Reduce Risk for Crohn's Disease Patients

NCT ID: NCT02852694

Last Updated: 2025-01-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 192 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-28
• Study Completion Date: 2021-06-14

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).

Conditions

Crohn's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

High Risk Group

subcutaneous methotrexate versus subcutaneous adalimumab

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

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.

Adalimumab

Intervention Type: DRUG

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.

Low risk group

subcutaneous methotrexate versus oral dose of azathioprine / 6 mercaptopurine

Group Type: ACTIVE_COMPARATOR

Methotrexate

Intervention Type: DRUG

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.

Azathioprine / 6 Mercaptopurine

Intervention Type: DRUG

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.

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).

Group Type: OTHER

Adalimumab

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

humira; imurel / purinethol

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

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Commission

OTHER

Sponsor Role: collaborator

PIBD-Net

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frank RUEMMELE, PhD / MD

Role: STUDY_DIRECTOR

PIBD-Net

Locations

Hôpital Necker -Enfants Malades (Service de gastro-enterologie)

Paris, , France

Countries

France

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Other Identifiers

2016-01

Identifier Type: -

Identifier Source: org_study_id