A Multicenter Randomized, Open-label Study to Compare the Efficacy of Subcutaneous Infliximab Monotherapy with Subcutaneous Infliximab and Concomitant Immunosuppression in the Treatment of Moderate to Severe Crohn's Disease
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 158
- 试验地点
- 1
- 主要终点
- Crohn's disease activity index <150 (-10 to 480) AND endoscopic response , where the higher score means worse outcome .
研究概览
简要总结
Study Design:
A Prospective Multicenter Randomized Controlled, Open-label Non-inferiority Study to Investigate the Efficacy of Subcutaneous (SC) Infliximab (IFX) with and without Immunomodulators during Induction treatment in Moderate to Severe Crohn's Disease.
Primary endpoint:
The proportion of patients in corticosteroid-free clinical remission (as defined by a Crohn's disease activity index (CDAI)<150) and endoscopic response (as defined by a simple endoscopic score for Crohn's disease (SES-CD) drop of at least 50%) at week 26.
Accrual and feasibility:
This study will enroll 158 subjects at approximately 20 sites in the Netherlands (peripheral and academic hospitals). The estimated enrollment is 0.5 patient/centre/month leading to an inclusion duration of 16 months once all centres are open. The first enrolment is anticipated in Q1 2021.
Treatment, dosage and administration:
Eligible patients will be randomized to receive SC IFX monotherapy (240mg at week 0 and week 2 and then 120mg every other week (EOW) OR SC IFX (240mg at week 0 and week 2 and then 120mg EOW) in combination with immunosuppression.
详细描述
Permitted concomitant medications:
Oral prednisone (≤40 mg per day) or budesonide (≤9 mg per day) are permitted if on stable dose 2 weeks prior to screening. After 2 weeks into treatment, systemic corticosteroids will be tapered at a rate of at least 5 mg per week and budesonide will be tapered at a rate of 3 mg every 2 weeks. If tapering fails, re-introduction of lowest effective dose of corticosteroid is allowed a single time at the discretion of the treating physician, after which tapering is required beginning 2 weeks later.
Stable doses of mesalazine (at a maximum dose of 4g/day) are permitted throughout the study.
Stable doses of antibiotics are permitted until week 12. Adverse events to antibiotics can prompt treatment discontinuation, in that case a switch is allowed during week 12.
Patients randomized to IFX combination therapy will also receive 6-mercaptopurine 1-1.5 mg/kg. If participants are already using azathioprine or thioguanine, they will receive continued dosing 2-2.5mg/kg or 20mg once daily, respectively (unless shunter status or previous adverse events suggest differently). In case of previous adverse event leading to thiopurine discontinuation methotrexate 15 mg/week sc. in combination with oral folic acid 5mg/week will be prescribed.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients 18 years or older diagnosed with Crohn's disease
- •Patients with moderate to severely active Crohn's disease with a Crohn's Disease Activity Index (CDAI) of 250 to 450 and presence of endoscopic ulceration in the terminal ileum, colon or both. Minimal SES-CD is ≥ 6 or ≥ 4 for isolated ileal disease.
- •Patients who had no response or loss of response to or have had intolerable side effects to one or more to the following: glucocorticoids, thiopurines (azathioprine/6-mercaptopurine/6-thioguanin), methotrexate , adalimumab, vedolizumab or ustekinumab OR patients in need of immediate top-down treatment with IFX at the discretion of the treating physician.
- •In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
- •The subject signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedure.
- •Male or non-pregnant, non-lactating females. No wish to become pregnant in the coming 26 weeks.
排除标准
- •Patients at imminent need of surgery as judged by the treating clinician
- •Patients with the short bowel syndrome, an ostomy or a symptomatic non-inflammatory stricture
- •Patients previously exposed to IFX (intravenous or subcutaneous)
- •Previously unacceptable side effects or intolerance to all immunosuppressants (both thiopurines and methotrexate)
- •Treatment with adalimumab or vedolizumab or ustekinumab within 30 days
- •Patients who have had a primary non-response to adalimumab or had intolerable class-related side effects (as evaluated at the discretion of the treating physician)
- •Enteric pathogens (such as Salmonella, Shigella, Yersinia, Campylobacter and C. difficile) detected by stool analysis within 2 weeks prior to enrollment or at screening
- •Ongoing participation in another interventional trial
- •Patients with Ulcerative Colitis or Inflammatory bowel disease unclassified (IBD-U)
- •Patients with ongoing abdominal or undrained perianal abscess
- •Patients with a history of colon cancer or colonic dysplasia, unless sporadic adenoma, which has been removed
- •Active or latent tuberculosis (screening according to national guidelines). Except when the latter has been treated appropriately according to national guidelines.
