The primary objective of our study is to determine the efficacy and safety of top-down IFX treatment in moderate-to-severe pediatric CD.Secundary objectives are determination of PK data and predictors of response to IFX in pediatric CD.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint at 52 weeks is steroid free remission.
Secondary outcome
The secondary endpoints will be mucosal healing at 10 weeks assessed by
endoscopy. Endoscopy at 52 weeks will be performed to assess mucosal healing in
case of persisting complaints. Faecal calprotectin will be performed at both
10, 52 weeks and at flare as an exploratory endpoint. Other secondary endpoints
will be duration of clinical remission and clinical response assessed by PCDAI
since induction, number of flares, prevention of complications (fistulas,
strictures, need for surgery), growth, cumulative use of steroids and
cumulative use of IFX and loss of IFX response. In patients with fistulizing
disease from onset response will be defined as a reduction of at least 50
percent from baseline in the number of draining fistulas at 52 weeks.
Background summary
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. Instead of this step-up approach, top-down use, with introduction of
IFX at an early stage of disease that may be more susceptible to
immunomodulation, might be more effective. In fact, top-down IFX treatment is
able to change the natural course of disease, as shown in immunomodulator naive
adult patients. Top-down IFX might prevent or postpone the emergence of
strictures and/or fistulas that require surgery. In children, pharmacokinetic
(PK) and -dynamic (PD) data on IFX are scarce. Mucosal healing, assessed by
endoscopy, predicts a favorable outcome in adults.
Study 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.
Secundary objectives are determination of PK data and predictors of response to
IFX in pediatric CD.
Study design
We will perform an international open-label RCT in 3 academic centers in the
Netherlands, 1 academic center in Brussels, Belgium and 1 academic center in
Rome, Italy.
Intervention
Patients will be randomized to either top-down IFX treatment or conventional
step-up treatment.
a. 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.
b. 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
azathioprine (AZA) 2-3 mg, once daily, as maintenance treatment. Patients with
primary non-response will step-up to IFX induction, followed by maintenance.
c. In both treatment arms, IFX will be (re)started in case of relapse (PCDAI >
30 or increase of PCDAI by 15 or more). Patients starting IFX will be treated
with IFX induction followed by maintenance every 8 weeks, patients re-starting
IFX (because of flare) will be treated with IFX maintenance every 8 weeks
(preceded by re-induction if indicated, at the discretion of the treating
physician). Patients with loss of response to IFX will receive intensified IFX
treatment by shortening the interval to 6 weeks and/or doubling the dose to 10
mg/kg.
Study burden and risks
The biggest burden for the study participants is the intravenous infusion of
infliximab (5 mg/kg in 2 hours; total 5 times) for patients in the top-down
treatment arm and undergoing colonoscopy at week 10 for all patients. The
standardized study visits will replace regular visits and drawing of blood will
be combined with regular drawings, therefore this is a minimal burden.
The benefit of the top-down treatment arm is the possible prevention of
complications such as growth failure, fistulas and strictures requiring
surgery. The benefit of the colonoscopy for the study participant is the
assessment of mucosal healing, which has been shown to predict a favorable
outcome in adult Crohn's disease patients.
Potential risks are concerns that infliximab (and other anti-TNF drugs) may
increase the likelihood of tumor development. One particular serious type of
lymphoma, hepatosplenic T-cell lymphoma (HSTCL) has been reported in 22 cases
in association with inflammatory bowel disease and treatment worldwide (see
E9).
Considering the very low absolute risk of developing a malignancy and the
multiple complications with uncontrolled inflammatory bowel disease, the
benefit of adequate treatment from diagnosis seems to outweigh the risk.
Dr Molewaterplein 60
Rotterdam 3000 CB
NL
Dr Molewaterplein 60
Rotterdam 3000 CB
NL
Listed location countries
Age
Inclusion criteria
Children (age 3-17 yrs) with new-onset CD with moderate-to-severe disease activity assessed by a PCDAI (pediatric Crohn's disease activity score) >= 30 after a diagnosis of Crohn's disease.
Exclusion criteria
Patients with disease limited to the ileocoecal region, immediate need for surgery, symptomatic stenosis or stricture in the bowel due to scarring, severe co-morbidity, infection, a positive tuberculin test or a chest radiograph consistent with tuberculosis or a malignancy. Patients that have already started drug treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-000645-13-NL |
| CCMO | NL39203.078.12 |