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

Crohn's Disease Clinical Trial

— SPARE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02177071
• Other study ID #: GETAID 2014-03
• Status: Completed
• Phase: Phase 4
• Start date: October 9, 2015
• Est. completion date: October 2021

Study information

• Verified date: August 2022
• Source: Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 211
• Est. completion date: October 2021
• Est. primary completion date: June 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Crohn Disease
• Crohn's Disease

Intervention

Drug:
• INFLIXIMAB

• AZATHIOPRINE

• MERCAPTOPURINE

• Methotrexate

Locations

Country	Name	City	State
Australia	St Vincent Hospital	Melbourne
Belgium	Gent University Hospital	Gent
Belgium	CHU LIEGE - Sart Tilman	Liege	Province De Liège
France	Chu Amiens	Amiens	Hauts De France
France	Chu Besancon	Besancon	Bourgogne-Franche-Comte
France	Caen Unversity Hospital	Caen	Normandie
France	Chu Clermont-Ferrand	Clermont-ferrand	Auvergne Rhone Alpes
France	Hopital Beaujon	Clichy	Ile De France
France	Hopital Bicetre	Le Kremlin Bicetre	Ile De France
France	Chu Kremlin Bicetre	Le Kremlin-Bicêtre	Ile De France
France	Chu Lille	Lille	Hauts De France
France	Chu Montpellier	Montpellier	Occitanie
France	Chu Nantes	Nantes	Pays De La Loire
France	CHU NICE	Nice	Provences Alpes Cote d'Azur
France	Hopital Saint Joseph	Paris
France	Hopital Saint Louis	Paris	Ile De France
France	Hopital St Antoine	Paris	Ile De France
France	Montsouris Mutualist Institute	Paris	Ile De France
France	CHU Bordeaux - Pessac	Pessac	Nouvelle-aquitaine
France	CHU LYON	Pierre Benite	Auvergne Rhone Alpes
France	Chu Reims	Reims	Grand Est
France	Chu Rennes	Rennes	Bretagne
France	Chu Saint Etienne	St Etienne	Auvergne Rhone Alpes
France	Chu Toulouse	Toulouse	Occitanie
France	Chu Tours	Tours	Centre Val De Loire
France	Chr Valencienne	Valenciennes	Hauts De France
France	Chu Nancy	Vandoeuvre Les Nancy	Grand Est

Sponsors (2)

Lead Sponsor	Collaborator
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives	Saint-Louis Hospital, Paris, France

Countries where clinical trial is conducted

Australia,  Belgium,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	disability index	disability index	2 YEARS
Other	adverse events and SAE	adverse events and SAE, events related to re-infusions,	2 YEARS
Other	BIOLOGICS	trough levels of infliximab, ATI , hsCRP, fecal calprotectin	2 YEARS
Other	SCORES AND COST	direct medical costs, work productivity and activity index, short IBDQ	2 YEARS
Primary	co-primary efficacy end points	There will be two co-primary efficacy end points; Relapse rate at 2 years, relapse being defined by either one of the following events: A CDAI>250 at any visit or between 150 and 250 with an increase of at least 70 points, over two consecutive visits one week apart associated with a CRP > 5 mg/l or a fecal calprotectin > 250 microg/g; A new opening fistula, perianal or entero-cutaneous.; An intra-abdominal abcess (size of at least 3 cm) or perianal abcess (size of at least 2 cm); An episode of intestinal obstruction due to Crohn's lesions confirmed by medical imaging and requiring hospitalisation (also considered as treatment failure, see below); Mean restricted time spent in remission This time will be computed in all patients, from baseline (CDAI <150 and with absence of fistula drainage) until relapse, as defined above, within the 2 first years. First and subsequent remissions will be summed up within the two first years.	2 ans
Secondary	relapse in each arm.	Time to relapse in each arm.; Factors associated with time to relapse.; Time to relapse according to CRP and calprotectin value measured every 2 months over the follow up.	2 years
Secondary	Sustained clinical remission	Sustained clinical remission defined by CDAI<150 without steroids over two years.	2years
Secondary	Treatment failure	Treatment failure rate. Treatment failure is defined by not achieving remission after treatment adaptation following a relapse according to protocol (CDAI<150 or, in case of relapse defined by the occurence of a new fistula, the absence of fistula closure). The occurence of an intra-abdominal or peri-anal abcess and the occurence of an intestinal obstruction due to Crohn's lesions and requiring a surgical resection or an endoscopic dilatation are also directly considered as treatment failure and will not be managed by treatment adaptation according to protocol.; Time to treatment failure.	2 years
Secondary	Tissue damage progression	- Tissue damage progression will be assessed by the Lémann Score absolute and relative change between baseline and en of the study (2 years).	2 years
Secondary	Endoscopic remission	Endoscopic remission at the end of study	2 years