conventional step-up versus infliximab monotherapy in patients with ulcerative colitis (p05553)

Conditions: Colitis, Ulcerative

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.

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.

Eligibility criteria:
inclusion criteria: * any race or ethnicity * must have a diagnosis of moderate-to-severe active ulcerative colitis (uc) with inflammation present beyond the rectum and including more than 20 cm of the colon (mayo score of 6 to 12 points, inclusive ≥ 2 in the endoscopy subscore) * must have responded inadequately to oral (with or without topical) 5-asa treatment (prerequisite oral: at a minimum 4 g/d for 7 days) and must be considered for the first course of systemic corticosteroids; participants with a uc and a mayo score of ≥ 9 are also eligible without prior 5-asa treatment * must agree to use acceptable methods of contraception for at least 2 weeks prior to starting any study treatment and to continue until at least 6 months after the last doses of study drugs * laboratory results must be within specified limits * must be negative for colorectal cancer or any associated lesions * must have a negative tuberculosis (tb) test * must have a chest x-ray within the 3 months with no clinically significant abnormality, or evidence of current active tb or latent tb * must have a negative stool culture exclusion criteria: * pregnant, nursing, or planning pregnancy * had received previous treatment for uc with the corticosteroids, infliximab, azathioprine/ 6-mercaptopurine (6-mp), cyclosporine, tacrolimus, methotrexate, sirolimus, mycophenolate, any tumor necrosis factor-alpha (tnf-α) inhibitor or receptor constructs that bind to τνf-α (e.g., etanercept or adalimumab) and any other biologic agents * frequent (chronic) use of non-steroidal anti-inflammatory drugs (nsaids) * use of laxatives or any murine recombinant product * had surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage in previous 2 months * history of colonic obstruction within the previous 6 months * history of mucosal dysplasia, fistula or colonic resection, adenomatous polyps or stoma, severe, fixed symptomatic stenosis of the large or small intestine * had serious infection with previous 2 months, including human immunodeficiency virus (hiv) and hepatitis * had organ transplant (with the exception of a corneal transplant) * any malignancy within 5 years, including lymphoma * history of demyelinating disease such as multiple sclerosis or optic neuritis * presence or history of congestive heart failure * requires chronic and frequent use of antimotility agents for control of diarrhea * requires total parenteral nutrition * had participated in any other clinical trial within 30 days or intention to participate in another clinical trial during participation in this study