Clinical trial NCT00984568
Conditions: Colitis, Ulcerative
Sponsor: Merck Sharp & Dohme LLC
Start date: 2009-11-01; Completion date: 2012-03-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be performed to compare the efficacy and safety of the classical "Step-Up" approach for treatment of moderate-to-severe active ulcerative colitis using oral prednisolone + oral 5-aminosalicylic acid (5-ASA) or oral prednisolone + oral azathioprine (AZA) with a more intensive and early "Top-Hold" approach with intravenous infliximab (5 mg/kg) administered at Weeks 0, 2, and 6 and 8 weeks thereafter.

Detailed description:
Participants will be randomized to receive either intravenous (IV) infliximab monotherapy (Top-Hold approach) starting at a dose of 5 mg/kg at Weeks 0, 2, and 6 and thereafter every 8 weeks in Level 1, or classical Step-Up treatment starting with oral prednisolone (40 mg/day for at least 3 days and at most 2 weeks followed by 1 mg/kg/day for a minimum of 7 days and up to 2 weeks in the case the participant does not show an improvement in clinical symptoms under 40 mg/day treatment) + oral 5-aminosalicylic acid (5-ASA) at a dose of 2 g/day in Level 1.

Participants receiving Step-Up treatment who have not achieved adequate response during the first 4 weeks of prednisolone treatment will directly enter Level 3 treatment after endoscopy is performed to confirm treatment eligibility. Furthermore, participants that have not achieved response at Week 4 will also directly enter Level 3 and be switched to treatment with IV infliximab.

If a participant experiences a first flare after initial response, participants in the Step-Up group will start prednisolone treatment at the last effective dose (i.e., participants that previously responded to prednisolone 40 mg/day will receive a dose of 40 mg/day for at least 3 days and up to 2 weeks; participants that previously responded to prednisolone 1 mg/kg/day will receive a dose of 1 mg/kg/day for a minimum of 7 days and up to 2 weeks). If the last effective dose was 40 mg/day and the participant does not respond within 14 days, the dose will be adjusted to 1 mg/kg/day for a minimum of 7 days and up to 2 weeks. In case the participant does not respond to prednisolone (i.e., does not return to their individual baseline partial Mayo score obtained at study Week 4), the participant will enter Level 3 and receive treatment with IV infliximab.

If a participant experiences a second flare after initial response at Week 4 (Level 1), the participant will enter treatment Level 2. In Level 2, participants will receive a prednisolone induction at the same effective dose as previously used in Level 1 + maintenance treatment with oral azathioprine (AZA) at a dose of 2.0-2.5 mg/kg/day. Participants that do not respond to this treatment at Level 2 or that develop a further flare after initial response at Level 2 will enter Level 3 and will receive treatment with IV infliximab following endoscopy to confirm treatment eligibility.

If at any time during treatment, a participant becomes prednisolone dependent (i.e., flare during tapering phase of prednisolone), the participant will enter Level 3 treatment with IV infliximab.

Participants in Level 1 of the Top-Hold treatment group (IV infliximab at Week 0, 2, and 6 and every 8 weeks thereafter) that have not achieved response at Week 4 will receive IV infliximab 5 mg/kg at reduced intervals of 4 weeks (Level 2) starting with the Week 10 infusion. Participants suffering a flare after initial response in Level 1 will be switched to to Level 2. Participants that do not respond to treatment at reduced intervals after 3 infusions (12 weeks), or that develop a further flare after initial response at Level 2, will be switched to treatment with oral prednisolone + AZA (Level 3) following colonoscopy to confirm eligibility.

When a participant responds to treatment with IV infliximab in Level 2, they will return to treatment with IV infliximab every 8 weeks when response is achieved at 3 consecutive visits.

Arms: arm 1: Level 1: Infliximab IV 5 mg/kg at Weeks 0, 2, and 6, and every 8 weeks thereafter. Level 2: Infliximab IV 5 mg/kg every 4 weeks. Level 3: Prednisolone induction + AZA 2.0-2.5 mg/kg/day. arm 2: Level 1: Oral prednisolone (40 mg/day or 1 mg/kg/day in the case of non-response) + oral 5-aminosalicylic acid (5-ASA) 2 g/day. Level 2: Oral prednisolone (40 mg/day or 1 mg/kg/day in the case of non-response) + oral azathioprine (AZA) at a dose of 2.0-2.5 mg/kg/day. Level 3: Infliximab 5 mg/kg at Weeks 0, 2, and 6 and every 8 weeks thereafter.
Interventions: intervention 1: Infliximab intervention 2: Prednisolone intervention 3: 5-aminosalicylic acid intervention 4: Azathioprine
Intervention descriptions: intervention 1: Infliximab intravenous infusion at a dose of 5 mg/kg. intervention 2: Oral prednisolone 40 mg/day or 1 mg/kg/day depending upon participant response. intervention 3: 5-ASA administered orally at a dose of 2 g/day. intervention 4: AZA administered orally at a dose of 2.0-2.5 mg/kg/day.

Protocol documents: