Conventional Step-Up Versus Infliximab Monotherapy in Patients With Ulcerative Colitis (P05553)

Conventional Step-Up Versus Infliximab Monotherapy in Patients With Active Moderate to Severe Ulcerative Colitis. A Randomized, Open Label, Prospective, Multicenter Study

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.

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