A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 in Subjects With Moderate to Severe Crohn's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 254
- 试验地点
- 2
- 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 efficacy of abrilumab as measured by the proportion of participants achieving Crohn's Disease Activity Index (CDAI) remission (CDAI < 150) after treatment for 8 weeks.
详细描述
The study consisted of a 24-week double-blind treatment period, a 108-week open-label treatment period, and a 2-year safety follow-up period.
Participants who did not reach minimal improvement, or experienced disease worsening after initial response, had the option to receive open-label abrilumab 210 mg every 3 months (Q3M) beginning at double-blind period week 12 or after. Not reaching minimal improvement was defined as not having an improvement in CDAI score of ≥ 70 points from baseline on 2 consecutive visits (at or after week 8) at least 2 weeks apart. Disease worsening after week 8 (or week 12) response was defined as having an increase in CDAI score of ≥ 70 points from the week 8 (or week 12) CDAI score on 2 consecutive visits at least 2 weeks apart, and a CDAI score of > 150.
Participants were planned to be randomized in a 2:1:2:1 ratio to SC placebo or abrilumab at 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 3:2:1. 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
- •Diagnosed with ileal, ileo-colonic, or colonic Crohn's disease for a minimum of 6 months prior to baseline
- •Moderately to severely active Crohn's disease defined by a CDAI score ≥ 220 and ≤ 450 at baseline
- •Evidence of active inflammation within 12 weeks prior to baseline
- •Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following agents: Immunomodulators and/or anti-tumor necrosis factor (TNF) agents or to 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
- •Subject has no known history of active tuberculosis and has a negative test for tuberculosis during screening
排除标准
- •Short bowel syndrome
- •Stricture with obstructive symptoms within 3 months
- •Bowel surgery within 12 weeks prior baseline, or has planned bowel surgery within 24 weeks from baseline
- •Ileostomy and/or colostomy
- •Any gastric or intestinal pouch
- •Evidence of an infected abscess
- •Bowel perforation or evidence of non-inflammatory obstruction during the 6 months prior to baseline
- •Stool positive for C. difficile toxin at screening
- •Any uncontrolled or clinically significant systemic disease
- •Known to have tested positive for hepatitis B virus surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV)
- •Any underlying condition that predisposes subject to infections
- •Subject has malignancy (other than resected cutaneous basal or cutaneous squamous cell carcinoma, or treated in situ cervical cancer considered cured) within 5 years of baseline
- •Received an anti-TNF agent, cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, tacrolimus, topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids, intravenous or intramuscular corticosteroids within protocol-specified time periods.
- •Any prior exposure to antagonists of integrins or integrin ligands (eg, natalizumab, efalizumab, or vedolizumab), rituximab, or TNF kinoid immunotherapies, AMG 181, or any form of cell-based transplantation
- •Received treatment of infection with intravenous (within 30 days of baseline) or oral (within 14 days prior to baseline) antibiotics, antivirals, or antifungals
- •Significant laboratory abnormalities
- •Pregnant or breast feeding
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 (Drug)
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 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 (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 (Drug)
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 (Drug)
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 (Drug)
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 Crohn's Disease Activity Index (CDAI) score \< 150 at week 8. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI Score (adjusted remission rate).
次要结局
- Percentage of Participants With Response at Week 12(Baseline and week 12)
- Percentage of Participants With Response at Week 8(Baseline and week 8)
- Percentage of Participants With Remission at Week 12(Week 12)
- Percentage of Participants With Sustained Remission at Both Week 12 and Week 24(Week 12 and week 24)
- Percentage of Participants With Sustained Remission at Both Week 8 and Week 24(Week 8 and week 24)
- Change From Baseline in CDAI Score at Week 12(Baseline and week 12)
- Change From Baseline in CDAI Score at Week 8(Baseline and week 8)