Gut Decontamination In Pediatric Allogeneic Hematopoietic

Acute GVH Disease Clinical Trial

Official title:

A Randomized Phase 2 Study to Examine the Impact of Gut Decontamination on Intestinal Microbiome Composition in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02641236
• Other study ID #: 15-394
• Status: Completed
• Phase: Phase 2
• Start date: March 2016
• Est. completion date: October 28, 2021

Study information

• Verified date: September 2023
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This research study is for participants who are undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and are at risk for developing acute graft-versus-host disease (GVHD). GVHD is a complication of HSCT in which immune cells from the donor cause inflammation and injury to tissues and organs of the HSCT recipient. Vancomycin-polymyxin B (commonly called "vancopoly") is an oral antibiotic that is given to people undergoing allogeneic HSCT as a preventive measure for acute GVHD. This research study is studying the effects of vancopoly on the microorganisms living in the intestine during and after stem cell transplantation.

Description:

This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease.

"Investigational" means that the intervention is being studied.

Pre-clinical studies performed in the 1970's showed that killing all the bacteria in the intestine with oral antibiotics could decrease the risk of acute GVHD following allogeneic HSCT. Based on this observation, many stem cell transplant centers adopted the practice of "gut decontamination" with oral antibiotics as a preventive measure for acute GVHD. There is no standard regimen for gut decontamination between transplant centers, and there are no definitive human studies showing that gut decontamination is beneficial for lowering the risk of acute GVHD.

Recent studies in adult patients undergoing stem cell transplant indicate that the types of bacteria living in the intestine can influence bone marrow transplant outcomes such as survival and development of acute GVHD. Some types of bacteria may be protective against GVHD and others may increase the risk of GVHD. Based on this newer research, it is possible that the practice of gut decontamination ("vancopolys") may not be beneficial for HSCT patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: October 28, 2021
• Est. primary completion date: April 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 30 Years

Eligibility

Inclusion Criteria:

• Eligibility Criteria for Patients Undergoing Allogeneic HSCT

• Recipient of 9/10 or 10/10 (HLA-A, -B, -C, -DRB1, -DQB1) matched bone marrow allogeneic hematopoietic stem cell transplantation (HSCT) OR 4/6, 5/6 and 6/6 (HLA-A, -B, -DR) matched cord blood allogeneic HSCT.

• Participants may have underlying malignant or non-malignant hematologic disease, except for primary immunodeficiency, as the indication for their allogeneic HSCT. Patients with immune dysregulation such as familial or secondary hemophagocytic lymphohistiocytosis (HLH) are eligible.

• Participants must may receive either a myeloablative or non-myeloablative(reduced-intensity) conditioning regimen. Anti-thymocyte globulin (ATG) in the conditioning regimen is permitted.

• Graft-versus-host disease (GVHD) prophylaxis with any of the following agents:

calcineurin inhibitor, and short-course methotrexate, with or without steroids, mycophenolate mofetil, and sirolimus.

• Age = 4 years old and toilet-trained. Participants must be able to deposit stool samples directly into stool collection containers. Stool specimens from diapers are difficult to obtain and are prone to more sampling error, particularly for loose or liquid stools which are common in the peri-transplant period.

• Lansky/Karnofsky performance status =60% (see Appendix A)

• Ability to understand and/or the willingness of their parent or legally authorized representative to sign a written informed consent document

• Eligibility Criteria for Healthy Bone Marrow Donors

• Healthy individuals, ages = 4 years and toilet-trained, who have been identified by BCH or DFCI providers as 9/10 or 10/10 (HLA-A, -B, -C, -DRB1, -DQB1 matched bone marrow donors for transplantation will also be eligible to participate in this study.

Exclusion Criteria:

• Patients undergoing allogeneic HSCT for correction of a primary immunodeficiency disorder (e.g. SCID).

• Patients with age = 10 years undergoing HSCT with a matched sibling donor. These patients are at very low risk of acute GVHD and do not receive gut decontamination per our institutional standard practice.

• Participants receiving GVHD prophylaxis with drugs other than calcineurin inhibitors, methotrexate or steroids.agents listed above (e.g. abatacept).

• History of allergic reactions attributed to oral vancomycin or oral polymyxin B.

