Rationale: Crohn’s disease (CD) is an incurable, debilitating inflammatory bowel disorder (IBD) and already presents during childhood and adolescence in 25% of all CD patients. CD requires lifelong medication and is accompanied by severe complications. The use of anti-TNF antibodies has dramatically changed CD management. Infliximab (IFX) is the only anti-TNF antibody registered for pediatric CD. Currently, IFX is reserved for immunomodulator refractory patients. We hypothesize that top-down use (instead of the current step-up approach) with introduction of IFX at an early stage of disease, may be more effective.
Objective: The primary objective of our study is to determine the efficacy and safety of top-down IFX treatment in moderate-to-severe pediatric CD. Secondary objectives are determination of pharmacokinetic data and predictors of response to IFX in pediatric CD.
Study design: an international open-label randomised controlled trial
Study population: Children (age 1-17 yrs) with new-onset, untreated, CD with moderate-to-severe disease activity
Intervention: Patients will be randomized to either top-down IFX treatment or conventional step-up treatment.
Treatment arm 1: Top-down IFX treatment will consist of IFX treatment by 5 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 as maintenance treatment. IFX will be discontinued after 5 IFX infusions, while AZA will be continued.
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, then tapering of prednisolone in 6 weeks until stop, combined with oral AZA 2-3 mg, once daily, as maintenance treatment.
Main study parameters/endpoints: The primary endpoint at 52 weeks is steroid free clinical remission. The secondary endpoints, amongst others, will be mucosal healing at 10 weeks assessed by endoscopy and prevention of complications (fistulas, strictures, need for surgery). Endoscopy at 52 weeks will be performed to assess mucosal healing in case of persisting complaints.
Nature and extent of the burden, risks and benefit associated with participation:
In total, approximately 8 study visits will take place. During each visit physical examination will take place. Patients are requested to collect a stool sample twice. Blood draws will be performed when patients undergo venous puncture for routine procedure anyway, in total 6 times. Patients will undergo ileocolonoscopy under general anaesthesia at week 10. During ileocolonoscopy mucosal biopsies of ileum and colon will be taken. Ileocolonoscopy is a safe procedure.
The short-term risks of IFX treatment are the risk of infections and immunogenicity. The
long-term risks of IFX treatment are currently unknown. It is likely that patients in treatment arm 2 eventually also will be treated with IFX, but in a later stage of the disease.
The benefit with participation is the higher likelihood of early achievement of mucosal healing in treatment arm 1: top-down IFX treatment which may well prevent complications such as growth failure and fistulas or strictures that require surgery. Pediatric CD has a more severe disease course than adult CD, as illustrated by a higher upper gastrointestinal involvement and more extensive disease. Active CD during childhood often leads to growth failure and/or delay of pubertal development. Moreover, short disease history and a younger age at diagnosis are possibly related to a better efficacy of IFX. Therefore, top-down IFX might be even more beneficial in pediatric than in adult patients.
Principle Investigator: Dr. L. de Ridder / Dr.J. Escher ErasmusMC-Sophia
Grant by ZonMW
Toetsing Online: NL39202.078.12
METC ErasmusMC: MEC-2012-345