A proSpective Randomized Controlled Trial comParing infliximAb-antimetabolites Combination Therapy to Anti-metabolites monotheRapy and Infliximab monothErapy in Crohn's Disease Patients in Sustained Steroid-free Remission on Combination Therapy
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      Phase IV

      Design : Prospective, open-label, randomized three-arms study

      Main Inclusion criteria Luminal Crohn's disease patients with steroid free remission for at
      least 6 months and a combination therapy with infliximab and anti-metabolites for at least 8
      months

      Primary objective To demonstrate that Infliximab scheduled maintenance with or without
      antimetabolites is superior to antimetabolites alone to maintain sustained steroid-free
      remission over 2 years, while the latter is non inferior with regards to the mean time spent
      in remission over the same duration

      Main co-primary end points Clinical relapse rate at 2 years Mean remission duration within 2
      years Study treatment Infliximab, Mercaptopurine, azathioprine, methotrexate.

      Number of subjects 225 randomized patients (75 per arm)

      Study duration: 3 + 2 years Enrollment: 3 years Follow-up: 2 years
    

Detailed description: 
      3. STUDY OBJECTIVES 3.1. Primary objective To assess the effect of two withdrawal strategies
      over two years in patients with stable remission for more than 6 months on combination
      therapy with infliximab and antimetabolites, and demonstrate that continued combination of
      infliximab and antimetabolites or continued monotherapy with infliximab are both superior to
      antimetabolites alone for maintaining sustained steroid-free clinical remission, while
      antimetabolites alone are non-inferior with regards to the mean time spent in remission 3.2.
      Secondary objectives

        -  To identify baseline predictive factors of relapse in the three study groups.

        -  To assess the ability of blood CRP and fecal calprotectin to predict short term relapse
           in the three groups.

        -  To assess time spent inclinical remission in the three groups.

        -  To assess the rate of treatment failure in the three study groups.

        -  To assess the time to treatment failure in the three study groups.

        -  To assess progression of bowel damage in the three groups.

        -  To assess the safety and efficacy of infliximab retreatment in the antimetabolites
           group.

        -  To assess safety in the three study groups.

        -  To assess the health related quality of life in the three study groups.

        -  To assess direct and indirect costs in the three study groups.

        -  To assess evolution of blood CRP and fecal calprotectin in the three study groups.

        -  To assess evolution of infliximab trough levels and ATI in the two infliximab scheduled
           maintenance groups.

        -  To assess genetic association with the various clinical and biological outcomes.

        -  To assess the impact of 6TGN levels on the various clinical and biological outcomes in
           the purine treated patients 4. STUDY POPULATION 4.1. Selection of study population
           Patients to be included are those who have been in steroid free remission for at least 6
           months and with scheduled infliximab/antimetabolites combination therapy for at least 8
           months, with a scheduled infliximab treatment administrated every 8 weeks for the last 4
           months.

      4.2. Source of recruitment Patients are recruited from participating GETAID IBD-centers in
      France, Belgium and SOIBD IBD-centers in Sweden, and selected centres in UK, Germany,
      Netherland and Australia 4.3. Inclusion criteria

      To be eligible all of the following criteria must be met:

        -  Diagnosis of Crohn's disease.

        -  Male or female, age > 18 years.

        -  Currently treated with a combination therapy with infliximab and anti-metabolites for
           luminal Crohn's disease.

        -  Combined therapy with scheduled infliximab and anti-metabolites for at least 8 months.

        -  Scheduled administration of infliximab 5 mg/Kg every 8 weeks over the last 4 months.

        -  Antimetabolites administered at a stable dosage for the last 3 months: at least 1 mg/Kg
           or 2 mg/Kg for mercaptopurine and azathioprine, respectively, or the highest tolerated
           dosage if intolerance to standard dose;(lower dose than standard dose is also allowed if
           6 TGN > 235 pmol) ; at least 15 mg/week subcutaneously for methotrexate.

        -  Patients in steroid free clinical remission for at least 6 months according to
           retrospective assessment of the patients' files.

        -  CDAI < 150 at baseline.

        -  A contraceptive during the whole study

        -  Patients able to understand the information provided to them and to give written
           informed consent for the study

      4.4. Exclusion criteria

        -  Patients who have presented a severe acute or delayed reaction to infliximab.

        -  Perianal fistulae as the main indication for infliximab treatment

        -  Active perianal/abdominal fistulae at time of inclusion, defined by active drainage

        -  Patients with ostomy or ileoanal pouch

        -  Pregnancy or planned pregnancy during the study

        -  Inability to follow study procedures as judged by the investigator

        -  Non-compliant subjects.

        -  Participation in another therapeutic study
    

Intervention name(s): INFLIXIMAB; AZATHIOPRINE; MERCAPTOPURINE; Methotrexate
Intervention type(s): Drug; Drug; Drug; Drug
Intervention MeSH terms: Infliximab; Methotrexate; Mercaptopurine; Azathioprine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CROHN DISEASE; INFLIXIMAB; COMBINATION THERAPY; steroid free remission; anti-metabolites