Protein Plus: Improving Infant Growth Through Diet and Enteric Health

Study Overview
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Brief Summary
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This cluster-randomized controlled trial is designed to address linear growth faltering in 6-12-mo-old Bangladesh infants through a proof-of-concept package of interventions to a) increase intake of high quality protein and b) control enteric pathogens.

Detailed Description
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Stunting a major public health problem in Bangladesh, where 36% of children under the age of five are too short for their age. While dietary data indicate that protein intakes of infants and young children are largely in line with requirements, the extent to which requirements derived for healthy infants and young children are relevant in the context of frequent infections remains an important research question. Recent investigations indicate widespread pathogen carriage among Bangladeshi infants, with virtually all having at least one detectable pathogen in nondiarrheal stools by six months of age. Campylobacter and pathogenic E. Coli predominate in this setting. Enteric pathogens can compete with the host for available nutrients or alter nutrient metabolism. Acting via environmental enteric dysfunction, they can alter both digestion-through loss of digestive enzymes-and absorption of nutrients. Microbial translocation may further alter specific amino acid requirements. Even in the absence of acute diarrheal disease, enteric pathogen carriage is strongly associated with linear growth faltering. Combining the effects of high pathogen burden and poor diet, as indicated by low energy and protein from complementary foods, observational evidence suggests that the potentially preventable length-for-age Z-score deficit may be as high as 0.98. The present trial will test the combination of a) protein supplementation in the form of a protein-rich blended food or an egg, both fed daily to infants 6-12 months of age, and b) azithromycin treatment for enteric pathogens. The primary outcome will be change in length-for-age Z-score from the 6 to 12 months. Biochemical, microbiological and clinical intermediates will be measured to inform our secondary aims.

Official Title
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Efficacy of Supplemental Protein, Delivered Alone or in Combination With Treatment for Enteric Pathogens, to Prevent Growth Faltering in Bangladeshi Infants

Conditions
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Stunting, Malnutrition; Protein, Enteric Pathogens, Campylobacter Infections

Intervention / Treatment
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* Drug: Azithromycin Oral Product
* Drug: Placebos
* Dietary Supplement: Protein Supplement
* Dietary Supplement: Isocaloric Supplement
* Dietary Supplement: Egg
* Behavioral: Nutrition Education


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Born to women enrolled in ongoing community trial (NCT02909179) over a one-year period Exclusion Criteria: Born to women not registered as part of the ongoing community trial (NCT02909179)

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 6 Months

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: For this 2 x 4 factorial, cluster-randomized trial, 566 previously defined clusters will be assigned independently to 8 different combinations of interventions: 1) azithromycin and protein supplementation; 2) azithromycin and isocaloric supplementation; 3) azithromycin and egg; 4) azithromycin and control (nutrition education); 5) placebo and protein supplementation; 6) placebo and isocaloric supplementation; 7) placebo and egg; 8) placebo and control (nutrition education).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo & Control<br>Placebo / Nutrition education | Drug: Placebos<br>* Contain inert excipients only<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Experimental: Placebo & Protein Supplement<br>Placebo / Protein-rich blended food / Nutrition education | Drug: Placebos<br>* Contain inert excipients only<br>Dietary Supplement: Protein Supplement<br>* Blended food providing 125 kcal and 10 g protein as egg white powder prepared as porridge and fed daily to infants from 6-12 months of age<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Placebo Comparator: Placebo & Isocaloric Supplement<br>Placebo / Isocaloric blended food / Nutrition education | Drug: Placebos<br>* Contain inert excipients only<br>Dietary Supplement: Isocaloric Supplement<br>* Blended food providing 125 kcal and 1 g protein as rice powder prepared as porridge and fed daily to infants from 6-12 months of age<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Experimental: Placebo & Egg<br>Placebo / Egg / Nutrition education | Drug: Placebos<br>* Contain inert excipients only<br>Dietary Supplement: Egg<br>* Egg provided daily to infants from 6-12 months of age<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Experimental: Azithromycin & Control<br>Azithromycin / Nutrition education | Drug: Azithromycin Oral Product<br>* Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age<br>* Other names: Azithrocin;Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Experimental: Azithromycin & Protein Supplement<br>Azithromycin / Protein-rich blended food / Nutrition education | Drug: Azithromycin Oral Product<br>* Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age<br>* Other names: Azithrocin;Dietary Supplement: Protein Supplement<br>* Blended food providing 125 kcal and 10 g protein as egg white powder prepared as porridge and fed daily to infants from 6-12 months of age<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Experimental: Azithromycin & Isocaloric Supplement<br>Azithromycin Isocaloric blended food Nutrition education | Drug: Azithromycin Oral Product<br>* Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age<br>* Other names: Azithrocin;Dietary Supplement: Isocaloric Supplement<br>* Blended food providing 125 kcal and 1 g protein as rice powder prepared as porridge and fed daily to infants from 6-12 months of age<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|
| Experimental: Azithromycin and Egg<br>Azithromycin Egg Nutrition education | Drug: Azithromycin Oral Product<br>* Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age<br>* Other names: Azithrocin;Dietary Supplement: Egg<br>* Egg provided daily to infants from 6-12 months of age<br>Behavioral: Nutrition Education<br>* Monthly messaging on infant and young child feeding<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length-for-age Z-score (LAZ) at 12 months of age |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nutrient biomarkers | Serum essential, conditionally essential amino acids and choline (by metabolomic analysis); retinol and tocopherols (HPLC); vitamin B12 (microbiological assay); zinc (AAS); ferritin and thyroglobulin (ELISA) | 6 and 12 months | 
| Growth hormone and stress axes biomarkers | Serum insulin-like growth factor 1 (IGF-1), IGF binding protein 3, cortisol, by ELISA | 6 and 12 months | 
| Enteropathogen burden | Campylobacter, enterotoxigenic Escherichia coli (ETEC), enteroaggregative Escherichia coli (EAEC), enteropathogenic Escherichia coli (EPEC), Shigella and Cryptosporidium, by quantitative polymerase chain reaction (qPCR) | 6, 6.5, 9, 9.5, 12, 15, and 18 months | 
| Gut microbiota composition | Microbial diversity and abundance, by 16S ribosomal RNA sequencing | 6, 6.5, 9, 9.5, 12, 15, and 18 months | 
| Environmental enteric dysfunction biomarkers | Stool myeloperoxidase and intestinal fatty acid-binding protein concentrations and plasma Endogenous endotoxin-core antibody (EndoCAb), by ELISA | 6 and 12 months | 
| Inflammatory biomarkers | Plasma alpha-1 acid glycoprotein, C-reactive protein and interleukin-6, by ELISA; stool inflammatory cytokines, by ELISA | 6 and 12 months | 
| Bone biomarkers | Plasma collagen type X and N-Terminal Pro-C-Type Natriuretic Peptide (NT-ProCNP), by ELISA | 6 and 12 months | 
| Morbidity incidence | Incident diarrhea/dysentery or respiratory infection, based on weekly recalls | 6-12 months | 
| Body composition | Fat mass by bioelectrical impedence | 6, 9, 12, 15, and 18 months | 
| Antibiotic resistance | Resistance of commensal E. coli (stool) or S. pneumoniae (nasopharyngeal swab) to panel of antibiotics, by culture | 6, 9, 12, 15, and 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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linear growth, infant feeding, environmental enteric dysfunction