Safety, Acceptability, and Feasibility of Enterade® (SAFE)

Safety, Acceptability, and Feasibility of Enterade® in Children at Risk for Environmental Enteric Dysfunction in Kakamega County, Kenya

This is a randomized, double-blinded, placebo-controlled pilot study to determine the safety, acceptability, and feasible pediatric dosage/tolerability of enterade® solution, an amino acid-based oral rehydration solution (AA-ORS), for potential use in the management of environmental enteric dysfunction (EED) among children aged 12-24 months in Kakamega County, Kenya.

Primary objectives:

1. To determine the safety of a 2-week course of AA-ORS among children with length-for-age Z-scores (LAZ) between -1 and -3.

2. To determine the feasibility and best tolerated dose of AA-ORS among children with LAZ between -3 and -1.

   Secondary objectives:

3. To determine the perceptions among caregivers on the acceptability of AA-ORS as a potential intervention for EED. (Qualitative)

   Exploratory objectives:

4. To determine the impact of AA-ORS on markers of metabolism, gut dysfunction, systemic inflammation, and micronutrient status among children with LAZ between -3 and - 1.

Qualitative results will not be reported on ClinicalTrials.gov.

Study Overview

• Status: Terminated
• Conditions: Environmental Enteric Dysfunction; Stunting
• Intervention / Treatment: Dietary supplement: Enterade; Dietary supplement: Placebo

Detailed Description

Environmental enteric dysfunction (EED) is an intestinal disorder common among people living in low-resource settings (LRS), which in children has been associated with increased risk of growth stunting, reduced cognitive development, and reduced oral vaccine responsiveness. An effective EED therapeutic would offer an opportunity to improve child growth and development in LRS. One promising intervention, enterade® (an amino acid-based oral rehydration solution [AA-ORS]), is a medical food product already sold in the United States. It consists of oral rehydration salts and a proprietary blend of amino acids designed to restore gut function, improve nutrient and electrolyte absorption, and improve barrier integrity. There is evidence that this AA-ORS reduces inflammation and promotes healing of damaged intestinal epithelium in murine models of intestinal damage (irradiated gut), and it may provide benefit to pediatric EED patients. Supplementation of amino acids may lessen or improve intestinal injury related to enteric illnesses commonly experienced in settings of poor hygiene and sanitation infrastructure. The results from this exploratory mixed-methods study could have broad implications for possible future studies among pediatric patients with intestinal injury resulting from EED and future product development and program strategies for EED interventions.

The study was terminated prematurely after study product was found on site that did not meet product specifications. Enrollment and all study product dosing was halted; previously enrolled participants were followed through planned study visits and assessments. An additional 6-week safety follow-up period was added to study procedures. No study-related adverse events were reported during per-protocol activities or from the additional 6-week follow-up.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Kenya
  • Kakamega, Kenya
    • Kakamega County General Teaching and Referral Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Pediatric and caregiver pairs (must meet inclusion criteria for both categories):

Child:

1. Is between 12 and 24 months of age.
2. LAZ between -3 and -1 standard deviations (SD).
3. At least one week post routine immunization, healthy child visit, or vitamin A supplementation visit at the study site.
4. Has a parent or legally acceptable representative willing and able to provide informed consent.
5. No plans for travel outside of the community for the duration of the study.

Caregiver of child:

1. Is a parent or legally accepted representative of a child eligible for this study.
2. Is 18 years of age or older.
3. Has a working mobile phone.
4. Is willing and able to provide informed consent.
5. If illiterate-there is at least one literate adult living in the child's household.

