Conditions: Ulcerative Colitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 242
Healthy volunteers: no

Brief summary:
Part 1 of this study is a 3-arm, randomized, active-controlled, parallel-group, multicenter, double-blind, double-dummy, 16-week study to compare the efficacy and safety of infliximab (IFX), as monotherapy or in combination with azathioprine (AZA) versus AZA monotherapy in adults with moderate to severe active ulcerative colitis (UC). Participants who qualify at the Baseline Visit will be eligible to be randomized to one of the three active treatment groups.

Participants in the IFX/AZA combination therapy and IFX monotherapy cohorts will receive IFX infusions at Weeks 0, 2, and 6 and daily oral AZA/placebo, respectively; participants in the AZA cohort will receive daily oral AZA and placebo infusions at Weeks 0, 2, and 6. At Week 8, all participants will be evaluated for response.

Participants responding to IFX treatment at Week 8, either as monotherapy or in combination with AZA, will receive one more IFX infusion at Week 14; non-responders to IFX therapy will receive placebo infusions at Weeks 8 and 10 and one additional IFX infusion at Week 14.

Participants responding to AZA monotherapy at Week 8 will continue on AZA therapy and receive one placebo infusion at Week 14; nonresponders to AZA will be eligible to receive IFX at Weeks 8, 10, and 14.

Part 2: Participants in remission on IFX monotherapy or IFX/AZA treatment at Week 16 will be randomized to either maintenance or intermittent open-label IFX treatment; randomization will be stratified based on oral AZA/placebo treatment in Part 1. Oral AZA/placebo treatment will continue to be double-blinded. All participants will continue to receive oral AZA/ placebo for the duration of the study.

Participants randomized to maintenance IFX treatment will receive scheduled IFX infusions every 8 weeks beginning at Week 22 (Week 6 for direct entry). If participants lose response, or if treatment has to be discontinued because of an adverse event, these participants are considered treatment failures, and should be followed up for safety at the scheduled 6-month visits (Weeks 38, 62, and 94 \[Weeks 22, 46, and 78 for direct entry\]). These participants will receive standard of care per their personal physician.

Participants randomized to intermittent IFX treatment will be evaluated every 8 weeks. Participants will receive IFX only upon relapse of disease. Treatment with IFX will be initiated at Weeks 0, 2, and 6 of the individual treatment cycle and will continue every 8 weeks until remission is regained. Throughout the study, individual treatment cycles will be repeated whenever a subject relapses.

In addition, to facilitate enrollment into Part 2, participants who received treatment outside of Part 1 and who are in remission on IFX with or without AZA/6-mercaptopurine (6-MP) will be allowed to enter directly into Part 2. In the Czech Republic, direct entry into Part 2 of the study is not allowed.

A higher than expected incidence of serious infusion reactions observed in the intermittent treatment arm of another study (Protocol P04563, NCT0358670) conducted in participants with moderate to severe psoriasis resulted in the termination of that study. Based on the similarities in study design between the intermittent treatment arm of P04563 and the intermittent treatment arm of Part 2 of this study, enrollment to Part 2 of this study was put on hold, for precautionary reasons. At the same time, all participants already enrolled in the intermittent treatment arm of Part 2 were asked to discontinue from the trial. In October 2009, a decision was made by the sponsor to terminate the whole study (Part 1 and 2). At that time, participants enrolled in Part 1 of the study were allowed to complete their treatment up to Week 16.

