Rifaximin for Infection Prophylaxis in Hematopoietic Stem Cell Transplantation

Study Overview
=================
Brief Summary
-----------------
Primary purpose of the study is to see if rifaximin can improve the balance of bacteria within the gut, which has been shown to improve transplant outcomes. It will also assess whether rifaximin can reduce the risk of infection in blood/marrow transplant (BMT).

Detailed Description
-----------------
This study is for patients who will be having a blood/marrow transplant (BMT) to treat leukemia, lymphoma or other cancer of the blood. The blood or marrow cells will come from another person (donor)-allogeneic BMT. Bacterial infections and acute graft versus host disease (AGVHD) are frequent complications of allogeneic BMT. Bacterial infections sometimes happen because injury to the gut during transplant allows gut bacteria to cross the injured gut barrier and get to the blood. AGVHD happens when certain white blood cells, called T-cells, in the donor cells (the graft) attack the patient's body. Primary purpose of the study is to see if rifaximin can improve the balance of bacteria within the gut, which has been shown to improve transplant outcomes. It will also assess whether rifaximin can reduce the risk of infection in blood/marrow transplant (BMT).

Official Title
-----------------
Rifaximin for Infection Prophylaxis in Hematopoietic Stem Cell Transplantation

Conditions
-----------------
Microbial Colonization

Intervention / Treatment
-----------------
* Drug: Rifaximin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Allogeneic HSCT recipients between the ages of 2 and 21 years. Underlying hematologic malignancy, regardless of donor type or graft source. Myeloablative conditioning regimen. Exclusion Criteria: Known hypersensitivity to rifaximin, or other rifamycin antimicrobial agents. Minimally toxic conditioning regimen (e.g. low dose TBI based). Since these regimens induce minimal myelosuppression and gut injury, patients receiving them probably stand little to gain from antibiotic prophylaxis. Patients with ongoing bacterial, viral or fungal active infections are not eligible for this study. Patients who remain on broad spectrum antibiotics for the treatment of a previous infection are not eligible. The use of prophylactic antibiotics is not permitted. Following the standard practice in blood and marrow transplantation, pregnant or breast feeding patients will be excluded

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Pilot, single arm prospective study with retrospective control arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifaximin<br>Rifaximin will be administered twice a day orally or by nasogastric tube to patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). | Drug: Rifaximin<br>* Rifaximin will be administered twice a day orally or by nasogastric tube, at a dose of 15 mg/kg divided BID with a maximum dose of 1,650 mg, day -7 to day +28 or discharge (maximum duration 36 days).<br>|
| No Intervention: Retrospective comparison cohort<br>Thirty six patients who underwent HSCT for hematologic malignancies, and received myeloablative conditioning, without prophylactic antibiotics, between 2013-2017 enrolled in the Aflac biorepository will comprise the comparison arm. Clinical data on transplant and infection characteristics is available and linked to stool microbiome samples already analyzed and described. Stored plasma and peripheral blood mononuclear cells are available for further analysis. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alterations to microbiome diversity in children treated with rifaximin compared to the historical cohort. | Composition will be assessed using 16S RNA sequencing. The Shannon index will be calculated for quantification of bacterial diversity. | Period between the start of the preparative regimen and day 28 post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of BSI pathogen infection/colonization frequency during the treatment period compared to the historical cohort. | Results of the GI pathogen panel, a test incorporated into routine patient care detecting DNA or RNA of 22 common viral, bacterial, and parasitic organisms, will provide a second assessment through molecular detection of the presence of common organisms associated with intestinal dysbiosis. | Period between the start of the preparative regimen and day 28 post transplant | 
| Transplant related mortality (TRM) | Number of deaths occurring in continuous complete remission. | Period between the start of the preparative regimen and day 28 post transplant | 
| Number of patients with Acute GVHD | Early onset (before day 100) acute GVHD (including all grades, and stratified by grades) will be assessed according to the Blood and Marrow Transplant Clinical Trials Network Manual version 2, 2005, section 1 using the NIH consensus criteria | Period between the start of the preparative regimen and day 100 post transplant | 
| Number of patients with Chronic GVHD including overlap syndrome | Chronic GVHD including overlap syndrome, will be assessed according to the 2014 NIH consensus criteria. | Period between the start of the preparative regimen and year 5 post-transplant. | 
| Number of patients with other Infections | Other Infections will be defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures | Period between the start of the preparative regimen and day 28 post transplant | 
| Number of patients with relapse free survival at 1 year | Survival without relapse of underlying malignancy. | Period between the start of the preparative regimen and year 1 post-transplant. | 
| Overall number of patients survived at 1 year | Survival with or without relapse of underlying malignancy. | Period between the start of the preparative regimen and year 1 post-transplant. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rifaximin, Microbiome, Allogeneic hematopoietic stem cell transplantation, Blood stream infections, Acute graft versus host disease