Clinical trial NCT02852694: Reduce Risk for Crohn's Disease Patients
Official title: Risk-stratified Randomized Controlled Trial in Paediatric Crohn Disease:Methotrexate Vs Azathioprine or Adalimumab for Maintaining Remission in Patients At Low or High Risk for Aggressive Disease Course, Respectively-a Treatment Strategy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Crohn's Disease
Lead sponsor: PIBD-Net
Sponsor class: OTHER
Collaborators: name: European Commission
First posted: 2016-08-02
Enrollment: 192
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the effectiveness of weekly subcutaneously administered Methotrexate for maintaining relapse-free sustained steroid/Enteral Nutrition -free 1-year remission compared with:

* daily oral Azathioprine / 6 mercaptopurine in low risk paediatric Crohn's disease
* subcutaneously administered adalimumab in high risk paediatric Crohn's disease

Detailed description: In this randomized controlled trial PIBDNet (pediatric inflammatory bowel diseases network) aims to compare the following treatment strategy by dividing patients into two risk groups for aggressive disease evolution: the effectiveness of Methotrexate versus Azathioprine / 6 mercaptopurine for the maintenance of remission in Crohn's disease in children who are at low risk for aggressive disease and the effectiveness of Methotrexate versus adalimumab in the high risk group. PIBDNet hypothesizes that Methotrexate is superior to Azathioprine / 6 mercaptopurine for maintaining remission in Crohn's disease in the low risk strata and adalimumab is superior to Methotrexate in the high risk strata. In addition, the ancillary study is planned to analyse of Adalimumab treated patients from inclusion (TOP-Down) versus patients switched to Adalimumab due to failure of immunomodulator therapy (STEP-Up).

Eligibility criteria: Inclusion Criteria:

1. Children 6-17, with a new-onset Crohn Disease diagnosed using established criteria (37, 38), requiring a steroid-based or Enteral nutrition based induction therapy
2. At initial diagnosis, wPCDAI \>40 or CRP\>2 times upper limit at diagnosis
3. all wPCDAI scores (0-120) are possible at inclusion (patients in remission and patients with active disease)
4. Luminal active Crohn Disease (B1) with or without B2 and/or B3 disease behavior
5. Initial exposure to 5-ASA and derivate is tolerated
6. Exposure to antibiotics is tolerated
7. If one of the following criteria is present, patients are allocated to the high risk group prior randomization:

   * Complex fistulizing perianal disease
   * Panenteric disease phenotype (defined as L3 with L4b per Paris classification or L3 with deep ulcers in duodenum, stomach or oesophagus (not HP (helicobacter pylori)- or NSAID-related))
   * Severe growth impairment (height z-score \<-2 or crossing 2 percentiles or more) likely related to CD
   * Significant hypoalbuminemia (\<30g/l), elevated C reactive protein (CRP) (at least 2 times above normal range), or wPCDAI \>12.5 despite 3 weeks of optimized induction therapy with steroids or Exclusive enteral nutrition
   * B2, B3 or B2B3 disease behavior
   * Overall cumulative disease extend of ≥60 cm
8. Informed and signed consent

Exclusion Criteria:

1. Patients with wPCDAI\<42,5 at initial diagnosis, except if CRP\>2 times upper limit
2. No induction therapy with steroids or enteral nutrition
3. Previous therapy with any IBD (inflammatory bowel desease) -related medications other than induction therapy as detailed in this protocol (except 5-ASA).
4. Pregnancy or refusal to use contraceptives during the study period in pubertal patients (both boys and girls) unless absolute abstinence (no sexual activity) is confirmed at each study visit. Positive pregnancy testing throughout the study will trigger prompt withdrawal of the patient from the study.
5. Lactating mothers
6. Children with perianal fistulising disease who require surgical therapy (drainage, seton placement)
7. Patients homozygous for Thiopurine methyl transferase or those with Thiopurine methyl transferase activity \<6 nmol/h/ml erythrocytes or \<9nmol 6MTG (6 methylthioguanine/g Hb/h), unless they qualify as high risk patients
8. Evidence of un-drained and un-controlled abscess/phlegmon
9. Contraindication to any drugs used in the trial (including intolerance/hypersensitivity or allergy to either study drug (thiopurines, methotrexate or adalimumab))
10. Current or previous malignancy
11. Serious comorbidities (such as renal insufficiency, hepatitis, respiratory insufficiency) interfering with drug therapy or interpretation of outcome parameters or will make it unlikely that the patients will finish the trial.
12. Infection with mycobacterium tuberculosis
13. Moderate to severe heart failure (NYHA classe III/IV)
14. Oral anticoagulant therapy, anti-malaria therapy
15. Live vaccines exposure (including yellow fever) less than 3 weeks prior inclusion

Primary outcomes:
measure: Rate of sustained steroid/EEN-free remission at Month 12
timeFrame: Month 12
Secondary outcomes:
measure: Time to first relapse
timeFrame: Month 12
measure: Remission at 12 weeks (measured by wPCDAI</=12.5 and normal CRP and being off steroids/exclusive enteral nutrition)
timeFrame: 12 weeks
measure: Linear height velocity
timeFrame: 12 months
measure: Steroid sparing effect of the regimens
timeFrame: 12 months
measure: Comparison of toxicity of the different protocol drugs
timeFrame: 12 months
measure: Questionnaire : health-related life of quality (IMPACT 3) between the different treatment arms
timeFrame: 12 months
measure: Clinical predictors for response, including genomic and serological markers
timeFrame: 12 months
measure: Predictive value of fecal calprotectin levels, CRP and other serum tests
timeFrame: 12 months
measure: Questionnaire : TUMMY-CD (patient reported outcome) at month 12
timeFrame: 12 months
measure: Questionnaire : WPAI:CD Caregiver (patient reported outcome) at month 12
timeFrame: 12 months
measure: Questionnaire : School Attendance (patient reported outcome) at month 12
timeFrame: 12 months
measure: DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) in relation to toxicity and response to therapy
timeFrame: 12 months
measure: Concentration of protocol drug (ADA or MTX) monitoring in relation to adherence, toxicity and response
timeFrame: 12 months
measure: 6 Mercaptopurine and azathioprine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response
timeFrame: 12 months
measure: Anti-adalimumab antibodies monitoring : concentration of anti-adalimumab antibodies in relation to adherence, toxicity and response
timeFrame: 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker -Enfants Malades (Service de gastro-enterologie)
Study officials:
affiliation: PIBD-Net
name: Frank RUEMMELE, PhD / MD
role: STUDY_DIRECTOR
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