Risk-stratified randomised controlled trial in paediatric Crohn's Disease: Methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or at high risk for aggressive disease course, respectively - a treatment strategy.

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2016-000522-18-GB
• Date of registration: 05/12/2017
• Prospective Registration: Yes
• Primary sponsor: PIBD net
• Public title: Risk-stratified randomised controlled trial in paediatric Crohn's Disease: Methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or at high risk for aggressive disease course, respectively - a treatment strategy.
• Scientific title: Risk Stratified randomised controlled trial in paediatric Crohn's Disease: Methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or at high risk for aggressive disease course, respectively - a treatment strategy - REDUCE-RISKinCD-PIBD -TRIAL
• Date of first enrolment: 28/03/2018
• Target sample size: 312
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000522-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: yes; Other: yes; Other trial design description: To ensure blinding of a 2nd physician who scores wPCDAI, OCDAI & PGA at each visit; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Belgium, Canada, Czech Republic, France, Germany, Israel, Italy, Netherlands, Poland, Spain, United Kingdom

Contacts

• Name: Sandrine Roux
• Affiliation: PIBD net

• Name: Sandrine Roux
• Affiliation: PIBD net

Key inclusion & exclusion criteria

Inclusion criteria:
- Children 6-17, with a new-onset CD diagnosed <6 months using established criteria, requiring a steroid-based or EN based induction therapy
- At initial diagnosis , wPCDAI>40 or CRP>2 times upper limit at diagnosis
- all wPCDAU scores (0-120) are possible at inclusion (patients in remission and patients with active disease)
- Luminal active CD (B1) or B2 and/or B3 disease behaviour
- Initial exposure to 5-ASA and derivate is tolerated
- Exposure to antibiotics is tolerated
- If one of the following criteria is present, patients are allocated to the high risk group prior randomisation:
*complex fistulising 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- 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 optimised induction therapy with steroids or EEN
*B2,B3 or B2B3 disease behaviour
*overall cumulative disease extend of >=60cm
*Informed and signed consent
Are the trial subjects under 18? yes
Number of subjects for this age range: 312
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
- 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-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)
- patients homozygous for TPMTor those with TPMT activity <6 nmol/h/ml erythrocytes or <9nmol 6MTG/g Hb/h), unless they qualify as high risk patients
- evidence of un-drained and un-controlled abscess/ phlegmom
- 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, hepatitis B or C, HIV
- moderate to severe heart failure (NYHA class III/IV)
- oral anticoagulant therapy, anti-malaria therapy
- live vaccines exposure (including yellow fever) less than 3 weeks prior inclusion



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Paediatric Crohn's Disease
MedDRA version: 20.0 Level: PT Classification code 10011401 Term: Crohn's disease System Organ Class: 10017947 - Gastrointestinal disorders
MedDRA version: 20.1 Level: PT Classification code 10021972 Term: Inflammatory bowel disease System Organ Class: 10017947 - Gastrointestinal disorders

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Trade Name: Humira 40mg/0.4ml pre-filled syringe
Product Name: Humira 40mg/0.4ml pre-filled syringe
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: ADALIMUMAB
CAS Number: 331731-18-1
Other descriptive name: SUB20016
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 40mg/0.4ml-

Product Name: Azathioprine
Pharmaceutical Form: Tablet
INN or Proposed INN: Azathioprine
CAS Number: 446-86-6
Other descriptive name: Azathioprine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
INN or Proposed INN: Azathioprine
CAS Number: 446-86-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Product Name: Methotrexate
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Product Name: Mercaptopurine
Pharmaceutical Form: Tablet
INN or Proposed INN: Mercaptopurine
CAS Number: 50-44-2
Other descriptive name: 6-Mercaptopurine
Concentration unit: mg milligram(s)
Concentration type: equa

Primary Outcome(s)

Main Objective: To compare the effectiveness of weekly subcutaneously administered MTX for maintaining relapse-free sustained steroid / EN-free 1-year remission compared with:
- daily oral AZA/6MP in low risk paediatric CD
- subcutaneously administered adalimumab in high risk paediatric CD

Secondary Objective: Comparison between the two treatment arms per risk group (high risk or low risk for aggressive disease evolution)(and inter-risk group analysis for MTX-treated patients)

Ancillary study: analysis of ADA-treated patients from inclusion (TOP-Down) versus patients switched to ADA due to failure of immunomodulator therapy (STEP-up)

Primary end point(s): Comparing the two treatment arms per group for sustained steroid / EN-free remission at Month 12, where sustained remission is defined as wPCDAI<=12.5 and CRP <=1, 5-fold upper limit without a relapse or need for EEN/steroids since week 12.

Timepoint(s) of evaluation of this end point: at 12 months

Secondary Outcome(s)

Secondary end point(s): Comparison between the two treatment arms per risk group (high risk or low risk for aggressive disease evolution) (and inter-risk group analysis for MTX-treated patients)
- To compare time to first relapse
- To compare remission at 12 weeks
- To compare linear height velocity
- To compare steroid sparing effects of the regimens
- To compare toxicity
- To compare health related life of quality (IMPACT 3) between the different treatment arms
- To evaluate clinical predictors for response, including genomic and serological markers
- To evaluate predictive value of fecal calprotectin levels, CRP and other serum tests
- To evaluate TUMMY-CD (patient reported outcome) between MTX, AZA/6MP, ADA treated patients at month 12)
- To evaluate the results of pharmacogenetics for AZA/6MP and MTX in relation to toxicity and response to therapy
- To evaluate results of drug monitoring (concentrations of drug (MTX, adalimumab) and metabolites (AZA/6MP) and anti-drug antibodies (ADA) in relation to adherence, toxicity and response.
Ancillary study: analysis of ADA-treated patients from inclusion (TOP-DOWN) versus patients switched to ADA due to failure of immunomodulator therapy (STEP-UP)

Timepoint(s) of evaluation of this end point: at 12 months

Secondary ID(s)

2016-000522-18-FR

NCT02852694

PIBD2016-01

Source(s) of Monetary Support

European Commission Horizon 20/20 Grant

Abbvie

Ethics review

Status: Approved
Approval date:
Contact: