Protein Plus: Improving Infant Growth Through Diet and Enteric Health (JiVitA-6)

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

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.

Study Overview

• Status: Completed
• Conditions: Stunting; Campylobacter Infections; Malnutrition; Protein; Enteric Pathogens
• Intervention / Treatment: Drug: Placebos; Behavioral: Nutrition Education; Dietary supplement: Protein Supplement; Dietary supplement: Isocaloric Supplement; Dietary supplement: Egg; Drug: Azithromycin Oral Product

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5283
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Gaibandha, Bangladesh
    • JiVitA Maternal and Child & Nutrition Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 6 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: QUADRUPLE

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo & Control; Placebo / Nutrition education	Drug: Placebos; Contain inert excipients only; Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding
EXPERIMENTAL: Placebo & Protein Supplement; Placebo / Protein-rich blended food / Nutrition education	Drug: Placebos; Contain inert excipients only; Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Dietary supplement: Protein Supplement; 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
PLACEBO_COMPARATOR: Placebo & Isocaloric Supplement; Placebo / Isocaloric blended food / Nutrition education	Drug: Placebos; Contain inert excipients only; Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Dietary supplement: Isocaloric Supplement; 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
EXPERIMENTAL: Placebo & Egg; Placebo / Egg / Nutrition education	Drug: Placebos; Contain inert excipients only; Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Dietary supplement: Egg; Egg provided daily to infants from 6-12 months of age
EXPERIMENTAL: Azithromycin & Control; Azithromycin / Nutrition education	Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Drug: Azithromycin Oral Product; Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age; Other Names: Azithrocin
EXPERIMENTAL: Azithromycin & Protein Supplement; Azithromycin / Protein-rich blended food / Nutrition education	Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Dietary supplement: Protein Supplement; 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; Drug: Azithromycin Oral Product; Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age; Other Names: Azithrocin
EXPERIMENTAL: Azithromycin & Isocaloric Supplement; Azithromycin Isocaloric blended food Nutrition education	Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Dietary supplement: Isocaloric Supplement; 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; Drug: Azithromycin Oral Product; Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age; Other Names: Azithrocin
EXPERIMENTAL: Azithromycin and Egg; Azithromycin Egg Nutrition education	Behavioral: Nutrition Education; Monthly messaging on infant and young child feeding; Dietary supplement: Egg; Egg provided daily to infants from 6-12 months of age; Drug: Azithromycin Oral Product; Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age; Other Names: Azithrocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: Bill and Melinda Gates Foundation; International Centre for Diarrhoeal Disease Research, Bangladesh
• Investigators: Principal Investigator: Md Iqbal Hossain, PhD, International Centre for Diarrhoel Disease Research, Bangladesh

Publications and helpful links

General Publications

• Arsenault JE, Brown KH. Dietary Protein Intake in Young Children in Selected Low-Income Countries Is Generally Adequate in Relation to Estimated Requirements for Healthy Children, Except When Complementary Food Intake Is Low. J Nutr. 2017 May;147(5):932-939. doi: 10.3945/jn.116.239657. Epub 2017 Feb 15.
• Uauy R. Keynote: rethinking protein. Food Nutr Bull. 2013 Jun;34(2):228-31. doi: 10.1177/156482651303400213. No abstract available.
• Lang D; MAL-ED Network Investigators. Opportunities to assess factors contributing to the development of the intestinal microbiota in infants living in developing countries. Microb Ecol Health Dis. 2015 May 29;26:28316. doi: 10.3402/mehd.v26.28316. eCollection 2015.
• MAL-ED Network Investigators. Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: findings from the MAL-ED birth cohort study. BMJ Glob Health. 2017 Dec 28;2(4):e000370. doi: 10.1136/bmjgh-2017-000370. eCollection 2017.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 23, 2018
• Primary Completion (ACTUAL): March 19, 2020
• Study Completion (ACTUAL): March 24, 2020

Study Registration Dates

• First Submitted: September 21, 2018
• First Submitted That Met QC Criteria: September 21, 2018
• First Posted (ACTUAL): September 25, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 5, 2022
• Last Update Submitted That Met QC Criteria: December 2, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: infant feeding; environmental enteric dysfunction; linear growth
• Additional Relevant MeSH Terms: Infections; Nutrition Disorders; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Severe Acute Malnutrition; Malnutrition; Campylobacter Infections; Kwashiorkor; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: 00008000; OPP1163259 (OTHER_GRANT: Bill and Melinda Gates Foundation)

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