Reduce Risk for Crohn's Disease Patients

Crohn's Disease Clinical Trial

— RCT  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02852694
• Other study ID #: 2016-01
• Status: Recruiting
• Phase: Phase 4
• Start date: February 28, 2017
• Est. completion date: July 2022

Study information

• Verified date: April 2020
• Source: PIBD-Net
• Contact: Laetitia BIGOT, PhD
• Phone: +33144492572
• Email: lbigot[@]pibd-net.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 312
• Est. completion date: July 2022
• Est. primary completion date: October 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Crohn Disease
• Crohn's Disease

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
France	Hôpital Necker -Enfants Malades (Service de gastro-enterologie)	Paris

Sponsors (2)

Lead Sponsor	Collaborator
PIBD-Net	European Commission

Country where clinical trial is conducted

France, 

References & Publications (39)

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* Note: There are 39 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time to first relapse	the goal is to compare the time of the first relapse	Month 12
Secondary	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
Secondary	Linear height velocity	the goal is to compare linear height velocity	12 months
Secondary	Steroid sparing effect of the regimens	the goal is to compare steroid sparing effect of the regimen	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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