Detailed description:

Arms:
arm 1: Part 1: IFX 5 mg/kg of body weight intravenous (IV) infusions was to be administered at Weeks 0, 2, and 6 and placebo to AZA was to be taken orally every day for 16 weeks. Responders to IFX at Week 8, were to receive one more IFX infusion at Week 14; non-responders to IFX were to receive placebo IFX infusions at Weeks 8 and 10 and an additional IFX infusion at Week 14. Part 2: Participants in steroid-free remission at Week 16 of Part 1 were to be randomized to either maintenance (every 8 weeks \[q8w\]) or intermittent (upon relapse) open-label IFX (last IFX infusion administered at Week 86) plus double-blind oral AZA/placebo treatment as allocated in Part 1 (last dose at the final visit, Week 94). Responders at Week 16 who had not achieved steroid-free remission were to continue to receive IFX infusions every 8 weeks. arm 2: AZA 2.5 mg/kg of body weight orally every day for 16 weeks. Responders to AZA monotherapy at Week 8 were to continue on AZA therapy and receive one placebo infusion at Week 14; non-responders to AZA at Week 8 would be eligible to receive an IFX infusion at Weeks 8, 10, and 14. Participants in steroid-free remission at Week 16 were to continue on AZA monotherapy and were to be followed up for safety in Part 2. Participants who experienced a relapse of disease after Week 16 were to continue daily AZA monotherapy and receive 3 infusions of IFX (induction therapy at Weeks 0, 2, and 6) followed by infusions every 8 weeks (maintenance therapy). arm 3: IFX 5 mg/kg of body weight IV infusions at Weeks 0, 2, and 6 plus AZA 2.5 mg/kg orally every day for 16 weeks. Responders to IFX/AZA at Week 8 were to receive one more IFX infusion at Week 14; non-responders to IFX/AZA were to receive placebo infusions at Weeks 8 and 10 and one additional IFX infusion at Week 14. Part 2: Participants in steroid-free remission at Week 16 of Part 1 were to be randomized to either maintenance (every 8 weeks \[q8w\]) or intermittent (upon relapse) open-label IFX (last IFX infusion administered at Week 86) plus double-blind oral AZA/placebo treatment as allocated in Part 1 (last dose at the final visit, Week 94). Responders at Week 16 who had not achieved steroid-free remission were to continue to receive IFX infusions every 8 weeks. arm 4: Participants randomized to maintenance IFX/AZA in Part 2 of the study were to receive IFX 5 mg/kg of body weight IV infusions every 8 weeks (beginning at Week 22, Week 6 for direct entry) plus AZA 2.5 mg/kg of body weight daily. Four participants were from Part 1 of the study and 1 participant was enrolled directly into Part 2 of the study. arm 5: Participants randomized to maintenance IFX were to receive IFX 5 mg/kg of body weight IV infusions every 8 weeks (beginning at Week 22, Week 6 for direct entry) in Part 2 of the study. Placebo to AZA therapy was to continue as allocated in Part 1 of the study. All participants were from Part 1 of the study. arm 6: Participants randomized to intermittent IFX/AZA were to receive IFX 5 mg/kg of body weight IV infusions only upon relapse of disease (initiated at Weeks 0, 2, and 6 of individual treatment cycle and continued every 8 weeks until remission was regained) plus AZA 2.5 mg/kg of body weight daily in Part 2 of the study. Three participants were from Part 1 of the study and 1 participant was enrolled directly into Part 2 of the study. arm 7: Participants randomized to intermittent IFX were to receive IFX 5 mg/kg of body weight IV infusions only upon relapse of disease (initiated at Weeks 0, 2, and 6 of individual treatment cycle and continued every 8 weeks until remission was regained). Placebo to AZA therapy was to continue as allocated in Part 1 of the study. One participant was from Part 1 of the study and 1 participant was enrolled directly into Part 2 of the study.

Interventions: intervention 1: Infliximab (IFX) intervention 2: Azathioprine (AZA) intervention 3: Placebo to Azathioprine intervention 4: Placebo infusion
Intervention descriptions: intervention 1: IFX intravenous (IV) infusion dosed at 5mg/kg of body weight intervention 2: AZA 50 mg tablet dosed at 2.5 mg/kg of body weight orally every day intervention 3: Placebo to AZA tablet orally every day intervention 4: Placebo to IFX intravenous (IV) infusion

Protocol document: