An Open-Label, Multicenter, Efficacy and Safety Study to Evaluate Two Treatment Algorithms in Subjects With Moderate to Severe Crohn's Disease
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 252
- 主要终点
- Percentage of Participants With Mucosal Healing and No Deep Ulcerations
研究概览
简要总结
The primary objective of this study was to demonstrate that tight control of disease activity, using stringent criteria based on Crohn's disease activity Index (CDAI), biomarkers (high sensitivity C-reactive protein [hs-CRP] and fecal calprotectin), and corticosteroid use, improves the rate of mucosal healing 48 weeks after randomization compared with management using less stringent criteria based only on CDAI and corticosteroid use.
详细描述
The study included a 1- to 3-week screening period, up to 8 weeks of prednisone run-in treatment, a 48-week post-randomization treatment period, and a 70 day follow-up phone call or clinic visit, for a total duration of up to 69 weeks.
Participants who met entry criteria were enrolled and initiated an oral prednisone regimen at Baseline (Week 0). At the first key visit, participants were randomized into 1 of 2 groups (Tight Control group or Clinically Driven group), with stratification according to screening smoking status, weight, and disease duration.
The first key visit was the randomization visit; subsequent key visits occurred every 12 weeks following the first key visit. Randomization normally took place 9 weeks after Baseline. However, participants who fulfilled the early randomization criteria may have been randomized as early as the Baseline (Week 0) visit. Therapeutic option changes, if appropriate, occurred at key visits based on results from previous success criteria visits.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of ileal, colonic (including rectal), or ileocolonic Crohn's disease (CD) confirmed using imaging technology or endoscopy not more than 6 years prior to Baseline.
- •CDAI score of greater than or equal to 220 and less than or equal to 450 at the Baseline visit in participants not receiving prednisone or equivalent at Baseline. CDAI score of greater than or equal to 200 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone less than or equal to 20 mg or equivalent for at least 7 days before Baseline. CDAI score of greater than 150 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone higher than 20 mg or equivalent for greater than or equal to 7 days before Baseline
- •Participant or his/her legal representative have voluntarily signed and dated an informed consent approved by and compliant with the requirements of this study protocol which has been approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
- •Adequate cardiac, renal and hepatic function as determined by the Principal Investigator and demonstrated by Screening laboratory evaluations, questionnaires and physical examination results that do not indicate an abnormal clinical condition which would place the participant at undue risk and thus preclude participation in the study.
- •Participant must be able to self-inject and orally administer study medication or have a designee or Healthcare Professional who can assist
排除标准
- •Previous or current biologic use for Crohn's disease or participation in a biologic study
- •Previous or current use of immunomodulators (e.g., methotrexate, azathioprine, 6-mercaptopurine, JAK inhibitor, alpha-integrin) for Crohn's disease or participation in a Crohn's disease study with immunomodulator(s). Current use of immunomodulators for non-Crohn's disease at Baseline.
- •Greater than two previous courses of corticosteroid (systemic corticosteroid) or budesonide) for Crohn's Disease. A course is defined as 1) total duration for burst and taper ≥ 4 weeks and 2) prednisone or equivalent ≥ 40 mg (or budesonide ≥ 9 mg) for at least 2 weeks.
- •Participants with a poorly controlled medical condition such as: uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, moderate to severe congestive heart failure (New York Heart Association [NYHA] class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the Investigator or the sponsor, would put the participant at risk by participation in the protocol
- •Participants with positive C. difficile stool assay at Screening.
研究组 & 干预措施
Tight Control Management
Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.
Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week.
干预措施: Adalimumab (Biological)
Tight Control Management
Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.
Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week.
干预措施: Prednisone (Drug)
Tight Control Management
Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.
Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week.
干预措施: Azathioprine (Drug)
Clinically Driven Management
Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine.
Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.
Therapy was escalated according to pre-specified failure criteria using less stringent criteria:
At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week.
干预措施: Adalimumab (Biological)
Clinically Driven Management
Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine.
Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.
Therapy was escalated according to pre-specified failure criteria using less stringent criteria:
At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week.
干预措施: Prednisone (Drug)
Clinically Driven Management
Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use.
Participants received customized therapy that could include prednisone, adalimumab, and azathioprine.
Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.
Therapy was escalated according to pre-specified failure criteria using less stringent criteria:
At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week.
干预措施: Azathioprine (Drug)
结局指标
主要结局
Percentage of Participants With Mucosal Healing and No Deep Ulcerations
时间窗: 48 weeks after Randomization
Percentage of participants with mucosal healing (defined as Crohn's disease endoscopy Index of severity \[CDEIS\] \< 4) and no deep ulcerations on ileocolonoscopy (defined as the absence of all deep ulcerations in all segments explored in CDEIS) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after Randomization were counted as non-responders.
次要结局
- Percentage of Participants in Deep Remission 48 Weeks After Randomization(48 weeks after Randomization)
- Percentage of Participants in Biologic Remission 48 Weeks After Randomization(48 weeks after Randomization)
- Percentage of Participants With Mucosal Healing 48 Weeks After Randomization(48 weeks after Randomization)
- Percentage of Participants With Endoscopic Response 48 Weeks After Randomization(48 weeks after Randomization)
- Change From Baseline in CDEIS at 48 Weeks After Randomization(Baseline and 48 weeks after Randomization)
- Change From Baseline in CDAI Over Time(Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.)
- Time to Crohn's Disease Flare(From Randomization to 48 weeks after Randomization)
- Time to Clinical Remission(From Randomization through 48 weeks after Randomization)
- Time to All-cause Hospitalization(From Randomization through 48 weeks after Randomization)
- Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication(From Randomization through 48 weeks after Randomization)
- Number of Major Crohn's Disease-related Surgeries After Randomization(From Randomization through 48 weeks after Randomization)
- Number of Crohn's Disease-related Hospitalizations After Randomization(From Randomization through 48 weeks after Randomization)
- Number of All-cause Hospitalizations After Randomization(From Randomization through 48 weeks after Randomization)
- Total Length of Stay in Hospital for All-cause Hospitalizations(From Randomization through 48 weeks after Randomization)
- Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations(From Randomization through 48 weeks after Randomization)
- Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization(48 weeks after Randomization)
- Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization(48 weeks after Randomization)
- Percentage of Participants in Steroid-free Remission Over Time(11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.)
- Time to Steroid-free Remission(From Randomization through 48 weeks after Randomization)
- Percentage of Participants in Clinical Remission Over Time(Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.)
- Number of Crohn's Disease-related Surgical Procedures After Randomization(From Randomization through 48 weeks after Randomization)
- Number of Crohn's Disease-related Hospitalizations Due to Emergency(From Randomization through 48 weeks after Randomization)
- Change in Crohn's Disease Behavior According to Montreal Classification(From Baseline to 48 weeks after Randomization)
- Change From Baseline in High Sensitivity C-Reactive Protein (Hs-CRP) Over Time(Baseline and 8 weeks during the prednisone run-in, and 11, 23, 35, and 48 weeks after Randomization.)
- Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization(Baseline and 48 weeks after Randomization)
- Total Dose of Prednisone(From Baseline through 48 weeks after Randomization)
- Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score(Baseline and 48 weeks after Randomization)
- Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD)(Baseline and 48 weeks after Randomization)
- Time to Crohn's Disease-related Hospitalization Due to Emergency(From Randomization through 48 weeks after Randomization)
- Change From Baseline in Patient Health Questionnaire - 9 (PHQ9)(Baseline and 48 weeks after Randomization)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score(Baseline and 48 weeks after Randomization)
- Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores(Baseline and 48 weeks after Randomization)