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Reduce Risk for Crohn's Disease Patients (RCT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02852694
Recruitment Status : Unknown
Verified April 2020 by PIBD-Net.
Recruitment status was:  Recruiting
First Posted : August 2, 2016
Last Update Posted : April 16, 2020
Sponsor:
Collaborator:
European Commission
Information provided by (Responsible Party):
PIBD-Net

Study Description
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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

Condition or disease Intervention/treatment Phase
Crohn's Disease Drug: Methotrexate Drug: Adalimumab Drug: Azathioprine / 6 Mercaptopurine Phase 4

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).
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 312 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 28, 2017
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Crohn's Disease

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: High Risk Group
subcutaneous methotrexate versus subcutaneous adalimumab
 Drug: Methotrexate
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.

Drug: Adalimumab
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.
Other Name: humira
Active Comparator: Low risk group
subcutaneous methotrexate versus oral dose of azathioprine / 6 mercaptopurine
 Drug: Methotrexate
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.

Drug: Azathioprine / 6 Mercaptopurine
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.
Other Name: imurel / purinethol
Ancillary
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
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.
Other Name: humira


Outcome Measures
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Primary Outcome Measures :
  1. Rate of sustained steroid/EEN-free remission at Month 12 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Time to first relapse [ Time Frame: Month 12 ]
    the goal is to compare the time of the first relapse

  2. Remission at 12 weeks (measured by wPCDAI</=12.5 and normal CRP and being off steroids/exclusive enteral nutrition) [ Time Frame: 12 weeks ]
    the goal is to compare the remission at 12 weeks

  3. Linear height velocity [ Time Frame: 12 months ]
    the goal is to compare linear height velocity

  4. Steroid sparing effect of the regimens [ Time Frame: 12 months ]
    the goal is to compare steroid sparing effect of the regimen

  5. Comparison of toxicity of the different protocol drugs [ Time Frame: 12 months ]
    Toxicity of the different protocol drugs will be compared using incidence of Adverse Events (AE) and Serious Adverse Events (SAE).

  6. Questionnaire : health-related life of quality (IMPACT 3) between the different treatment arms [ Time Frame: 12 months ]
    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

  7. Clinical predictors for response, including genomic and serological markers [ Time Frame: 12 months ]
    Clinical predictors for response to Study treatment will be determined, using genomic and serological markers, such as ASCA.

  8. Predictive value of fecal calprotectin levels, CRP and other serum tests [ Time Frame: 12 months ]
    the goal is to evaluate predictive value of fecal calprotectin levels, CRP and other serum tests

  9. Questionnaire : TUMMY-CD (patient reported outcome) at month 12 [ Time Frame: 12 months ]
    the goal is to evaluate questionnaire : TUMMY-CD (patient reported outcome) for all patients patients at month 12

  10. Questionnaire : WPAI:CD Caregiver (patient reported outcome) at month 12 [ Time Frame: 12 months ]
    the goal is to evauate WPAI:CD Caregiver (patient reported outcome) for all patients at month 12

  11. Questionnaire : School Attendance (patient reported outcome) at month 12 [ Time Frame: 12 months ]
    the goal is to evauate School Attendance questionnaire (patient reported outcome) for all patients at month 12

  12. DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) in relation to toxicity and response to therapy [ Time Frame: 12 months ]
    the goal is to evaluate DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) in relation to toxicity and response to therapy

  13. Concentration of protocol drug (ADA or MTX) monitoring in relation to adherence, toxicity and response [ Time Frame: 12 months ]
    the goal is to evaluate concentration of protocol drug (ADA or MTX) monitoring in relation to adherence, toxicity and response

  14. 6 Mercaptopurine and azathioprine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response [ Time Frame: 12 months ]
    the goal is to evaluate 6 Mercaptopurine and azathioprine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response

  15. Anti-adalimumab antibodies monitoring : concentration of anti-adalimumab antibodies in relation to adherence, toxicity and response [ Time Frame: 12 months ]
    the goal is to evaluate anti-adalimumab antibodies monitoring : concentration of anti-adalimumab antibodies in relation to adherence, toxicity and response


Eligibility Criteria
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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02852694


Contacts
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Contact: Laetitia BIGOT, PhD +33144492572 lbigot@pibd-net.org
Contact: Christine NGUYEN-DEMANGE cndemange@pibd-net.org

Locations
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France
Hôpital Necker -Enfants Malades (Service de gastro-enterologie) Recruiting
Paris, France, 75015
Contact: Frank RUEMMELE, MD    +33 (0)144492516    frank.ruemmele@aphp.fr   
Sponsors and Collaborators
PIBD-Net
European Commission
Investigators
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Study Director: Frank RUEMMELE, PhD / MD PIBD-Net
More Information
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Publications:
Rosh JR. Methotrexate. In: Mamula P, Baldassano RN, Markowitz JE, editors. Pediatric inflammatory bowel disease2007. p. In press.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: PIBD-Net
ClinicalTrials.gov Identifier: NCT02852694    
Other Study ID Numbers: 2016-01
First Posted: August 2, 2016    Key Record Dates
Last Update Posted: April 16, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Adalimumab
Methotrexate
Mercaptopurine
Azathioprine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
 Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Inflammatory Agents