Personalized AZithromycin/metronidAZole, in Combination With Standard Induction Therapy, to Achieve a Fecal Microbiome Community Structure and Metagenome Changes Associated With Sustained Remission in Pediatric Crohn's Disease (CD): a Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 5
- 主要终点
- Number of Participants With Sustained Remission
研究概览
简要总结
This is a multi-center, randomized, controlled open-label add-on design trial pilot study to evaluate the efficacy of personalized adjunctive antibiotic (azithromycin + metronidazole) therapy in pediatric subjects with mild to moderate Crohn's disease (CD) who have a microbiome profile associated with increased risk of early relapse. This an add-on design trial for subjects already receiving standard of care therapy to induce remission; there will be no placebos.
详细描述
The study hypothesis is that adjunctive antibiotic therapy will improve clinical response to standard of care (SOC) induction therapy in a subgroup of CD patients with a relapse-associated microbiome profile.
Prior to starting SOC induction therapy at week 0, subjects will provide a baseline stool sample that will be screened for microbiome profiles associated with risk of relapse according to an established statistical model.
At week 4, subjects with a relapse-associated microbiome will be randomized into either a control arm that will continue to receive SOC induction therapy for an additional 8 weeks, or a treatment arm that will receive adjunctive antibiotic therapy in addition to continuing to receive SOC induction therapy for an additional 8 weeks. Subjects who do not have a relapse-associated microbiome will enter a separate control arm that will continue to receive SOC induction therapy and will have data collected for exploratory objectives. Subjects who are not in clinical remission by week 4 will receive antibiotic therapy regardless of microbiome signature at baseline. Subjects will be monitored for an additional 40 weeks after the treatment period (52 weeks total).
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
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of signed and dated informed consent form (and assent form, as applicable);
- •Stated willingness to comply with all study procedures and availability for the duration of the study;
- •Male or female, aged 3 to 17 years;
- •Diagnosed with CD according to standard clinical and histological criteria, within 36 months of week 0;
- •Exhibiting mild to moderate symptoms of active disease, as determined by a Pediatric Crohn's Disease Activity Index (PCDAI) score >10 (or > 7.5 excluding the height item) and ≤37.5;
- •Fecal calprotectin level >=250 µg/g within 30 days prior to week 0 visit based on local measurement, if available, or to be arranged with lead site if an endoscopy is not performed within 30 days prior to week 0 visit.
排除标准
- •Current or previous use of biologic therapy;
- •Presence of stricturing, penetrating (intestinal or perianal) and/or fistulizing CD;
- •Pregnancy or lactation;
- •Have undergone intestinal resection;
- •Positive Clostridium Difficile toxin;
- •Treatment with another investigational drug or other intervention within 30 days before week 0;
- •Risk factors for arrhythmia including history of prolonged corrected QT interval (QTc), hypokalemia or hypomagnesemia, resting bradycardia, or concurrent treatment with other drugs with potential for QT prolongation;
- •History of cockayne syndrome;
- •Prior diagnosis of any hematologic condition/blood dyscrasia which may result in leukopenia (even if leukocyte count is normal at screening);
- •Known allergy or intolerance to azithromycin or metronidazole;
- •Subjects who received intravenous anti-infective within 35 days prior to week 0 visit or anti-infectives within 14 days prior to the week 0 visit;
- •Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued within, at least 14 days prior to week 0;
- •Subject on cyclosporine, tacrolimus or mycophenolate mofetil. Stable doses (no change within 14 days prior to week 0) of azathioprine, 6-mercaptopurine or methotrexate (MTX) are not a reason for exclusion;
- •Subject who received fecal microbial transplantation within 35 days prior to week 0 visit;
- •Screening laboratory and other analyses show any of the following abnormal results:
- •aspartate transaminase (AST), alanine transaminase (ALT) > 2 X upper limit of the reference range,
- •White blood cell (WBC) count < 3.0 X 109/L,
- •Total bilirubin >= 20 micromol/liter (1.17 mg/dL); except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome,
- •Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula of < 30 mL/min/1.73 m²,
- •Hemoglobin < 80 gram/liter,
- •Platelets < 100,000/µL.
研究组 & 干预措施
Standard of Care
SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.
干预措施: Standard of Care (Other)
Standard of Care + Antibiotics
SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.
Azithromycin (weeks 4-12)
Metronidazole (weeks 4-12)
干预措施: Azithromycin (Drug)
Standard of Care + Antibiotics
SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.
Azithromycin (weeks 4-12)
Metronidazole (weeks 4-12)
干预措施: Metronidazole (Drug)
Standard of Care + Antibiotics
SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.
Azithromycin (weeks 4-12)
Metronidazole (weeks 4-12)
干预措施: Standard of Care (Other)
结局指标
主要结局
Number of Participants With Sustained Remission
时间窗: Week 52
Participants stratified based on carriage of an at-risk microbiome without need for re-induction for clinical flare (new course of nutritional therapy, need to restart steroids), steroid dependence, biologic (e.g. anti-TNF) use, and/or intestinal surgery.
Feasibility of Multinational Microbiome-randomized Trial
时间窗: Week 4/5
The number of participants with microbiome data available at Week 4/5.
次要结局
- Number of Participants With Normal Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 52(Week 52)
- Number of Participants With Normal Fecal Calprotectin Levels in Stool at Week 52(Week 52)
- Number of Participants With Normal C-Reactive Protein (CRP) Levels in Blood at Week 52(Week 52)
- IMPACT-III Score at Week 52(Week 52)