Conventional Step-Up Versus Infliximab Monotherapy in Patients With Active Moderate to Severe Ulcerative Colitis. A Randomized, Open Label, Prospective, Multicenter Study
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 28
- 主要终点
- Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Top-Hold
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.
干预措施: Infliximab (Biological)
Top-Hold
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.
干预措施: Prednisolone (Drug)
Top-Hold
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.
干预措施: Azathioprine (Drug)
Step-Up
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.
干预措施: Infliximab (Biological)
Step-Up
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.
干预措施: Prednisolone (Drug)
Step-Up
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.
干预措施: 5-aminosalicylic acid (Drug)
Step-Up
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.
干预措施: Azathioprine (Drug)
结局指标
主要结局
Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50
时间窗: Week 50
Response at Week 4 was defined as a minimum decrease from baseline in Mayo score of 3 points and 30%. Steroid-free remission at Week 50 was defined as a total Mayo score (including endoscopic assessment) of 2 points or lower and no individual subscore exceeding 1. The Mayo score consists of the following 4 subscores: stool frequency; rectal bleeding; endoscopy results; physician's global assessment. Each subscore is rated on a scale from 0 (best) to 3 (worst). The total Mayo score is calculated as the sum of the 4 subscores and ranges from 0 (best) to 12 (worst).
次要结局
- Number of Participants Achieving Treatment Response(Up to Week 4)