AzTrials
AzTrials

Crohn's DiseasePhase 4RCTNCT02852694

Reduce Risk for Crohn's Disease Patients

A Phase 4 study testing Methotrexate, Adalimumab and Azathioprine / 6 Mercaptopurine in people with Crohn's Disease, run by PIBD-Net at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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… Read more about this study

Who is it for?
Ages 6 to 17 years
Conditions the study is for
Crohn's Disease
What is being tested?
Methotrexate, Adalimumab and Azathioprine / 6 Mercaptopurine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
192 participants
Where
1 siteFrance
Study dates
28 Feb 2017to 14 Jun 2021
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 6 to 17 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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
  • At initial diagnosis, wPCDAI >40 or CRP>2 times upper limit at diagnosis
  • all wPCDAI scores (0-120) are possible at inclusion (patients in remission and patients with active disease)
  • Luminal active Crohn Disease (B1) with or without B2 and/or B3 disease behavior
  • Initial exposure to 5-ASA and derivate is tolerated
  • Exposure to antibiotics is tolerated
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  • 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
  • Informed and signed consent

Who cannot join

  • Patients with wPCDAI<42,5 at initial diagnosis, except if CRP>2 times upper limit
  • No induction therapy with steroids or enteral nutrition
  • Previous therapy with any IBD (inflammatory bowel desease) -related medications other than induction therapy as detailed in this protocol (except 5-ASA).
  • 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.
  • Lactating mothers
  • Children with perianal fistulising disease who require surgical therapy (drainage, seton placement)
Show all 15Show fewer
  • 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
  • Evidence of un-drained and un-controlled abscess/phlegmon
  • Contraindication to any drugs used in the trial (including intolerance/hypersensitivity or allergy to either study drug (thiopurines, methotrexate or adalimumab))
  • Current or previous malignancy
  • 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.
  • Infection with mycobacterium tuberculosis
  • Moderate to severe heart failure (NYHA classe III/IV)
  • Oral anticoagulant therapy, anti-malaria therapy
  • Live vaccines exposure (including yellow fever) less than 3 weeks prior inclusion

Trial locations and contacts

1 site in 1 country.

France1 site

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

    Paris, 75015

Other trials in France

About this study

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

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
Read the 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
Being tested
Methotrexate, Adalimumab, Azathioprine / 6 Mercaptopurine
Medical subject headings
Crohn Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MethotrexateDrug

    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.

  • AdalimumabDrug

    Also called humira

    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 MercaptopurineDrug

    Also called imurel / purinethol

    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.

Study groups in NCT02852694
Study groupRoleWhat they receive
High Risk GroupActive comparatorsubcutaneous methotrexate versus subcutaneous adalimumab
Receives: Drug: Methotrexate; Drug: Adalimumab
Low risk groupActive comparatorsubcutaneous methotrexate versus oral dose of azathioprine / 6 mercaptopurine
Receives: Drug: Methotrexate; Drug: Azathioprine / 6 Mercaptopurine
AncillaryOtherthe 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).
Receives: Drug: Adalimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Month 12

Secondary outcomes (15)

  1. Time to first relapse

    the goal is to compare the time of the first relapse

    Measured: Month 12

  2. 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

    Measured: 12 weeks

  3. Linear height velocity

    the goal is to compare linear height velocity

    Measured: 12 months

  4. Steroid sparing effect of the regimens

    the goal is to compare steroid sparing effect of the regimen

    Measured: 12 months

  5. 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).

    Measured: 12 months

  6. 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

    Measured: 12 months

  7. 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.

    Measured: 12 months

  8. 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

    Measured: 12 months

  9. 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

    Measured: 12 months

  10. 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

    Measured: 12 months

  11. 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

    Measured: 12 months

  12. 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

    Measured: 12 months

  13. 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

    Measured: 12 months

  14. 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

    Measured: 12 months

  15. 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

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Aug 2016 (estimated)
  2. Study start28 Feb 2017
  3. Primary completion14 Jun 2021
  4. Study completion14 Jun 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
192 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02852694
Sponsor's protocol ID
2016-01
Acronym
RCT
Status last verified
Jan 2025
First submitted
9 Jun 2016
Last updated
31 Jan 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev. 2000;(2):CD000067. doi: 10.1002/14651858.CD000067.

