Cognitive Development, Enteric Pathogens, Malnutrition, Stunting
Conditions
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.
Interventions
Azithromycin 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months
DRUGNitazoxanide Oral Suspension
Nitazoxanide 100 mg given twice daily for 3 days at 12 and 15 months
DIETARY_SUPPLEMENTNicotinamide
Mothers in the nicotinamide arm will be given nicotinamide 250 mg daily from delivery through 6 months post-partum in capsule form. Children in the nicotinamide arm will be given 100 mg/d in powder form between 6 and 18 months of age
DRUGPlacebos
Contain inert excipients only. Azithromycin placebo 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months. Nitazoxanide placebo 100 mg given twice daily for 3 days at 12 and 15 months. Mothers in the nicotinamide placebo arm will be given placebo 250 mg daily from delivery through 6 months post-partum in capsule form. Children in the nicotinamide placebo arm will be given 100 mg/d of placebo in powder form between 6 and 18 months of age
Sponsors
University of Virginia
Bill and Melinda Gates Foundation
Haydom Lutheran Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Both participants and investigators will be blinded to the treatments allocated to each participant. The members of the DSMB will also be blinded.
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.
Eligibility
Sex/Gender
ALL
Age
0 Days to 14 Days
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Height-for-age z-score (HAZ) at 18 months | 18 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Head circumference-for-age z-score (HCAZ) at 18 months | 18 months | — |
| Stunting | 18 months | HAZ \<-2 |
| All cause mortality | 0-18 months | — |
| Hospitalization | 0-18 months | — |
| Childhood illness | 0-18 months | Incidence of diarrhea, lower respiratory infection and febrile illness |
| Anemia | 12 and 18 months | Moderate to severe anemia by WHO definition for age and altitude |
| Enteropathogen burden | 6, 6.5, 12, 12.5, 18 months | — |
| Microbiota composition | 6, 6.5, 12, 18 months | Composition of intestinal microbiome |
| Weight-for-age z-score (WAZ) at 18 months | 18 months | — |
| C-reactive protein concentration in serum | 12 and 18 months | High-sensitivity CRP concentration |
| Insulin-like growth factor 1 concentration in serum | 12 and 18 months | — |
| Collagen X concentration in serum | 12 and 18 months | — |
| Tryptophan-kynurenine ratio | 12 and 18 months | Ratio of tryptophan concentration to kynurenine concentration in metabolomic testing |
| Niacin and nicotinamide metabolite concentration | 6, 12, 18 months | Concentration of downstream metabolites of niacin and nicotinamide as tested by metabolomic analysis |
| Small intestinal bacterial overgrowth | 6, 12 and 18 months | Prevalence of SIBO as tested via exhaled hydrogen |
| Malawi Developmental Assessment Tool score | 18 months | The MDAT is a measure of child cognitive development |
| Stool myeloperoxidase concentration | 6, 12, 18 months | Stool myeloperoxidase ELISA |
Countries
Tanzania
Outcome results
None listed