• Participants undergoing active therapy for immune-mediated or infectious colitis upon admission for allogeneic HSCT.

• Participants receiving antibiotic therapy for treatment of a bacterial infection or bacterial prophylaxis upon admission for allogeneic HSCT. Use of any agent (e.g. sulfamethoxazole/trimethoprim) for prophylaxis of Pneumocystis jirovecii pneumonia is permitted. Concurrent use of anti-fungal and anti-viral therapies is also permitted.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.

Related Conditions & MeSH terms

• Acute GVH Disease
• Graft vs Host Disease
• Hematopoietic Stem Cell Transplantation (HSCT)

Intervention

Drug:
• Vancomycin-polymyxin B

Locations

Country	Name	City	State
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Dana-Farber Cancer Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Gut Microbiome Description	Shannon diversity index (range: 0-6), measured at 2 weeks post stem cell transplant. Shannon diversity is a way to calculate biodiversity in a community, and assumes that all species are represented in a sample and that they are randomly sampled. Shannon Diversity is a measurement sensitive to the loss of rare taxa (34 in the JCI Insight manuscript, Konopinski MK, PeerJ. 2020;8:e9391) and estimates microbial richness (e.g., the number of species) and evenness (e.g., the relative abundance of organisms within a sample).; Formula 1: H = -?[(pi) * ln(pi)],; H: Shannon diversity index (H = 0 indicates that a community has only one species) pi: Proportion of individuals of i-th species in a whole community Formula 2: pi = n / N,; n: individuals of a given type/species; N: total number of individuals in a community	2 Weeks post HSCT
Secondary	Diarrhea Frequency	The number of daily bowel movements during the first 7 days post-HSCT is charted by floor nurses and/or clinical assistants and will be obtained from within each patient's electronic medical record in PowerChart. Diarrhea frequency is defined the proportion of participants who had greater than 3 bowel movements per day.	Participants were followed 7 days after HSCT.
Secondary	Median Absolute Cell Numbers of T-, B-, NK- and Dendritic Cell Subsets by Flow Cytometry	CD4+ Tregs were defined as CD3+CD4+CD25med-hiCD127lo, CD4+; Tcon as CD3+CD4+CD25neg-lo CD127med-hi, B cells as CD19+, cytotoxic T cells as CD8+, and natural killer cells as CD56+CD3-. Within CD4+ Tregs and CD4+ Tcon, subsets were defined as follows: naive T cells (CD45RO-CD62L+), central memory (CD45RO+CD62L+), and effector memory (CD45RO+CD62L-).	Performed at the post-transplant time points (1,2,3,6,9,12 months post-transplant)
Secondary	Incidence of Acute GVHD (Grade 2-4)	Grade 2 acute GVHD was defined as skin stage 3 or GI stage 1 or liver stage 1. Skin stage 3 was defined as maculopapular rash >50% of body surface or generalized erythroderma; GI stage 1 was defined as adults: 500 - 1000 mL/day, children: 10 - 19.9 mL/kg/day or nausea, anorexia or vomiting with biopsy (EGD) confirmation of upper GI GVHD; liver stage 1 was defined as bilirubin 2.1-3 mg/dL. Grade 3 acute GVHD was defined as GI stage 2-4 or liver stage 2-3. GI stage 2-4 was defined as >1001 mL/day (adults), >30 ml/kg/day(children) or large volume stool with severe abdominal pain with our whiteout ileus or stool with frank blook or melena; liver stage 2-3 was defined as bilirubin 3.1-15mg/dL. Grade 4 acute GVHD was defined as skin stage 4 or liver stage 4. Skin stage 4 was defined as generalized erythroderma with bullous formation and desquamation; liver stage 4 was defined as bilirubin > 15mg/dL.	Each stool collection time point after neutrophil engraftment until day +100
Secondary	Overall Survival Rate at 12 Months (OS12)	OS12 is the proportion of participants alive at 12 months after study entry.	All participants were followed for 1 years after study entry.
Secondary	Relapse Free Rate at 12 Months	Relapse free rate at 12 months was defined as the proportion of patients surviving without any signs or symptoms of that cancer after 12 months.	Patients were followed for 12 months.