Clinical trial NCT03268902: Early Life Interventions for Childhood Growth and Development In Tanzania
Official title: Early Life Interventions for Childhood Growth and Development In Tanzania
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Malnutrition
Stunting
Cognitive Development
Enteric Pathogens
Lead sponsor: Haydom Lutheran Hospital
Sponsor class: OTHER
Collaborators: name: University of Virginia
name: Bill and Melinda Gates Foundation
First posted: 2017-08-31
Enrollment: 1188
Sex: ALL
Minimum age (years): 0
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Each intervention will be assigned independently. Intervention domains will be randomized separately on an individual basis. This will provide 4 different combinations of interventions: 1). Nicotinamide, azithromycin and nitazoxanide 2). Azithromycin and nitazoxanide 3). Nicotinamide only 4). No active treatment.
Primary purpose: TREATMENT

Brief summary: This study aims to assess growth and cognitive effects of treatment with azithromycin and nitazoxanide and/or nicotinamide (vitamin B3) supplementation nicotinamide.

Detailed description: Children living in rural sub-Saharan Africa experience massive challenges to child thriving, with poor linear growth and delays in child development. In a cohort of 211 children living in the rural Haydom area of Tanzania (participating in the Interactions of Malnutrition \& Enteric Infections: Consequences for Child Health and Development "MAL-ED" Study), 70.6% had stunted growth at 18 months. This rate of moderate and severe stunting (length-for-age z-score \[HAZ\] \<-2 standard deviations) was the highest of the 8 study sites in MAL-ED.

This enormous deficit is likely associated with high rates of enteric infections with Campylobacter, E. coli pathotypes, Cryptosporidium, and Giardia, organisms susceptible to azithromycin and/or nitazoxanide. Infections such as these occur frequently in developing areas and are often associated with environmental enteropathy, including ongoing enteric inflammation and loss of enterocyte integrity, leading to possible bacterial translocation and poorer absorption of ingested nutrients. The consequences of these infections, enteric dysfunction and poor nutrient absorption frequently include growth stunting, learning delays, and an overall loss of human capital.

Emerging evidence suggests a potential role for the tryptophan-niacin pathway (including the end-product nicotinamide, an isoform of vitamin B3) in decreasing mucosal inflammation and affecting enteral microbiota. At the Tanzania site of MAL-ED, serum levels of tryptophan were related to subsequent linear growth, further suggesting importance of the tryptophan-niacin pathway. What is not clear is whether early childhood growth and development could be improved by targeting enteric infection and the tryptophan-niacin pathway by 1) delivering antibiotics against specific bacteria and/or 2) providing vitamin B3 as nicotinamide/niacinamide.

The main analysis will be intention-to-treat but a secondary analysis will be per protocol.

Eligibility criteria: Inclusion Criteria:

1. Maternal age ≥18
2. Infant ≤ 14 days

Exclusion Criteria:

1. Maternal inability to adhere to protocol
2. Multiple gestation
3. Severe illness (significant birth defect, hospitalization, severe neonatal illness)
4. Birth weight \<1500 g
5. Lack of breastfeeding at enrollment (and lack of intention to continue breastfeeding at time of enrollment).

Primary outcomes:
measure: Height-for-age z-score (HAZ) at 18 months
timeFrame: 18 months
Secondary outcomes:
measure: Weight-for-age z-score (WAZ) at 18 months
timeFrame: 18 months
measure: Head circumference-for-age z-score (HCAZ) at 18 months
timeFrame: 18 months
measure: Stunting
timeFrame: 18 months
measure: All cause mortality
timeFrame: 0-18 months
measure: Hospitalization
timeFrame: 0-18 months
measure: Childhood illness
timeFrame: 0-18 months
measure: Anemia
timeFrame: 12 and 18 months
measure: Enteropathogen burden
timeFrame: 6, 6.5, 12, 12.5, 18 months
measure: Microbiota composition
timeFrame: 6, 6.5, 12, 18 months
measure: Stool myeloperoxidase concentration
timeFrame: 6, 12, 18 months
measure: C-reactive protein concentration in serum
timeFrame: 12 and 18 months
measure: Insulin-like growth factor 1 concentration in serum
timeFrame: 12 and 18 months
measure: Collagen X concentration in serum
timeFrame: 12 and 18 months
measure: Tryptophan-kynurenine ratio
timeFrame: 12 and 18 months
measure: Niacin and nicotinamide metabolite concentration
timeFrame: 6, 12, 18 months
measure: Small intestinal bacterial overgrowth
timeFrame: 6, 12 and 18 months
measure: Malawi Developmental Assessment Tool score
timeFrame: 18 months
Other outcomes:
Locations:
city: Haydom
country: Tanzania
facility: Haydom Lutheran Hospital
state: Manyara
Study officials:
affiliation: Haydom Lutheran Hospital
name: Estomih Mduma
role: PRINCIPAL_INVESTIGATOR
References:
citation: DeBoer MD, Platts-Mills JA, Elwood SE, Scharf RJ, McDermid JM, Wanjuhi AW, Jatosh S, Katengu S, Parpia TC, Rogawski McQuade ET, Gratz J, Svensen E, Swann JR, Donowitz JR, Mdoe P, Kivuyo S, Houpt ER, Mduma E. Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized, double-blind, placebo-controlled trial. PLoS Med. 2021 Sep 28;18(9):e1003617. doi: 10.1371/journal.pmed.1003617. eCollection 2021 Sep.
citation: DeBoer MD, Platts-Mills JA, Scharf RJ, McDermid JM, Wanjuhi AW, Gratz J, Svensen E, Swann JR, Donowitz JR, Jatosh S, Houpt ER, Mduma E. Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT): a protocol for a randomised factorial, double-blind, placebo-controlled trial of azithromycin, nitazoxanide and nicotinamide. BMJ Open. 2018 Jul 7;8(7):e021817. doi: 10.1136/bmjopen-2018-021817.