Intervention and Mechanisms of Alanyl-Glutamine for Inflammation, Nutrition, and Enteropathy

Study Overview
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Brief Summary
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Several host factors underlie the pathogenesis of the reciprocal cycle of childhood diarrhea and undernutrition in developing countries. These include intestinal inflammation, mucosal damage, and alterations in intestinal barrier function that lead to malabsorption, growth failure, and heightened susceptibility to recurrent and prolonged episodes of diarrhea. Recent studies from Northeast Brazil demonstrate the benefits of a novel alanyl-glutamine-based oral rehydration and nutrition therapy (Ala-Gln ORNT) in speeding the recovery of damaged intestinal barrier function in cell culture, animal models, patients with AIDS, and underweight children. Oral supplementation with Alanyl-Glutamine (Ala-Gln; 24g a day for 10 days) improves short-term gut integrity and weight velocity 4 months after therapy in a group of undernourished children from Northeast Brazil. Intervention and Mechanisms of Alanyl-Glutamine for Inflammation, Nutrition, and Enteropathy (IMAGINE) is a study designed to answer the following questions: 1) What is the lowest dose of Ala-Gln that improves intestinal barrier function, intestinal inflammation, and nutritional status in children at risk of underweight, wasting, or stunting? 2) What are the mechanisms by which Ala-Gln exerts these benefits?

Official Title
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Intervention and Mechanisms of Alanyl-Glutamine for Inflammation, Nutrition, and Enteropathy (IMAGINE)

Conditions
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Malnutrition, Environmental Enteropathy, Diarrhea

Intervention / Treatment
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* Dietary Supplement: Alanyl-Glutamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children who are undernourished or at risk of undernutrition, with anthropometric z-scores less than or equal to -1 for one of these parameters: height-for-age, weight-for-age, or weight-for-height. Children ages 2 months to 5 years old. Exclusion Criteria: Children who are exclusively breastfed. Have participated in another intervention study in the past two years. Fever greater than 38.8 ° C. Use of antibiotics. Systemic disease or other serious medical condition (including, but not limited to meningitis, pneumonia, tuberculosis, and chickenpox). Children who are unable to ingest, retain or absorb nutritional supplements. Children whose families plan to move from the study area within the next 6 months.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alanyl-Glutamine 3g/d<br>Alanyl-Glutamine orally 3g/day for 10 days | Dietary Supplement: Alanyl-Glutamine<br>* Alanyl-Glutamine and Glycine doses will be prepared immediately prior to administration by dissolving in formula, milk, or fruit juice. Administration of each dose will be directly observed by a study nurse or health agent.<br>* Other names: AminoStable (Ajinomoto);|
| Active Comparator: Alanyl-Glutamine 6g/d<br>Alanyl-Glutamine orally 6g/day for 10 days | Dietary Supplement: Alanyl-Glutamine<br>* Alanyl-Glutamine and Glycine doses will be prepared immediately prior to administration by dissolving in formula, milk, or fruit juice. Administration of each dose will be directly observed by a study nurse or health agent.<br>* Other names: AminoStable (Ajinomoto);|
| Active Comparator: Alanyl-Glutamine 12g/d<br>Alanyl-Glutamine orally 12g/d for 10 days | Dietary Supplement: Alanyl-Glutamine<br>* Alanyl-Glutamine and Glycine doses will be prepared immediately prior to administration by dissolving in formula, milk, or fruit juice. Administration of each dose will be directly observed by a study nurse or health agent.<br>* Other names: AminoStable (Ajinomoto);|
| Placebo Comparator: Glycine 12.5g/d<br>Glycine orally 12.5 g/d for 10 days. This dose is calculated to be isonitrogenous to 12g of Alanyl-Glutamine. | Dietary Supplement: Alanyl-Glutamine<br>* Alanyl-Glutamine and Glycine doses will be prepared immediately prior to administration by dissolving in formula, milk, or fruit juice. Administration of each dose will be directly observed by a study nurse or health agent.<br>* Other names: AminoStable (Ajinomoto);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Lactulose: Mannitol Intestinal Permeability Test | Determine the dose-and time-effect of alanyl-glutamine on intestinal barrier function recovery using the intestinal permeability test, with measurement of the percentage of urinary excretion of lactulose, mannitol and ratio of lactulose:mannitol. | Urine Collection on Day 1, 10-13, 30-37 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal Lactoferrin Test | To evaluate the effect of time and dose-response of alanyl-glutamine on intestinal inflammation, as measured by qualitative or quantitative testing for fecal lactoferrin in stools of children at risk of undernutrition. | Fecal sample collected on Day 1, 10-13, 30-37 | 
| Fecal Cytokine Measurement | To evaluate the effect of alanyl-glutamine on intestinal inflammation, by measuring proinflammatory cytokines interleukin-1, interleukin-8, tumor necrosis factor-alpha (TNF), and regenerating gene 1B (REG1B) in stools of children at risk of undernutrition. | Fecal sample collected on Day 1, 10-13 | 
| Anthropometry | To evaluate the time and dose-effect of alanyl-glutamine on short and medium-term nutritional status by evaluating changes in anthropometric measures (z scores) over time: height-for-age, weight-for-age, and weight-for-height. | Measured and calculated Day 1, 10-13, 30-37, 90-104, 120-141 | 
| Fecal Calorimetry | To evaluate the effect of time and dose-response of alanyl-glutamine on the intestinal absorption of fat, protein, and carbohydrates, by measurement of fecal energy content by bomb calorimetry. | Fecal sample collected on Day 1, 10-13, 30-37 | 
| Metabolomic Profile of Urine | To evaluate the time and dose-effect of alanyl-glutamine on metabolism in children at risk of undernutrition by means of urine metabolomic profile tests. | Collected on Day 1, 10-13, 30-37 | 
| History of Diarrhea in the Previous Two Weeks | History of diarrhea in the previous two weeks. A day of diarrhea will be defined as 3 or more looser than normal bowel movements in a 24-hour period. Distinct episodes must be separated by at least 2 days without diarrhea. Duration of episodes will be classified as acute (< 7 days), prolonged acute (>6 and <14 days), or persistent (>13 days). | Day 1, 30-37, 90-104, 120-141 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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L-Alanyl-L-Glutamine, Environmental enteric dysfunction, Tropical enteropathy