Reduce Risk for Crohn's Disease Patients

Study Overview
=================
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).

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

Conditions
-----------------
Crohn's Disease

Intervention / Treatment
-----------------
* Drug: Methotrexate
* Drug: Adalimumab
* Drug: Azathioprine / 6 Mercaptopurine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 At initial diagnosis, wPCDAI >40 or CRP>2 times upper limit at diagnosis all wPCDAI scores (0-120) are possible at inclusion (patients in remission and patients with active disease) Luminal active Crohn Disease (B1) with or without B2 and/or B3 disease behavior Initial exposure to 5-ASA and derivate is tolerated Exposure to antibiotics is tolerated 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 Informed and signed consent Exclusion Criteria: Patients with wPCDAI<42,5 at initial diagnosis, except if CRP>2 times upper limit No induction therapy with steroids or enteral nutrition Previous therapy with any IBD (inflammatory bowel desease) -related medications other than induction therapy as detailed in this protocol (except 5-ASA). 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. Lactating mothers Children with perianal fistulising disease who require surgical therapy (drainage, seton placement) 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 Evidence of un-drained and un-controlled abscess/phlegmon Contraindication to any drugs used in the trial (including intolerance/hypersensitivity or allergy to either study drug (thiopurines, methotrexate or adalimumab)) Current or previous malignancy 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. Infection with mycobacterium tuberculosis Moderate to severe heart failure (NYHA classe III/IV) Oral anticoagulant therapy, anti-malaria therapy Live vaccines exposure (including yellow fever) less than 3 weeks prior inclusion

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High Risk Group<br>subcutaneous methotrexate versus subcutaneous adalimumab | Drug: Methotrexate<br>* Subcutaneous methotrexate once weekly 15mg/m2 body surface area (19, 30), with a maximal dose of 25mg/week. Odansetron (Zofran) premedication (4-8mg 1Hour prior to injection) is recommended, folate acid substitution (15mg po, 3 days after Methotrexate injection, for children <20kg: 1x 5mg) is recommended.<br>Drug: Adalimumab<br>* Subcutaneous Adalimumab started at a dose of 160mg followed by 80mg 2 weeks later and then 40mg every 2 weeks in patients over 40kg. In patients < 40kg sc doses of Adalimumab are as follows: induction 160mg/1,73m2 BSA (max 160mg), followed by 80mg/1,73m2 Body surface area (max 80mg) 2 weeks later and maintenance of 40mg/1,73m2 Body surface area (max 40mg) every 2 weeks, all doses rounded up to the nearest 5 multiplications.<br>* Other names: humira;|
| Active Comparator: Low risk group<br>subcutaneous methotrexate versus oral dose of azathioprine / 6 mercaptopurine | Drug: Methotrexate<br>* Subcutaneous methotrexate once weekly 15mg/m2 body surface area (19, 30), with a maximal dose of 25mg/week. Odansetron (Zofran) premedication (4-8mg 1Hour prior to injection) is recommended, folate acid substitution (15mg po, 3 days after Methotrexate injection, for children <20kg: 1x 5mg) is recommended.<br>Drug: Azathioprine / 6 Mercaptopurine<br>* Oral Azathioprine /6mercaptopurine at a dose of 2.5 mg/kg once daily rounded to the nearest multiplication of 12.5mg or oral 6mercaptopurine at a dose of 1.5mg/kg once daily rounded to the nearest multiplication of 12.5mg.<br>* Other names: imurel / purinethol;|
| Other: Ancillary<br>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). | Drug: Adalimumab<br>* Subcutaneous Adalimumab started at a dose of 160mg followed by 80mg 2 weeks later and then 40mg every 2 weeks in patients over 40kg. In patients < 40kg sc doses of Adalimumab are as follows: induction 160mg/1,73m2 BSA (max 160mg), followed by 80mg/1,73m2 Body surface area (max 80mg) 2 weeks later and maintenance of 40mg/1,73m2 Body surface area (max 40mg) every 2 weeks, all doses rounded up to the nearest 5 multiplications.<br>* Other names: humira;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of sustained steroid/EEN-free remission at Month 12 | Rate of sustained steroid/EEN-free remission at Month 12, where sustained remission is defined as wPCDAI (weighted pediatric crohn disease activity index) ≤12.5 and CRP ≤1,5 fold the normal upper limit without a relapse since week 12. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first relapse | the goal is to compare the time of the first relapse | Month 12 | 
| Remission at 12 weeks (measured by wPCDAI</=12.5 and normal CRP and being off steroids/exclusive enteral nutrition) | the goal is to compare the remission at 12 weeks | 12 weeks | 
| Linear height velocity | the goal is to compare linear height velocity | 12 months | 
| Steroid sparing effect of the regimens | the goal is to compare steroid sparing effect of the regimen | 12 months | 
| Comparison of toxicity of the different protocol drugs | Toxicity of the different protocol drugs will be compared using incidence of Adverse Events (AE) and Serious Adverse Events (SAE). | 12 months | 
| Questionnaire : health-related life of quality (IMPACT 3) between the different treatment arms | Health-related life of quality willl be compared between the different treatment arms, based on the IMPACT-III questionnaire, a questionnaire developed for use in pediatric inflammatory bowel disease | 12 months | 
| Clinical predictors for response, including genomic and serological markers | Clinical predictors for response to Study treatment will be determined, using genomic and serological markers, such as ASCA. | 12 months | 
| Predictive value of fecal calprotectin levels, CRP and other serum tests | the goal is to evaluate predictive value of fecal calprotectin levels, CRP and other serum tests | 12 months | 
| Questionnaire : TUMMY-CD (patient reported outcome) at month 12 | the goal is to evaluate questionnaire : TUMMY-CD (patient reported outcome) for all patients patients at month 12 | 12 months | 
| Questionnaire : WPAI:CD Caregiver (patient reported outcome) at month 12 | the goal is to evauate WPAI:CD Caregiver (patient reported outcome) for all patients at month 12 | 12 months | 
| Questionnaire : School Attendance (patient reported outcome) at month 12 | the goal is to evauate School Attendance questionnaire (patient reported outcome) for all patients at month 12 | 12 months | 
| DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) in relation to toxicity and response to therapy | the goal is to evaluate DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) in relation to toxicity and response to therapy | 12 months | 
| Concentration of protocol drug (ADA or MTX) monitoring in relation to adherence, toxicity and response | the goal is to evaluate concentration of protocol drug (ADA or MTX) monitoring in relation to adherence, toxicity and response | 12 months | 
| 6 Mercaptopurine and azathioprine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response | the goal is to evaluate 6 Mercaptopurine and azathioprine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response | 12 months | 
| Anti-adalimumab antibodies monitoring : concentration of anti-adalimumab antibodies in relation to adherence, toxicity and response | the goal is to evaluate anti-adalimumab antibodies monitoring : concentration of anti-adalimumab antibodies in relation to adherence, toxicity and response | 12 months |