An Open Label Interventional Phase 4 Study to Evaluate Efficacy, Safety and Mucosal Healing of Early Versus Late Use of Vedolizumab in Crohn's Disease: the LOVE-CD Study (LOw Countries VEdolizumab in CD Study)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 260
- 试验地点
- 23
- 主要终点
- The proportion of patients with clinical and endoscopic remission at Week 26
研究概览
简要总结
This multi-centre open label study will involve a minimum of 260 patients in 2 cohorts: 86 patients with 'early CD' defined as disease duration < 24 months and no other treatments than corticosteroids and/or thiopurines and 174 patients with 'late CD' defined as active disease despite treatment with immunosuppressives and anti-TNF. Patients with intolerance to IS and anti-TNF will also be allowed in the latter group. Participants will be treated with 12 months of open label vedolizumab (study medication followed by commercial medication once reimbursement is available) and undergo monitoring of endoscopic, histological and clinical disease parameters. No randomization or blinding will be performed but the study management will ensure that recruitment in either study group is comparable for number and profile of patients (on/off steroids).
详细描述
Crohn's disease (CD) is a chronic inflammatory disease of the small bowel and colon. Symptoms commonly include bloody diarrhea, abdominal pain, weight loss, and fever. There is no known cause or cure for CD. The aim of current CD treatments is to induce and maintain remission, to reduce the need of corticosteroids and avoid resections and fistulas.
Treatment options include systemic and/or topical corticosteroids, purine analogues (6-mercaptopurine and azathioprine), anti-TNF antibodies and surgery. In 2013, results from the GEMINI II, phase 3, randomized controlled trial demonstrated the efficacy of vedolizumab (VDZ) in inducing and maintaining remission in adult patients with active CD.
VDZ (MLN0002, or MLN02), inhibits the interaction between α4β7 integrin on memory T and B cells and mucosal addressin cell adhesion molecule-1 expressed on the vascular endothelium of the gut and has been shown to be effective in both inducing and maintaining clinical remission in ulcerative colitis. The ideal positioning of vedolizumab in the therapeutic armamentarium for CD remains unknown. With other (anti-TNF) biologics, outcomes have usually been better if the treatment was started earlier in the disease course and if the patients had not been exposed to prior antibody treatments. Therefore, it appears appropriate and desirable to test the potency of vedolizumab in an earlier phase of CD.
Indeed, also with vedolizumab patients previously exposed to biologics appear to have lower success rates with vedolizumab, so a position earlier in the disease course would most likely lead to better outcomes.
This is an investigator-initiated open label study of VDZ therapy in 2 distinct populations of CD patients with active disease: 1. patients who have been diagnosed < 2 years ago and who only been exposed to aminosalicylates and corticosteroids and 2. patients who have been exposed to immunomodulators and/or anti-TNF agents in addition to steroids and aminosalicylates.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •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 procedures.
- •Age 18 to 80
- •Male or non-pregnant, non-lactating females. Females of child bearing potential must have a negative serum pregnancy test prior to randomization, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the source records (i.e., tubal ligation, hysterectomy, or post-menopausal [defined as a minimum of one year since the last menstrual period]).
- •Established diagnosis of ileal, ileocolonic or colonic Crohn's disease with histopathological confirmation available in the record of the patient.
- •Moderately to severely active CD (CDAI 220-450) with objective evidence of ulcerations visualized on endoscopy.
- •Anti-TNF discontinued for at least 4 weeks prior to baseline.
- •GROUP 1 (EARLY CD):
- •Diagnosis of CD < 24 months prior to enrollment
- •Demonstrated failure to respond to topical or systemic corticosteroids or intolerance to corticosteroids or: need for > 2 courses of steroids since diagnosis or: steroid dependency at any dose since diagnosis and additionally, but not mandatory, lack of efficacy of thiopurines or intolerance to thiopurines (any duration). Patients who are using thiopurines at screening must have used them for > 3 months (last 4 weeks at stable dose).
- •GROUP 2 (LATE CD)
- •Demonstrated failure to respond to at least 3 months of thiopurines or intolerance to thiopurines and: failure to respond to at least 1 anti-TNF or intolerance to anti-TNF or loss of response to at least 1 anti-TNF.
排除标准
- •Previous exposure to any anti-integrin antibodies including- vedolizumab ; α4β7 anti-bodies ; β7 antibodies ; anti- MADCAM-1
- •Contraindication for endoscopy.
- •History of colonic dysplasia/cancer
- •Presence of stoma
- •Received other biologics within the last 4 weeks of baseline
- •Use of 5-aminosalicylic acid (5-ASA) or corticosteroid enemas/suppositories within 2 weeks of enrollment
- •Chronic hepatitis B or C infection
- •Evidence of or treatment for C. difficile infection or other intestinal pathogen at screening within 4 weeks prior to enrollment
- •Active or latent tuberculosis
- •Conditions which in the opinion of the investigator may interfere with the subject's ability to comply with the study procedures.
- •Received any investigational drug in the past 30 days or 5 half-lives, whichever is longer.
- •Positive progressive multifocal leukoencephalopathy ( PML) subjective symptom checklist before enrollment.
- •Subjects with known allergy or hyposensitivity to vedolizumab or its components
研究组 & 干预措施
Early Crohn's disease
VEDOLIZUMAB 300 mg at week 0,2,6, (10), 14, 22, 30,(34), 38, (42), 46, (50)
week 10 = only required for subjects not responding week 34, 42 and 50- only required for subjects who have no endoscopic improvement at week 26
干预措施: vedolizumab (Drug)
Late Crohn's disease
VEDOLIZUMAB 300 mg at week 0,2,6, (10), 14, 22, 30,(34), 38, (42), 46, (50)
week 10 = only required for subjects not responding week 34, 42 and 50- only required for subjects who have no endoscopic improvement at week 26
干预措施: vedolizumab (Drug)
结局指标
主要结局
The proportion of patients with clinical and endoscopic remission at Week 26
时间窗: week 26
Crohns disease activity index (CDAI) of 150 or lower and Simple endoscopic score for Crohn's disease (SES-CD) \< 4.
次要结局
- Quality of life measured by Euroqol (EQ-5D)(Screening, week 10, week 26 and week 52)
- Proportion of patients with no granulocytes in the biopsies at Weeks 26 and 52.(Week 26 and week 52)
- Proportion of patients with 25%, 50% and 75% reduction in the Geboes histology score at Weeks 26 and 52(Week 26 and week 52)
- Proportion of patients with sustained clinical response (response at all time points after week 10)(After week 10)
- Proportion of patients with sustained clinical remission(After week 10)
- Proportion of patients that need to be hospitalized(52 weeks)
- Quality of life measured by Inflammatory Bowel Disease Questionnaire ( IBDQ)(Screening, week 10, week 26 and week 52)
- Proportion of patients with 25% and 75% reduction of SES-CD at Weeks 26 and 52(26 and 52 weeks)
- Proportion of patients with clinical response(52 weeks)
- Proportion of patients with clinical remission(52 weeks)
- Proportion of patients with endoscopic response at Weeks 26 and 52(26 and 52 weeks)
- Proportion of patients with corticosteroid- free clinical remission(52 weeks)
- Proportion of patients with normalized serum C-reactive protein (CRP) at all time points(52 weeks)
- Proportion of patients with draining fistulas(52 weeks)
- Work productivity Index(Screening, week 10, week 26 and week 52)
- Serum concentrations of vedolizumab and antibodies to vedolizumab before every infusion(52 weeks)
研究者
Geert D'Haens
Coordinating Investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)