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Reduce Risk for Crohn's Disease Patients (RCT)

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ClinicalTrials.gov Identifier: NCT02852694
Recruitment Status : Recruiting
First Posted : August 2, 2016
Last Update Posted : May 30, 2019
Sponsor:
Collaborator:
European Commission
Information provided by (Responsible Party):
PIBD-Net

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).

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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

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




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. Toxicity of protocol drug methotrexate by blood methotrexate assessments [ Time Frame: 12 months ]
    the goal is to compare toxicity of protocol drug methotrexate by blood methotrexate assessments

  5. Toxicity of protocol drug adalimumab by blood adalimumab assessments [ Time Frame: 12 months ]
    the goal is to compare toxicity of protocol drug adalimumab by blood adalimumab assessments

  6. Toxicity of protocol drug 6 mercaptopurine by blood 6 mercaptopurine assessments [ Time Frame: 12 months ]
    the goal is to compare toxicity of protocol drug 6 mercaptopurine by blood 6 mercaptopurine assessments

  7. Toxicity of protocol drug azathioprine by blood azathioprine assessments [ Time Frame: 12 months ]
    the goal is to compare toxicity of protocol drug azathioprine by blood azathioprine assessments

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

  9. Effectiveness of methotrexate in case of therapy failure based on physiological parameters, questionnaires [ Time Frame: 12 months ]
    the goal is to evaluate effectiveness of methotrexate in case of therapy failure based on physiological parameters, questionnaires

  10. Effectiveness of adalimumab in case of therapy failure based on physiological parameters, questionnaires [ Time Frame: 12 months ]
    the goal is to evaluate effectiveness of adalimumab in case of therapy failure based on physiological parameters, questionnaires

  11. Effectiveness of azathioprine in case of therapy failure based on physiological parameters, questionnaires [ Time Frame: 12 months ]
    the goal is to evaluate effectiveness of azathioprine in case of therapy failure based on physiological parameters, questionnaires

  12. Effectiveness of 6 mercaptopurine in case of therapy failure based on physiological parameters, questionnaires [ Time Frame: 12 months ]
    the goal is to evaluate effectiveness of 6 mercaptopurine in case of therapy failure based on physiological parameters, questionnaires

  13. Genomic predictors for response by measuring physiological parameters [ Time Frame: 12 months ]
    the goal is to evaluate genomic predictors for response by measuring physiological parameters

  14. Serological markers predictors for response by measuring physiological parameters such as ASCA (anti saccharomyces cerevisiae antibody) [ Time Frame: 12 months ]
    the goal is to evaluate serological markers predictors for response by measuring physiological parameters such as ASCA (anti saccharomyces cerevisiae antibody)

  15. Predictive value of fecal calprotectin levels [ Time Frame: 12 months ]
    the goal is to evaluate predictive value of fecal calprotectin levels

  16. Predictive value of CRP [ Time Frame: 12 months ]
    the goal is to evaluate predictive value of CRP

  17. 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

  18. 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

  19. 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

  20. DNA (desoxy ribonucleic acid) pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) for methotrexate 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) for methotrexate in relation to toxicity and response to therapy

  21. DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) for 6 mercaptopurine 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) for 6 mercaptopurine in relation to toxicity and response to therapy

  22. DNA pharmacogenetics (multiplex genotyping of polymorphism in drug metabolism) for azathioprine 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) for azathioprine in relation to toxicity and response to therapy

  23. Concentration of methotrexate drug monitoring in relation to adherence, toxicity and response [ Time Frame: 12 months ]
    the goal is to evaluate concentration of methotrexate drug monitoring in relation to adherence, toxicity and response

  24. Concentration of adalimumab drug monitoring in relation to adherence, toxicity and response [ Time Frame: 12 months ]
    the goal is to evaluate concentration of adalimumab drug monitoring in relation to adherence, toxicity and response

  25. 6 Mercaptopurine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response [ Time Frame: 12 months ]
    the goal is to evaluate 6 Mercaptopurine metabolites monitoring : concentration of metabolites in relation to adherence, toxicity and response

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

  27. 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



Information from the National Library of Medicine

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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

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
Layout table for location contacts
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

Publications:
Rosh JR. Methotrexate. In: Mamula P, Baldassano RN, Markowitz JE, editors. Pediatric inflammatory bowel disease2007. p. In press.

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Responsible Party: PIBD-Net
ClinicalTrials.gov Identifier: NCT02852694     History of Changes
Other Study ID Numbers: 2016-01
First Posted: August 2, 2016    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: May 2019
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
Azathioprine
Mercaptopurine
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