Clinical trial NCT03683667: Protein Plus: Improving Infant Growth Through Diet and Enteric Health
Official title: Efficacy of Supplemental Protein, Delivered Alone or in Combination With Treatment for Enteric Pathogens, to Prevent Growth Faltering in Bangladeshi Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Stunting
Malnutrition; Protein
Enteric Pathogens
Campylobacter Infections
Keywords: linear growth
infant feeding
environmental enteric dysfunction
Lead sponsor: Johns Hopkins Bloomberg School of Public Health
Sponsor class: OTHER
Collaborators: name: International Centre for Diarrhoeal Disease Research, Bangladesh
name: Bill and Melinda Gates Foundation
First posted: 2018-09-25
Enrollment: 5283
Sex: ALL
Minimum age (years): 3
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention 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).
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Length-for-age Z-score (LAZ) at 12 months of age
timeFrame: 12 months
Secondary outcomes:
measure: Nutrient biomarkers
timeFrame: 6 and 12 months
measure: Growth hormone and stress axes biomarkers
timeFrame: 6 and 12 months
measure: Enteropathogen burden
timeFrame: 6, 6.5, 9, 9.5, 12, 15, and 18 months
measure: Gut microbiota composition
timeFrame: 6, 6.5, 9, 9.5, 12, 15, and 18 months
measure: Environmental enteric dysfunction biomarkers
timeFrame: 6 and 12 months
measure: Inflammatory biomarkers
timeFrame: 6 and 12 months
measure: Bone biomarkers
timeFrame: 6 and 12 months
measure: Morbidity incidence
timeFrame: 6-12 months
measure: Body composition
timeFrame: 6, 9, 12, 15, and 18 months
measure: Antibiotic resistance
timeFrame: 6, 9, 12, 15, and 18 months
Other outcomes:
Locations:
city: Gaibandha
country: Bangladesh
facility: JiVitA Maternal and Child & Nutrition Research Site
Study officials:
affiliation: Johns Hopkins Bloomberg School of Public Health
name: Amanda C Palmer, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: International Centre for Diarrhoel Disease Research, Bangladesh
name: Md Iqbal Hossain, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Uauy R. Keynote: rethinking protein. Food Nutr Bull. 2013 Jun;34(2):228-31. doi: 10.1177/156482651303400213. No abstract available.
citation: 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.
citation: 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.