    PubMed 10796482

  • Faubion WA Jr, Bousvaros A. Medical therapy for refractory pediatric Crohn's disease. Clin Gastroenterol Hepatol. 2006 Oct;4(10):1199-213. doi: 10.1016/j.cgh.2006.05.031. Epub 2006 Jul 26.

    PubMed 16872913

  • Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut. 1995 Nov;37(5):674-8. doi: 10.1136/gut.37.5.674.

    PubMed 8549944

  • Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology. 2000 Oct;119(4):895-902. doi: 10.1053/gast.2000.18144.

    PubMed 11040176

  • D'Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine. Gastrointest Endosc. 1999 Nov;50(5):667-71. doi: 10.1016/s0016-5107(99)80017-0.

    PubMed 10536324

  • Chatu S, Subramanian V, Saxena S, Pollok RC. The role of thiopurines in reducing the need for surgical resection in Crohn's disease: a systematic review and meta-analysis. Am J Gastroenterol. 2014 Jan;109(1):23-34; quiz 35. doi: 10.1038/ajg.2013.402. Epub 2013 Dec 10.

    PubMed 24322839

  • Panes J, Lopez-Sanroman A, Bermejo F, Garcia-Sanchez V, Esteve M, Torres Y, Domenech E, Piqueras M, Gomez-Garcia M, Gutierrez A, Taxonera C, Sans M; AZTEC Study Group. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn's disease. Gastroenterology. 2013 Oct;145(4):766-74.e1. doi: 10.1053/j.gastro.2013.06.009. Epub 2013 Jun 13.

    PubMed 23770132

  • Cosnes J, Bourrier A, Laharie D, Nahon S, Bouhnik Y, Carbonnel F, Allez M, Dupas JL, Reimund JM, Savoye G, Jouet P, Moreau J, Mary JY, Colombel JF; Groupe d'Etude Therapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Early administration of azathioprine vs conventional management of Crohn's Disease: a randomized controlled trial. Gastroenterology. 2013 Oct;145(4):758-65.e2; quiz e14-5. doi: 10.1053/j.gastro.2013.04.048. Epub 2013 Apr 30.

    PubMed 23644079

  • Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD003459. doi: 10.1002/14651858.CD003459.pub2.

    PubMed 15674908

  • Feagan BG, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, Greenberg GR, Koval J, Wong CJ, Hopkins M, Hanauer SB, McDonald JW. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med. 2000 Jun 1;342(22):1627-32. doi: 10.1056/NEJM200006013422202.

    PubMed 10833208

  • Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, Greenberg GR, Gillies R, Hopkins M, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med. 1995 Feb 2;332(5):292-7. doi: 10.1056/NEJM199502023320503.

    PubMed 7816064

  • Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med. 1989 Mar 1;110(5):353-6. doi: 10.7326/0003-4819-110-5-353.

    PubMed 2492786

  • Holtmann MH, Krummenauer F, Claas C, Kremeyer K, Lorenz D, Rainer O, Vogel I, Bocker U, Bohm S, Buning C, Duchmann R, Gerken G, Herfarth H, Lugering N, Kruis W, Reinshagen M, Schmidt J, Stallmach A, Stein J, Sturm A, Galle PR, Hommes DW, D'Haens G, Rutgeerts P, Neurath MF. Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients. Dig Dis Sci. 2006 Sep;51(9):1516-24. doi: 10.1007/s10620-005-9037-5. Epub 2006 Aug 22.

    PubMed 16927148

  • Lemann M, Mary JY, Colombel JF, Duclos B, Soule JC, Lerebours E, Modigliani R, Bouhnik Y; Groupe D'Etude Therapeutique des Affections Inflammatoires du Tube Digestif. A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine. Gastroenterology. 2005 Jun;128(7):1812-8. doi: 10.1053/j.gastro.2005.03.031.

    PubMed 15940616

  • Lemann M, Zenjari T, Bouhnik Y, Cosnes J, Mesnard B, Rambaud JC, Modigliani R, Cortot A, Colombel JF. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol. 2000 Jul;95(7):1730-4. doi: 10.1111/j.1572-0241.2000.02190.x.

    PubMed 10925976

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Methotrexate, Adalimumab and Azathioprine / 6 Mercaptopurine in people with Crohn's Disease, run by PIBD-Net at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of sustained steroid/EEN-free remission at Month 12 (time frame: Month 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02852694, which also lists 41 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2025.

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