Infliximab Top-down in Pediatric Crohn (ITSKids)

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

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

Study Overview

• Status: Terminated
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Infliximab; Drug: Azathioprine; Drug: Prednisolon

Detailed Description

Objective: The purpose of this study is to determine whether a top-down treatment approach, prescribing infliximab and azathioprine at diagnose, yields better outcome in comparison to the usual step-up treatment approach, starting with prednison and azathioprine, in moderate-to-severe pediatric Crohn's disease (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; nQuery Advisor).

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 Intervention: Patients will be randomised to either top-down IFX treatment 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 azathioprine (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 oral prednisolone 1 mg/kg (maximum 40 mg) once daily for 4 weeks, followed by tapering in 6 weeks until stop. Prednisolone 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 IBD related therapy or surgery. Secondary endpoints include clinical response, remission and mucosal healing at week 10 and 52, growth and adverse events.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy
    • Sapienza University
• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3000 CA
      • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Children (age 3-17 years, both male and female) 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Top-down; 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; Other Names: Remicade; Drug: Azathioprine; Other Names: Imuran
Active Comparator: Step-up; Prednisolon and azathioprine; Patients will receive induction treatment with oral prednisolone 1 mg/kg (maximum 40 mg) once daily for 4 weeks, then tapering of prednisolone in 6 weeks until stop, and receive oral azathioprine 2-3 mg/kg, once daily as maintenance treatment.	Drug: Azathioprine; Other Names: Imuran; Drug: Prednisolon

What is the study measuring?

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 Pediatric Crohn's Disease Activity Index (wPCDAI) score of less than 10 points	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mucosal healing	Assessed by endoscopy (SES-CD) and/or fecal calprotectin (<100microgram/gram)	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
Clinical response and remission rate	Response is defined by a decrease in PCDAI score above 15 points compared to baseline. Remission is PCDAI<10	10 weeks
Growth	Change in height and BMI Z-scores, bone age and pubertal development	10 and 52 weeks
Cumulative therapy use		52 weeks
Adverse events rates	Adverse events includes therapy side effects, disease complications (fistulas, abscesses, strictures, surgery, extra-intestinal manifestations)	52 weeks
Long-term yearly remission rates without need for additional CD related therapy or surgery		260 weeks
Long-term yearly clinical remission, response and mucosal healing (calprotectin) rates		260 weeks
Yearly number of flares		260 weeks
Cumulative therapy use		260 weeks
Adverse event rates		260 weeks

Other Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic properties of infliximab	52 weeks
Identification of predictive biomarkers of therapy response	52 weeks
Correlation between clinical disease activity, fecal calprotectin and endoscopic disease severity	52 weeks

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: University of Roma La Sapienza; Universitair Ziekenhuis Brussel
• Investigators: Principal Investigator: Lissy Ridder, de, MD, PhD, Erasmus Medical Center

Publications and helpful links

Helpful Links

• Summary on Medicines for Children Research Network

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: June 7, 2013
• First Submitted That Met QC Criteria: June 14, 2013
• First Posted (Estimate): June 18, 2013

Study Record Updates

• Last Update Posted (Estimate): July 2, 2015
• Last Update Submitted That Met QC Criteria: July 1, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: pediatric; Crohn's disease; infliximab; top-down; ITSKids
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Prednisolone; Infliximab; Azathioprine
• Other Study ID Numbers: NL39202.078.12; 2014-005702-37 (EudraCT Number); 2012-000645-13 (EudraCT Number)