Exclusion Criteria:

Pediatric and caregiver pairs (must meet none of the exclusion criteria for either category):

Child:

1. Has any sign of acute illness, including but not limited to fever, cough, and diarrhea.
2. Is wasted (weight for length z-score < -2 or mid-upper arm circumference [MUAC] < 12.4 cm) or has pitting edema.
3. Is exclusively breastfed.
4. Is seeking medical attention at the health facility other than for routine, preventative care (e.g., immunization visit, vitamin supplementation).
5. Has suffered within the prior week from illnesses that might impact nutritional status (e.g., severe diarrhea or pneumonia; vomiting; persistent diarrhea; cleft lip or palate; blindness; tuberculosis; jaundice; renal or cardiac disease; cerebral palsy; known metabolic disorders; and chromosomal disorders, including trisomy 21).
6. Medical history of chronic health condition (i.e., HIV, hepatitis B or C, end stage renal disease, severe liver disease-absence of a diagnosis is sufficient).
7. Participating in any other clinical trials.
8. Recent (prior 2 weeks) use of antibiotics or any other medical treatments (including oral re-hydration solution), but not including vaccines or vitamin/mineral supplementation).
9. Cannot give the necessary biological (blood) sample.

Caregiver:

Reports diarrhea in the household in the prior 7 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AA-ORS; Those receiving enterade oral re-hydration solution with amino acids	Dietary supplement: Enterade; enterade® (an amino acid-based oral rehydration solution [AA-ORS]) is a medical food product that consists of oral rehydration salts, natural flavor, steviol (sweetener), purified water, and a blend of amino acids that drive the uptake of water and electrolytes.
Placebo Comparator: Placebo; Those receiving placebo solution without amino acids or rehydration salts	Dietary supplement: Placebo; a placebo solution containing natural flavor, steviol (sweetener), and purified water.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Adverse Events or Serious Adverse Events	Frequency of adverse events or serious adverse events in study product and placebo arms through 21 days of follow-up as assessed by physical/clinical examination.	0-21 days
Volume of Daily Consumption of Study Product	Total, average, and trends in daily study product volume consumed measured as milliliters per day through the 14 days of dosing.	0-14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory - Metabolism: Plasma Concentration of Acylcarnitines	Plasma concentration of acylcarnitines assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Gut Damage: Plasma Concentration of Intestinal Fatty Acid-binding Protein [I-FABP]	Plasma concentration of intestinal fatty acid-binding protein [I-FABP] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Microbial Translocation: Plasma Concentration of Soluble CD14 [sCD14]	Plasma concentration of soluble CD14 [sCD14] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Gut Repair: Plasma Concentration of Glucagon-like Peptide 2 [GLP-2]	Plasma concentration of glucagon-like peptide 2 [GLP-2] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Growth Hormone Axis: Plasma Concentration of Insulin-like Growth Factor 1 [IGF-1]	Plasma concentration of insulin-like growth factor 1 [IGF-1] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Growth Hormone Axis: Plasma Concentration of Fibroblast Growth Factor 21 [FGF21]	Plasma concentration of fibroblast growth factor 21 [FGF21] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Systemic Inflammation: Plasma Concentration of Alpha-1-acid Glycoprotein [AGP]	Plasma concentration of alpha-1-acid glycoprotein [AGP] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Systemic Inflammation:Plasma Concentration of C-reactive Protein [CRP]	Plasma concentration of c-reactive protein [CRP] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Micronutrient Status: Plasma Concentration of Ferritin	Plasma concentration of ferritin assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Micronutrient Status: Plasma Concentration of Soluble Transferrin Receptor [sTfR]	Plasma concentration of soluble transferrin receptor [sTfR] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Micronutrient Status: Plasma Concentration of Retinol-binding Protein 4 [RBP4]	Plasma concentration of retinol-binding protein 4 [RBP4] assessed at baseline and day 15 of follow-up.	Day 0 and Day 15
Exploratory - Micronutrient Status: Plasma Concentration of Thyroglobulin	Plasma concentration of thyroglobulin assessed at baseline and day 15 of follow-up.	Day 0 and Day 15

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: Maseno University; Kakamega County General Teaching & Referral Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2019
• Primary Completion (Actual): March 20, 2019
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: May 16, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Actual): February 4, 2021
• Last Update Submitted That Met QC Criteria: February 2, 2021
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Growth Disorders
• Other Study ID Numbers: 1191395-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No