |  | 260 weeks | 
| Long-term yearly clinical remission rates | Clinical remission is defined as a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) score of less than 12.5 points | 260 weeks | 
| Long-term yearly mucosal healing (calprotectin) rates | fecal calprotectin <100microgram/gram | 260 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, pediatric, infliximab, top-down, TISKids