Clinical trial NCT04263597: Oral Supplementation of 2'-Fucosyllactose in Allogeneic Bone Marrow Transplant Recipients
Official title: Oral Supplementation of 2'-Fucosyllactose in Allogeneic Bone Marrow Transplant Recipients to Maintain Intestinal Homeostasis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hematopoietic Stem Cell Transplant
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
First posted: 2020-02-11
Enrollment: 70
Sex: ALL
Minimum age (years): 0
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible patients will be allocated into the following arms as determined by age at enrollment.

Arm 1: 0-5 years; Arm 2: 5.1-10 years; Arm 3: \>10 years
Primary purpose: PREVENTION

Brief summary: High dose chemotherapy and radiation used as preparative regimens in patients undergoing an allogeneic hematopoietic stem cell transplant (HSCT) disrupts intestinal homeostasis by damaging the intestinal epithelium and altering the intestinal microbiome. The investigators hypothesize that 2'-fucosyllactose (2FL) supplementation will be safe and tolerable and result in an increase in the relative abundance of intestinal Bifidobacteria. The investigators also hypothesize that 2FL supplementation will lead to reduction of Firmicutes and/or Proteobacteria, and improved intestinal homeostasis at day+30 as measured by lower pro-inflammatory cytokines, reduced levels of T-cell activation, lower markers of intestinal injury (fecal human DNA and plasma reg-3-alpha), increased fecal butyrate levels and ultimately lower incidence of acute GVHD and BSI at day+100.

Phase II:

The investigators hypothesize that 2FL supplementation will be safe and tolerable and result in an increase in the relative abundance of fecal short chain fatty acids such as butyrate, acetate and propionate at day+7 compared to baseline values.

Detailed description: This phase I/IIa study is a single center prospective study at Cincinnati Children's Hospital Medical Center (CCHMC).

This study will assess the safety and tolerability of various doses of 2FL. Eligible patients will be allocated to the following arms as determined by age at enrollment:

Arm 1: 0-5 years; Arm 2: 5.1-10 years; Arm 3: \>10 years

The investigators will first enroll 5 patients of ages ≥10 years undergoing allogeneic HSCT. 2'-FL will be administered to these patients from day-7 until day+30 after HSCT at the starting dose for the ≥10 years age group. Once safety is determined the investigators will then enroll an additional 5 patients of ages 5-10 years and 5 patients of ages 0-5 years and administer 2'FL at starting doses according to their age group to children from day-7 to day+30 after HSCT. Enrollment in the 2 defined age groups (5-10 years and 0-5 years) will occur independent of each other/in parallel to establish safety. Once safety is established in these patients the investigators will proceed with the 3x3 study design dose finding portion of our study

Three patients will be enrolled in each arm at the starting dose level. Investigators will perform a dose escalation or de-escalation based on rates of dose limiting toxicities.

Phase II:

Initial 15 patients to establish safety as per the FDA have been enrolled. An additional 10 patients were enrolled and interim analyses demonstrating safety, lack of any dose limiting toxicities and a positive signal of increase in fecal acetate and propionate at day+7 compared to baseline values) were performed. The investigators will enroll approximately 65 additional patients to test efficacy of 2FL supplementation in children and young adult allogeneic HSCT patients with a goal to reduce intestinal inflammation and improve post HSCT outcomes such as acute GVHD and bloodstream infections.

Eligibility criteria: Inclusion Criteria:

* Be scheduled for allogeneic stem cell transplant
* All ages and underlying diagnoses, preparative regimens, stem cell sources and acute GVHD prophylaxes

Exclusion Criteria:

* Unable to take anything orally or enterally (i.e. intestinal failure)
* Actively breastfeeding infants
* Recent (within the week prior to enrollment) GI infection
* Patients receiving anti-diarrheal medications such as loperamide
* Patients who have received probiotics or prebiotics during the previous month
* Patients who have had any type of gut damage within the past 3 months such as previous bowel perforations, previous episode of Grade 4 neutropenic colitis or typhlitis
* Patients with inflammatory bowel disease, short bowel syndrome, and patients with a history of bowel resections

Primary outcomes:
measure: Number of bloodstream infections
timeFrame: Day+100 after transplant
measure: Number of patients able to take 2FL
timeFrame: 1 week prior to start of chemotherapy until day+30 after transplant
measure: Change in fecal butyrate/acetate/propionate levels
timeFrame: Day+ 7 after transplant
Secondary outcomes:
measure: Relative abundance of fecal Bifidobacteria at day+30 compared to baseline by >/=10%
timeFrame: Day+30 after transplant
measure: Relative abundance of fecal Firmicutes and Proteobacteria at day+30 compared to baseline for patients on 2FL
timeFrame: Day+30 after transplant
measure: Incidence of acute GVHD
timeFrame: Day+100 after transplant
measure: Incidence of bloodstream infections
timeFrame: Day+100 after transplant
measure: Incidence of mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI)
timeFrame: Day+ 100 after transplant
measure: Incidence of graft versus host disease (GVHD)
timeFrame: Day+ 100 after transplant
measure: Urine 3-indoxyl sulfate (3-IS) Levels
timeFrame: Baseline, day+7, day+14, day+30 after transplant
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Pooja Khandelwal, MD
role: PRINCIPAL_INVESTIGATOR
References: