Clinical trial NCT02177071: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Crohn's Disease
Keywords: CROHN DISEASE
INFLIXIMAB
COMBINATION THERAPY
steroid free remission
anti-metabolites
Lead sponsor: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Sponsor class: OTHER
Collaborators: name: Saint-Louis Hospital, Paris, France
First posted: 2014-06-27
Enrollment: 211
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Eligibility criteria: Inclusion Criteria:

* 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; 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 for childbearing potential female patients.
* Patients able to understand the information provided to them and to give written informed consent for the study

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
* Steroid use ≤6 months prior to screening
* Currently receiving steroids, immunosuppressive agents (other than purine, methotrexate), biologic treatment (other than infliximab) or thalidomide

Primary outcomes:
measure: co-primary efficacy end points
timeFrame: 2 ans
Secondary outcomes:
measure: relapse in each arm.
timeFrame: 2 years
measure: Sustained clinical remission
timeFrame: 2years
measure: Treatment failure
timeFrame: 2 years
measure: Tissue damage progression
timeFrame: 2 years
measure: Endoscopic remission
timeFrame: 2 years
Other outcomes:
measure: disability index
timeFrame: 2 YEARS
measure: adverse events and SAE
timeFrame: 2 YEARS
measure: BIOLOGICS
timeFrame: 2 YEARS
measure: SCORES AND COST
timeFrame: 2 YEARS
Locations:
city: Melbourne
country: Australia
facility: St Vincent Hospital
city: Liege
country: Belgium
facility: CHU LIEGE - Sart Tilman
state: Province De Liège
city: Gent
country: Belgium
facility: Gent University Hospital
city: Clermont-ferrand
country: France
facility: Chu Clermont-Ferrand
state: Auvergne Rhone Alpes
city: Pierre Benite
country: France
facility: CHU LYON
state: Auvergne Rhone Alpes
city: St Etienne
country: France
facility: Chu Saint Etienne
state: Auvergne Rhone Alpes
city: Besancon
country: France
facility: Chu Besancon
state: Bourgogne-Franche-Comte
city: Rennes
country: France
facility: Chu Rennes
state: Bretagne
city: Tours
country: France
facility: Chu Tours
state: Centre Val De Loire
city: Reims
country: France
facility: Chu Reims
state: Grand Est
city: Vandoeuvre Les Nancy
country: France
facility: Chu Nancy
state: Grand Est
city: Amiens
country: France
facility: Chu Amiens
state: Hauts De France
city: Lille
country: France
facility: Chu Lille
state: Hauts De France
city: Valenciennes
country: France
facility: Chr Valencienne
state: Hauts De France
city: Clichy
country: France
facility: Hopital Beaujon
state: Ile De France
city: Le Kremlin Bicetre
country: France
facility: Hopital Bicetre
state: Ile De France
city: Le Kremlin-Bicêtre
country: France
facility: Chu Kremlin Bicetre
state: Ile De France
city: Paris
country: France
facility: Hopital Saint Louis
state: Ile De France
city: Paris
country: France
facility: Hopital St Antoine
state: Ile De France
city: Paris
country: France
facility: Montsouris Mutualist Institute
state: Ile De France
city: Caen
country: France
facility: Caen Unversity Hospital
state: Normandie
city: Pessac
country: France
facility: CHU Bordeaux - Pessac
state: Nouvelle-aquitaine
city: Montpellier
country: France
facility: Chu Montpellier
state: Occitanie
city: Toulouse
country: France
facility: Chu Toulouse
state: Occitanie
city: Nantes
country: France
facility: Chu Nantes
state: Pays De La Loire
city: Nice
country: France
facility: CHU NICE
state: Provences Alpes Cote d'Azur
city: Paris
country: France
facility: Hopital Saint Joseph
Study officials:
affiliation: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
name: David Laharie
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hirten RP, Lakatos PL, Halfvarson J, Colombel JF. Reply. Clin Gastroenterol Hepatol. 2021 Jun;19(6):1301-1302. doi: 10.1016/j.cgh.2020.07.061. Epub 2020 Nov 26. No abstract available.