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

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.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Infliximab; Drug: Prednisolone; Drug: Azathioprine; Other: Exclusive enteral nutrition

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • University Hospital Brussels
  • Leuven, Belgium
    • University Hospitals Leuven
• Finland
  • Helsinki, Finland
    • Helsinki University Central Hospital
• Netherlands
  • Amsterdam, Netherlands
    • VU University Medical Center
  • Amsterdam, Netherlands
    • Academic Medical Center
  • Breda, Netherlands
    • Amphia Hospital
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Nijmegen, Netherlands
    • Radboud University Medical Center
  • Rotterdam, Netherlands
    • Maasstad Hospital
  • Utrecht, Netherlands
    • University Medical Center Utrecht
  • Zwolle, Netherlands
    • Isala hospital
  • 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

Description

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

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: Inflectra; Drug: Azathioprine; Other Names: Imuran
Active Comparator: Step-up; 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; Drug: Azathioprine; Other Names: Imuran; Other: Exclusive enteral nutrition

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 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

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Hospira, now a wholly owned subsidiary of Pfizer; ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Lissy de Ridder, MD PhD, Erasmus Medical Center

Publications and helpful links

General Publications

• Jongsma MME, Aardoom MA, Cozijnsen MA, van Pieterson M, de Meij T, Groeneweg M, Norbruis OF, Wolters VM, van Wering HM, Hojsak I, Kolho KL, Hummel T, Stapelbroek J, van der Feen C, van Rheenen PF, van Wijk MP, Teklenburg-Roord STA, Schreurs MWJ, Rizopoulos D, Doukas M, Escher JC, Samsom JN, de Ridder L. First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial. Gut. 2022 Jan;71(1):34-42. doi: 10.1136/gutjnl-2020-322339. Epub 2020 Dec 31.
• Cozijnsen MA, van Pieterson M, Samsom JN, Escher JC, de Ridder L. Top-down Infliximab Study in Kids with Crohn's disease (TISKids): an international multicentre randomised controlled trial. BMJ Open Gastroenterol. 2016 Dec 22;3(1):e000123. doi: 10.1136/bmjgast-2016-000123. eCollection 2016.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: July 1, 2015
• First Submitted That Met QC Criteria: August 6, 2015
• First Posted (Estimated): August 7, 2015

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: pediatric; Crohn's disease; infliximab; top-down; TISKids
• 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; Tumor Necrosis Factor Inhibitors; Prednisolone; Infliximab; Azathioprine
• Other Study ID Numbers: NL52030.078.15; 2014-005702-37 (EudraCT Number); MEC-2015-080 (Other Identifier: Medical Ethical Trial Committee Erasmus MC)