Effect of Rifaximin on gut bacterial flora post Stem Cell Transplant in patients with Acute Leukemia.

Phase 2

Recruiting

Conditions: Malignant neoplasms of lymphoid, hematopoietic and related tissue,

Registration Number: CTRI/2023/07/054803

Lead Sponsor: Lady Tata Memorial Trust

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: Open to Recruitment

Sex: All

Target Recruitment: 166

Inclusion Criteria

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).

Exclusion Criteria

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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To determine the impact of rifaximin on gut microbial alpha	15 days post transplant
diversity as measured by inverse simpson index (ISI) and compare it with controls.	15 days post transplant

Secondary Outcome Measures

Name	Time	Method
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,

Trial Locations

Locations (1): Advanced Centre for Training, Research and Education in Cancer (ACTREC), Tata Memorial Centre
🇮🇳
Raigarh, MAHARASHTRA, India
Advanced Centre for Training, Research and Education in Cancer (ACTREC), Tata Memorial Centre
🇮🇳Raigarh, MAHARASHTRA, India
Dr Anant Gokarn
Principal investigator
022-68735000
anantgokarn@gmail.com