- •Cardiac failure in the New York heart Association (NYHA) stage III-IV
- •History of demyelinating disease
- •Recent live vaccination (≤ 4 weeks)
- •Patients with ongoing acute/chronic infection (including but not limited to HIV, hepatitis B and C) with the exception of chronic herpes labialis or cervical human papillomavirus (HPV)
- •History of cancer in the last 5 years with the exception of non-melanoma skin cancer
- •Male patients with Epstein-Barr virus (EBV) negative serology
- •A history of alcohol or illicit drug use that in the opinion of the principal investigator (PI) would interfere with study procedures
- •Patients with psychiatric problems that in the opinion of the PI would interfere with study procedures
- •Patients unable to attend all study visits
- •Patients with a history of non-compliance with clinical study protocols
- •Contraindication for endoscopy
- •Patients who received any investigational drug in the past 30 days or 5 half-lives, whichever is longer
- •Pregnancy or lactation or wish to become pregnant in the coming 26 weeks
研究组 & 干预措施
Monotherapy
Group 1: Monotherapy group
Patients randomized to IFX monotherapy start with subcutaneous IFX 240mg at week 0 and 2 and then from week 4, 120mg s.c.EOW.
干预措施: Infliximab subcutaneous (Drug)
Combination therapy
Group 2: Combination therapy group
Patients randomized to IFX combination therapy start with subcutaneous IFX 240mg at week 0 and 2 and then from week 4, 120mg s.c. EOW.
Patients randomized to IFX combination therapy also receive Immunosuppressives EOW.
干预措施: Infliximab subcutaneous (Drug)
Combination therapy
Group 2: Combination therapy group
Patients randomized to IFX combination therapy start with subcutaneous IFX 240mg at week 0 and 2 and then from week 4, 120mg s.c. EOW.
Patients randomized to IFX combination therapy also receive Immunosuppressives EOW.
干预措施: Immunosuppressive Agents (Drug)
结局指标
主要结局
Crohn's disease activity index <150 (-10 to 480) AND endoscopic response , where the higher score means worse outcome .
时间窗: at week 0 and 26
The proportion of patients in corticosteroid-free clinical remission.
次要结局
- Endoscopic remission(week 0 and 26)
- Simple Endoscopic score for Crohn's disease ≤2 ( 0-60) where a higher score means worse outcome(week 0 and 26)
- Patient reported outcome PRO-2 (stool frequency and abdominal pain) <8 (0 to na) where the higher score is the worse outcome(week 0, 2, 4, 8, 14 and 26)
- CRP ≤ 5.0 mg/L(at week 0 and 4, 8, 14 and week 26)
- Crohn's disease activity index <150 (-10 to 480) where a higher score is a worse outcome(week 0, 2, 4, 8, 14 and 26)
- Crohn's disease activity index improved with 70 points (-10 to 480) where a higher score is a worse outcome.(week 0, 2, 4, 8, 14 and 26)
- Crohn's disease activity index improved by100 points( -10 to 480) where a higher score is a worse outcome(at week 26)
- Inflammatory bowel disease questionnaire(at week 0, 2, 4, 8, 14 and week 26)
- Drug-tolerant assay(week 2, 4, 8, 14 and 26)
- Thiopurine metabolites test(At baseline, week 14 and week 26 (for patients randomized for the combination therapy group. Only at baseline for those in the monotherapy group and with previous IS use))
- IFX concentrate levels(week 2, 4, 8, 14 and 26)
- Histological analysis(week 0 and week 26)
- Fistula drainage assessment(week 0 and week 26)
- Number of adverse event reports(week 0 to week 26)
- EuroQol-5Dimension-5Level questionnaire(at week 0, 2, 4, 8, 14 and week 26)
研究者
Krisztina Gecse
Medical Docter IBD specialist
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)