Reduce Risk for Crohn's Disease Patients (RCT)

April 14, 2020 updated by: PIBD-Net

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

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

312

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75015
        • Recruiting
        • Hôpital Necker -Enfants Malades (Service de gastro-enterologie)
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 17 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • imurel / purinethol
Other: 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 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
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.
Month 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to first relapse
Time Frame: Month 12
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)
Time Frame: 12 weeks
the goal is to compare the remission at 12 weeks
12 weeks
Linear height velocity
Time Frame: 12 months
the goal is to compare linear height velocity
12 months
Steroid sparing effect of the regimens
Time Frame: 12 months
the goal is to compare steroid sparing effect of the regimen
12 months
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).
12 months
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
12 months
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.
12 months
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
12 months
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
12 months
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
12 months
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 months
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
12 months
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
12 months
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
12 months
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
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

PIBD-Net

Collaborators

European Commission

Investigators

  • Study Director: Frank RUEMMELE, PhD / MD, PIBD-Net

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 28, 2017

Primary Completion (Anticipated)

October 1, 2021

Study Completion (Anticipated)

July 1, 2022

Study Registration Dates

First Submitted

June 9, 2016

First Submitted That Met QC Criteria

July 28, 2016

First Posted (Estimate)

August 2, 2016

Study Record Updates

Last Update Posted (Actual)

April 16, 2020

Last Update Submitted That Met QC Criteria

April 14, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2016-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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