A Randomized, Double Blind, Multiple Dose Placebo Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 in Subjects With Moderate to Severe Ulcerative Colitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 359
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Remission at Week 8
研究概览
简要总结
The primary objective of this study is to evaluate the effect of abrilumab on induction of remission in adults with moderate to severe ulcerative colitis after 8 weeks of treatment as assessed by a total Mayo Score ≤ 2 points, with no individual subscore > 1 point.
详细描述
The study consisted of a 24-week double-blind, placebo-controlled treatment period followed by an open-label period of approximately 108 weeks. Participants were eligible to enter the open-label period of the study early if they did not achieve a response at week 8 and had an inadequate response at week 12 or later or if they experienced disease worsening after achieving response and/or remission at week 8. Failure to achieve response at week 8 was defined as failure to achieve a decrease from baseline in total Mayo Score ≥ 3 points and ≥ 30% decrease from baseline. Inadequate response at week 12 or later was defined as failure to achieve a 2-point decrease and 25% improvement in partial Mayo Score compared with screening and minimum partial Mayo Score ≥ 5 points. Disease worsening was defined as an increase in partial Mayo Score ≥ 3 points from the week 8 value and minimum partial Mayo Score ≥ 5 points with recto-sigmoidoscopy sub-score ≥ 2.
Participants were planned to be randomized in a 2:1:2:2:2 ratio to placebo or abrilumab at 7 mg, 21 mg, 70 mg (on day 1, week 2, week 4, and every 4 weeks thereafter until week 24), or 210 mg (on day 1 followed by placebo in weeks 2 and 4 and every 4 weeks thereafter until week 24), respectively. Due to a consistent discrepancy between the investigational product (IP) instruction manual (IPIM) description of vial positions and the actual vial positions in the IP package participants were initially randomized to 3 arms (placebo, 70 mg, and 210 mg) with a randomization ratio of 4:3:2. The study was temporarily paused while this issue was investigated. Once the discrepancy was corrected, Protocol Amendment 3 implemented, and affected participants completed their double-blind treatment period, the study resumed enrollment and randomization per protocol. Neither the randomization nor study blind was compromised and therefore the intent-to-treat principle was maintained.
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of ulcerative colitis (UC) established ≥ 3 months before baseline by clinical and endoscopic evidence and corroborated by a histopathology report.
- •Moderate to severe active UC as defined by a total Mayo score of 6 to 12 with a centrally read rectosigmoidoscopy score ≥2 prior to baseline
- •Inadequate response to, loss of response to, or intolerance to at least one of the following treatments:
- •Immunomodulators
- •Anti-TNF agents
- •Corticosteroids (non-US sites only).
- •Neurological exam free of clinically significant, unexplained signs or symptoms during screening and no clinically significant change prior to randomization
排除标准
- •Disease limited to the rectum (ie, within 10 cm of the anal verge)
- •Toxic megacolon
- •Crohn's Disease
- •History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC
- •Planned bowel surgery within 24 weeks from baseline
- •Stool positive for C. Difficile toxin at screening
- •History of gastrointestinal surgery within 8 weeks of baseline
- •Primary Sclerosing Cholangitis
- •Any uncontrolled or clinically significant systemic disease
- •Condition or disease that, in the opinion of the investigator would pose a risk to subject safety or interfere with study evaluation, procedures or completion.
- •Known to have tested positive for hepatitis B virus surface antigen, hepatitis C virus antibody or human immunodeficiency virus (HIV)
- •Underlying condition that predisposes subject to infections (eg, uncontrolled diabetes; history of splenectomy)
- •Known history of drug or alcohol abuse within 1 year of screening
- •Malignancy (other than resected cutaneous basal or cutaneous squamous cell carcinoma, or treated in situ cervical cancer considered cured) within 5 years of screening visit (if a malignancy occurred > 5 years ago, subject is eligible with documentation of disease free state since treatment)
- •Immunosuppressive therapy with either cyclosporine A, tacrolimus, or mycophenolate mofetil, within 1 month prior to baseline
- •Prior exposure to anti tumor necrosis factor (TNF) agents, within 2 months, or 5 times the respective elimination half life (whichever is longer) prior to baseline
- •Any prior exposure to vedolizumab, rituximab, efalizumab, natalizumab
- •Use of topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to baseline
- •Use of intravenous or intramuscular corticosteroids within 2 weeks prior to screening and during screening
- •Previously treated with AMG 181
- •Received any type of live attenuated vaccine < 1 month prior to baseline or is planning to receive any such live attenuated vaccine over the course of the study
- •Treatment of infection with intravenous (within 30 days of baseline) or oral (within 14 days prior to baseline) antibiotics, antivirals, or antifungals
- •Abnormal laboratory results at screening
- •Any other laboratory abnormality, which, in the opinion of the investigator, will prevent the subject from completing the study or will interfere with the interpretation of the study results
- •Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
研究组 & 干预措施
Placebo Q4W/Abrilumab 210 mg Q3M
Participants received placebo by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Abrilumab (Biological)
Placebo Q4W/Abrilumab 210 mg Q3M
Participants received placebo by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Placebo (Drug)
Abrilumab 7 mg Q4W/Abrilumab 210 mg Q3M
Participants received 7 mg abrilumab by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks (Q4W) thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Abrilumab (Biological)
Abrilumab 21 mg Q4W/Abrilumab 210 mg Q3M
Participants received 21 mg abrilumab by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Abrilumab (Biological)
Abrilumab 70 mg Q4W/Abrilumab 210 mg Q3M
Participants received 70 mg abrilumab by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Abrilumab (Biological)
Abrilumab 210 mg/Abrilumab 210 mg Q3M
Participants received a single dose of 210 mg abrilumab by subcutaneous injection on day 1, followed by placebo at week 2, week 4, and every 4 weeks thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Abrilumab (Biological)
Abrilumab 210 mg/Abrilumab 210 mg Q3M
Participants received a single dose of 210 mg abrilumab by subcutaneous injection on day 1, followed by placebo at week 2, week 4, and every 4 weeks thereafter until week 24.
During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Participants With Remission at Week 8
时间窗: Week 8
Remission was defined as a total Mayo Score ≤ 2 points, with no individual subscore \> 1 point. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician's global assessment) with each item graded semi-quantitatively on a score of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. The remission rate (percentage of participants with remission) was calculated based on observed data (unadjusted remission rate) and also after applying a logistic regression model including the factors of treatment group, stratification factors (prior anti-TNF use and pre- versus post-Protocol Amendment 3) and baseline total Mayo Score (adjusted remission rate).
次要结局
- Percentage of Participants With Response at Week 8(Baseline and week 8)
- Percentage of Participants With Sustained Remission at Week 8 and Week 24(Week 8 and week 24)
- Percentage of Participants With Mucosal Healing at Week 8(Week 8)