Randomized Trial to Study the Effect of Rifaximin on Gut Microbiome Diversity post Allogeneic Stem Cell Transplant in Acute Leukemia.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 166
- 试验地点
- 1
- 主要终点
- To determine the impact of rifaximin on gut microbial alpha
研究概览
简要总结
The gut microbiome plays a significant role in modulating the immune re-constitution post allogeneic stem cell
transplant (ASCT). Low gut microbial diversity has been consistently associated with poor outcomes of
transplant including increased incidence of acute graft versus host disease (aGVHD), post-transplant bacterial
sepsis and non-relapse mortality (NRM). However, the exact mechanism by which gut microbiome influences
local as well as systemic immunity is not completely known, and is thought to be due to the impact of microbial
metabolites on intestinal epithelial cells and host antigen-presenting cells. Understanding these mechanisms
and modulating the microbiome may be crucial to improving transplant outcomes. Rifaximin is a locally acting
antibiotic that has been approved for manipulating the gut microbiome in hepatic failure. It is unique because of
its ability to clear pathogenic bacteria, while preserving the anaerobic commensals. It can potentially modify the
gut microbiome to increase the alpha diversity and this may help reduce aGVHD, infectious complications, and
mortality post-transplant. High incidence of multidrug resistant sepsis and frequent use of broad spectrum
antibiotics in India, would result in higher rates of dysbiotic gut- making microbiome manipulation to improve
transplant outcomes more relevant in our country.
We are proposing a randomized controlled trial to understand the benefits of modulating the gut microbiome in
patients of ASCT while investigating the local and global immune repertoire using single cell sequencing and
multicolour flow cytometry.
Study design: Single center, open-labeled, phase II study, randomized controlled trial.
Primary Objective: To determine the impact of rifaximin on gut microbial alpha diversity and compare it with
controls.
Secondary Objectives: To determine impact of rifaximin on 1 year non relapse mortality post-transplant,
incidence of grade III/IV aGVHD, incidence of MDR sepsis, patterns of immune cell reconstitution, and cytokine
profile post-transplant.
Exploratory objective: To use single-cell transcriptomics (SCT) to identify immune cell profiles in
gut biopsies post ASCT in order to get insights into the impact of the microbiome on local gut immunity.
Study population: Adult patients who undergo ASCT at the Tata Memorial Centre.
Study Methodology in brief:
Patients would be randomized to receive either oral tablet rifaximin 200 mg twice daily along with standard posttransplant
treatment or to receive standard of care treatment alone. Stool samples and blood samples will be
collected at different time points for microbiome analysis and immune cell profiling respectively.
We plan to perform 16s rRNA-based next-generation sequencing of all variable regions using a phased primer
approach using stool DNA as a template. Gut microbiome diversity will be calculated using the inverse Simpson
index. Immune cell profile would be analyzed using 16 color flow cytometry. In selected
cases where patients undergo colonoscopic gut biopsy, we will also obtain samples for transcriptome
sequencing. This will help us understand how immune cells interact with gut mucosa and microbiome in patients
of aGVHD
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 70.00 Year(s)（—）
- 性别
- All
入选标准
- •a.Patients with acute leukemia and planned for aHSCT.
- •b.Patients with age more than 18 years (> 18 years).
- •c.Patients who give written informed consent.
- •d.Underlying hematologic malignancy in which aHSCT is indicated.
- •e.ECOG performance status 0, 1 or 2 (on day of enrolment).
- •f.Adequate Liver function test with serum SGOT/AST and SGPT/ALT < 3.0 times upper normal limit (ULN) and total bilirubin < 2.0 times ULN (on day of enrolment).
排除标准
- •a.Known hypersensitivity to rifaximin or other rifampicin antimicrobial agents b.Patients on therapy with antibiotics for bacterial or fungal infections on day of enrolment (Except for azole prophylaxis for fungal infections, acyclovir prophylaxis for herpes and cotrimoxazole prophylaxis for pneumocystis jerovecii infections, which are permissible).
- •c.Patients with current or past history of inflammatory bowel disease d.Patients with history of major bowel resection or patients with colostomy.
- •e.Use of rifampicin or rifaximin in last 1 month before enrolment.
- •f.Any serious medical condition or psychiatric illness that would prevent the subject from signing the informed consent form or in opinion of the investigator make the patient unfit for enrolment in the trial.
- •g.Patients on the following P-glycoprotein inhibitors at time of enrolment: Verapamil, ketoconazole and itraconazole will be excluded from the study.
结局指标
主要结局
To determine the impact of rifaximin on gut microbial alpha
时间窗: 15 days post transplant
diversity as measured by inverse simpson index (ISI) and compare it with controls.
时间窗: 15 days post transplant
次要结局
- To determine non relpase mortality (NRM) at 1 year post transplant in patients who receive peritransplant(transplant rifaximin and compare it with controls.)
- To use single cell transcriptomics (SCT) to identify immune cell(profile in gut biopsies post allogeneic stem cell transplant in order to get insights into)
- To determine the impact of rifaximin induced gut manipulation on immune(reconstitution, T cell repertoire post transplant and cytokine profile.)
- To compare the incidence of severe (grade III/IV) acute graft versus host disease (aGVHD) in patients who receive(peri-transplant rifaximin with that in control arm.)
- To determine impact of gut decontamination with rifaximin on incidence of(multidrug resistant (MDR) sepsis and usage of higher antibiotics (e.g. Carbapenems, colistin,)