InDuctIon TREatment with SubCuTaneous Infliximab for Crohn's Disease

Overview

Study Design: A Prospective Multicenter Randomized Controlled, Open-label Non-inferiority Study to Investigate the Efficacy of Subcutaneous (SC) Infliximab (IFX) with and without Immunomodulators during Induction treatment in Moderate to Severe Crohn's Disease. Primary endpoint: The proportion of patients in corticosteroid-free clinical remission (as defined by a Crohn's disease activity index (CDAI)\<150) and endoscopic response (as defined by a simple endoscopic score for Crohn's disease (SES-CD) drop of at least 50%) at week 26. Accrual and feasibility: This study will enroll 158 subjects at approximately 20 sites in the Netherlands (peripheral and academic hospitals). The estimated enrollment is 0.5 patient/centre/month leading to an inclusion duration of 16 months once all centres are open. The first enrolment is anticipated in Q1 2021. Treatment, dosage and administration: Eligible patients will be randomized to receive SC IFX monotherapy (240mg at week 0 and week 2 and then 120mg every other week (EOW) OR SC IFX (240mg at week 0 and week 2 and then 120mg EOW) in combination with immunosuppression.

Permitted concomitant medications: Oral prednisone (≤40 mg per day) or budesonide (≤9 mg per day) are permitted if on stable dose 2 weeks prior to screening. After 2 weeks into treatment, systemic corticosteroids will be tapered at a rate of at least 5 mg per week and budesonide will be tapered at a rate of 3 mg every 2 weeks. If tapering fails, re-introduction of lowest effective dose of corticosteroid is allowed a single time at the discretion of the treating physician, after which tapering is required beginning 2 weeks later. Stable doses of mesalazine (at a maximum dose of 4g/day) are permitted throughout the study. Stable doses of antibiotics are permitted until week 12. Adverse events to antibiotics can prompt treatment discontinuation, in that case a switch is allowed during week 12. Patients randomized to IFX combination therapy will also receive 6-mercaptopurine 1-1.5 mg/kg. If participants are already using azathioprine or thioguanine, they will receive continued dosing 2-2.5mg/kg or 20mg once daily, respectively (unless shunter status or previous adverse events suggest differently). In case of previous adverse event leading to thiopurine discontinuation methotrexate 15 mg/week sc. in combination with oral folic acid 5mg/week will be prescribed. Immunosuppressive treatment will be stopped at screening (approximately 2 weeks before randomization) for all patients and will be restarted for patients in the combination treatment group. Patients randomized to IFX monotherapy will not receive concomitant immunosuppression. Primary Objectives: The aim of this study is to investigate the efficacy of subcutaneous IFX in the treatment of moderate to severe Crohn's disease with and without concomitant immunosuppression, as measured by the proportion of patients in corticosteroid-free clinical remission (as defined by a CDAI\<150) and endoscopic response (as defined by a SES-CD drop of at least 50%) at week 26. The Investigator hypothesizes that subcutaneous IFX monotherapy is non-inferior to subcutaneous IFX with concomitant immunosuppression in inducing this combined primary endpoint of corticosteroid free remission (CSF), clinical remission and endoscopic response by week 26. Secondary Objectives: (not hierarchical) * The proportion of patients in endoscopic remission at week 26 (defined as the absence of ulcerations larger then 5mm) * Proportion of patients with endoscopic remission at week 26 (as measured by SES-CD≤2) * Proportion of patients with endoscopic response at week 26 (as measured by at least 50% reduction in the SES-CD as compared to baseline) * Proportion of patients in corticosteroid-free clinical remission at week 26 (defined as a CDAI\<150) * The proportion of patients in corticosteroid-free remission (CSF) deep remission at week 26, as defined by corticosteroid-free clinical (CDAI\<150) AND endoscopic remission (defined as the absence of ulcerations larger then 5mm) * Proportion of patients in clinical remission at week 2, 4, 8, 14 and 26 (defined as a CDAI\<150) * Proportion of patients achieving clinical response at week 2, 4, 8, 14 and 26 (defined as a CDAI-70) * Proportion of patients achieving clinical response at week 26 (defined as a CDAI-100) * Proportion of patients in symptomatic remission at week 2, 4, 8, 14 and 26 (defined as a patient reported outcome (PRO-2) (stool frequency and abdominal pain) \<8) * Proportion of patients achieving symptomatic response at week 2, 4, 8, 14 and 26 (defined as a PRO-2 -8) * Time to symptomatic remission (defined as a PRO-2 (stool frequency and abdominal pain) \<8) * Proportion of patients in biochemical remission at week 8, 14 and 26 : C-reactive protein (CRP ≤ 5.0 mg/L and fecal calprotectin \< 250 mg/g) * Time to biochemical remission (CRP ≤ 5.0 mg/L and fecal calprotectin \< 250 mg/g) * Proportion of patients achieving minimally clinically important difference in quality of life at week 2, 4, 8, 14 and week 26 compared to baseline as assessed by the inflammatory bowel disease questionnaire (IBDQ) and EuroQol - 5 dimension - 5 level (EQ-5D-5L) questionnaire * Proportion of patients developing anti-drug antibodies (ADA) against IFX at week 2, 4, 8, 14 and 26 as measured by a drug-tolerant assay * IFX trough levels at week 2, 4, 8, 14 and 26 * Human Leukocyte antigen (HLA) haplotyping and correlation with anti-drug antibodies (ADA) development * Thiopurine metabolites at baseline, week 14 and week 26 (for patients randomized for the combination therapy group, only at baseline for those in the monotherapy group and with previous IS use) * Proportion of patients having IFX trough levels of \>5ug/ml at week 26 * Proportion of patients achieving histological healing at week 26 * Proportion of patients (of those with active perianal disease at baseline) in clinical remission and response of their perianal disease, as defined by the fistula drainage assessment at week 26 * Proportion of patients with extraintestinal manifestations at week 26 as compared to baseline * Adverse events. Subject Population: 158 patients with moderate to severe Crohn's disease between the age of 18-80 years who are starting with IFX treatment. Treatment Arms: Group 1: Subcutaneous IFX monotherapy 240mg at week 0 and week 2 and then 120mg EOW. Group 2: Subcutaneous IFX 240mg at week 0 and week 2 and then 120mg EOW in combination with immunosuppressive. Randomly assigned to either of these groups in a 1:1 ratio. Randomization will be stratified according to immunosuppressive use at screening. Duration of Treatment: 26 weeks. Period of evaluation: 26 weeks.