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 (SPARE)

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

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

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

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

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.

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.

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.

- Tissue damage progression will be assessed by the Lémann Score absolute and relative change between baseline and en of the study (2 years).

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

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.