Pre-treatment With Azithromycin to Reduce Immunogenicity to Anti-Tumor Necrosis Factor-α Agents in Patients With Crohn's Disease
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 180
- 试验地点
- 9
- 主要终点
- Anti-drug antibody development
研究概览
简要总结
This is a randomized placebo-controlled trial in Crohn's disease patients before initiation of anti-tumor necrosis factor-α (anti-TNF) therapy that aims to test the effect of a pre-treatment short course of azithromycin therapy on immunogenicity
详细描述
Anti-TNF agents are considered the mainstay of therapy for patients with inflammatory bowel diseases (IBD). Still, its efficacy is hampered by the development of anti-drug antibodies (ADA), which lead to non-responsiveness to this medication. A combination with immunosuppressive agents is currently utilized to reduce ADA development but is accompanied by an increased risk of side effects (i.e. malignancy and infections). The investigators have recently found an epidemiologic link between prior antibiotic use and the development of ADA, and shown an antibiotic-specific effect on ADA development in a mouse model. Macrolide antibiotics were specifically associated with ADA prevention and led to increased durability of the treatment. Since the microbiome has been associated with the response to anti-TNF therapy, the investigators hypothesize that microbial manipulation with azithromycin prior to the initiation of anti-TNF therapy will lower ADA development. the investigators propose a randomized controlled study to test our hypothesis and compare it to matched historical cohorts with available clinical and serological data. The primary outcome will be ADA development at 1 year of therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind masking
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability to provide written informed consent prior to any study procedures and willing and able to attend all study visits, comply with the study procedures, read and write in order to complete questionnaires, and be able to complete the study period.
- •Aged 18 to 80 years of age, inclusive, at the time of signing the informed consent.
- •Diagnosis of CD with an onset of symptoms for a minimum of 3 months prior to Screening as determined by the investigator based on clinical history, exclusion of infectious causes, and characteristic endoscopic and histologic findings.
- •Prior decision of starting infliximab or adalimumab therapy (including biosimilar drugs).
- •Thiopurine and corticosteroid co-therapy will be permitted.
排除标准
- •Inclusion in another interventional study
- •Patients who cannot provide informed consent and do not have a legal guardian
- •Patients with perianal involvement who are expected to require antibiotic therapy for their disease
- •Patients on chronic antibiotic therapy due to any cause
- •Patients with ongoing fluid collection/abscess either internal or perianal
- •Known history of allergy to the study intervention formulation or any of its excipients or components of the delivery device
- •Prolonged QTc interval or conditions leading to additional risk for QT prolongation
- •Chronic kidney disease stage 5 (GFR < 10)
- •Crohn's Disease complication requiring surgical treatment
- •Planned/ongoing methotrexate co-therapy
- •Fecal microbiota transplantation within 8 weeks prior to randomization
- •Participant has any disorder that, in the opinion of the investigator, may compromise the ability to participate in the study
- •Pregnancy
- •Patients who received azithromycin therapy in the previous year (we will not exclude prior use of other antibiotic therapy)
- •Patients who received any antibiotic treatment within 4 weeks prior to randomization
- •Re-induction of the same anti-TNF medication
- •Patients who are on chronic therapy which cannot be withheld in one of these medications: colchicine, phenytoin, and digoxin
研究组 & 干预措施
Azithromycin
5-day consecutive treatment with oral azithromycin 500 mg once daily
干预措施: Azithromycin Pill (Drug)
Control
5-day consecutive oral placebo once daily
干预措施: Placebo (Other)
结局指标
主要结局
Anti-drug antibody development
时间窗: 1 year after the initiation of therapy
Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay
次要结局
- Sustained corticosteroid-free clinical remission(At both 3 months and a 1 year after the initiation of therapy)
- Clinical response(1 year after the initiation of therapy)
- Sustained corticosteroid-free biochemical remission(at both 6 months and a 1 year after the initiation of therapy)
- Anti-TNF drug levels(At 6 weeks, 26 weeks and a 1 year after the initiation of therapy)
- Early anti-drug antibody development(At 6 weeks, 26 weeks and a 1 year after the initiation of therapy)
- Treatment durability(at both 6 months and a 1 year after the initiation of therapy)
- Sustained corticosteroid-free PRO-2 clinical remission(At both 14 and a 1 year after the initiation of therapy)
- Addition of immunomodulator treatment(At any time during the study)
- Immunomodulator treatment termination(At 14 weeks and not restarting by 1 year after the initiation of therapy)
- Endoscopic remission(At 26 and 52 weeks)
- Endoscopic improvement(At 26 weeks)
- PRO-2 remission at Week 52(1 year after the initiation of therapy)
研究者
Haggai Bar-Yoseph MD
Principal investigator
Rambam Health Care Campus