A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Conventional and/or Biologic Therapies
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 526
- 试验地点
- 432
- 主要终点
- Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12
研究概览
简要总结
The objective of this study is to evaluate the efficacy and safety of upadacitinib compared to placebo as induction therapy in adults with moderately and severely active Crohn's disease (CD).
详细描述
This study includes two parts:
- Part 1: a randomized double-blind placebo-controlled induction period and
- Part 2: an extended treatment period for non-responders from Part 1.
In Part 1, participants will be randomized in a 2:1 ratio to upadacitinib 45 mg once daily (QD) or matching placebo for 12 weeks. The randomization will be stratified by baseline corticosteroid use (yes or no), endoscopic disease severity (Simplified Endoscopic Score for Crohn's disease [SES-CD] < 15 and ≥ 15), and number of prior biologics with prior inadequate response or intolerance (0, 1, > 1).
Participants who do not achieve clinical response at Week 12 will be able to enroll in Part 2 to receive a double-blind extended treatment with upadacitinib until Week 24. Clinical response is defined as a ≥ 30% decrease in average daily very soft or liquid stool frequency (SF) and/or ≥ 30% decrease in average daily abdominal pain (AP) score (both not worse than Baseline).
Participants who achieve clinical response at Week 12 may be eligible to enter the 52-week, double-blind, maintenance portion of Study M14-430 (NCT03345823).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of CD for at least 3 months prior to Baseline.
- •Confirmed diagnosis of moderate to severe CD as assessed by stool frequency (SF), abdominal pain (AP) score.
- •Evidence of mucosal inflammation based on the Simplified Endoscopic Score for Crohn's disease (SES-CD) on an endoscopy confirmed by a central reader.
- •Demonstrated an inadequate response or intolerance to one or more conventional and/or biologic therapies (oral locally acting steroids, intravenous or oral corticosteroids, immunosuppressants or biologic therapies for CD), in the opinion of the investigator.
- •Note: Participants who have had inadequate response or intolerance to conventional therapy who have received prior biologic may be enrolled; however, participants must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease).
- •If female, participant must meet the contraception recommendations.
排除标准
- •Participant with a current diagnosis of ulcerative colitis or indeterminate colitis.
- •Participant not on stable doses of CD related antibiotics, oral aminosalicylates, corticosteroids or methotrexate (MTX).
- •Participant with the following ongoing known complications of CD: abscess (abdominal or peri-anal), symptomatic bowel strictures, fulminant colitis, toxic megacolon, > 2 entire missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum, or any other manifestation that might require surgery while enrolled in the study.
- •Participant with ostomy or ileoanal pouch.
- •Participant diagnosed with conditions that could interfere with drug absorption including but not limited to short gut or short bowel syndrome.
- •Screening laboratory and other analyses show abnormal results.
研究组 & 干预措施
Placebo
Participants will receive placebo once daily for 12 weeks in Part 1. Clinical non-responders will receive 45 mg upadacitinib once daily for 12 weeks in Part 2.
干预措施: Upadacitinib (Drug)
Placebo
Participants will receive placebo once daily for 12 weeks in Part 1. Clinical non-responders will receive 45 mg upadacitinib once daily for 12 weeks in Part 2.
干预措施: Placebo for Upadacitinib (Drug)
Upadacitinib
Participants will receive 45 mg upadacitinib once daily for 12 weeks in Part 1. Clinical non-responders will receive 30 mg upadacitinib once daily for 12 weeks in Part 2.
干预措施: Upadacitinib (Drug)
结局指标
主要结局
Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12
时间窗: Week 12
The co-primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission defined based on two patient reported outcomes, average daily stool frequency (SF) and average daily abdominal pain score (APS). Clinical remission per PROs was defined as average daily very soft or liquid SF ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and the number of very soft or liquid SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily very soft or liquid SF and APS were calculated using the 4-7 most recent useable days of patient-report outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 12 visit.
Percentage of Participants With Clinical Remission Per Crohn's Disease Activity Index (CDAI) at Week 12
时间窗: Week 12
The co-primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was clinical remission based on CDAI at Week 12. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. These items are scored individually, weighted, and do not contribute equally to the overall score. The CDAI is derived from summing up the weighted individual scores of eight items. CDAI approximately ranges from 0 to 600 with higher scores indicating more severe disease. Clinical remission is defined as a CDAI score less than 150.
Percentage of Participants With Endoscopic Response at Week 12
时间窗: Baseline and Week 12
Endoscopic response at Week 12 was a co-primary endpoint for both the US/FDA and EU/EMA regulatory purposes. Endoscopic response was defined as greater than 50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) from Baseline of the induction study (or for participants with an SES-CD of 4 at Baseline, at least a 2-point reduction from Baseline), as scored by independent external and blinded central readers. The SES-CD evaluates 4 endoscopic variables (ulcer size, ulcerated surface, affected surface, and narrowing, each on a scale from 0 (none) to 3 in 5 segments assessed during ileocolonoscopy (ileum, right colon, transverse colon, sigmoid and left colon, and rectum). The total score is the sum of the 4 endoscopic variable scores and ranges from 0 to 56, where higher scores indicate more severe disease.
次要结局
- Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 12(Baseline and Week 12)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 12(Baseline and Week 12)
- Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 2(Baseline and Week 2)
- Percentage of Participants With Endoscopic Remission at Week 12(Baseline and Week 12)
- Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per CDAI at Week 12(Week 12)
- Percentage of Participants With Resolution of Extra-Intestinal Manifestation (EIMs) at Week 12(Week 12)
- Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 12(Baseline and Week 12)
- Percentage of Participants With Clinical Remission Per CDAI at Week 4(Week 4)
- Percentage of Participants With Hospitalizations Due to Crohn's Disease (CD) During the 12-Week Induction Period(12 weeks)
- Percentage of Participants With Clinical Remission Per PROs at Week 4(Week 4)
- Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per PROs at Week 12(Week 12)