Early Life Interventions for Childhood Growth and Development In Tanzania

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

Detailed Description
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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.

Official Title
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Early Life Interventions for Childhood Growth and Development In Tanzania

Conditions
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Malnutrition, Stunting, Cognitive Development, Enteric Pathogens

Intervention / Treatment
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* Drug: Azithromycin Oral Liquid Product
* Drug: Nitazoxanide Oral Suspension
* Dietary Supplement: Nicotinamide
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Maternal age ≥18 Infant ≤ 14 days Exclusion Criteria: Maternal inability to adhere to protocol Multiple gestation Severe illness (significant birth defect, hospitalization, severe neonatal illness) Birth weight <1500 g Lack of breastfeeding at enrollment (and lack of intention to continue breastfeeding at time of enrollment).

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 14 Days

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: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide and Antimicrobials<br>Nicotinamide Azithromycin Oral Liquid Product Nitazoxanide Oral Suspension | Drug: Azithromycin Oral Liquid Product<br>* Azithromycin 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months<br>* Other names: Throza DPS;Drug: Nitazoxanide Oral Suspension<br>* Nitazoxanide 100 mg given twice daily for 3 days at 12 and 15 months<br>* Other names: Alinia;Dietary Supplement: Nicotinamide<br>* 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<br>* Other names: Vitamin B3;|
| Experimental: Antimicrobials only<br>Placebo Azithromycin Oral Liquid Product Nitazoxanide Oral Suspension | Drug: Azithromycin Oral Liquid Product<br>* Azithromycin 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months<br>* Other names: Throza DPS;Drug: Nitazoxanide Oral Suspension<br>* Nitazoxanide 100 mg given twice daily for 3 days at 12 and 15 months<br>* Other names: Alinia;Drug: Placebos<br>* 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<br>|
| Experimental: Nicotinamide only<br>Nicotinamide Placebo Placebo | Dietary Supplement: Nicotinamide<br>* 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<br>* Other names: Vitamin B3;Drug: Placebos<br>* 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<br>|
| Placebo Comparator: No active treatment<br>Placebo Placebo Placebo | Drug: Placebos<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height-for-age z-score (HAZ) at 18 months |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight-for-age z-score (WAZ) at 18 months |  | 18 months | 
| Head circumference-for-age z-score (HCAZ) at 18 months |  | 18 months | 
| Stunting | HAZ <-2 | 18 months | 
| All cause mortality |  | 0-18 months | 
| Hospitalization |  | 0-18 months | 
| Childhood illness | Incidence of diarrhea, lower respiratory infection and febrile illness | 0-18 months | 
| Anemia | Moderate to severe anemia by WHO definition for age and altitude | 12 and 18 months | 
| Enteropathogen burden |  | 6, 6.5, 12, 12.5, 18 months | 
| Microbiota composition | Composition of intestinal microbiome | 6, 6.5, 12, 18 months | 
| Stool myeloperoxidase concentration | Stool myeloperoxidase ELISA | 6, 12, 18 months | 
| C-reactive protein concentration in serum | High-sensitivity CRP concentration | 12 and 18 months | 
| Insulin-like growth factor 1 concentration in serum |  | 12 and 18 months | 
| Collagen X concentration in serum |  | 12 and 18 months | 
| Tryptophan-kynurenine ratio | Ratio of tryptophan concentration to kynurenine concentration in metabolomic testing | 12 and 18 months | 
| Niacin and nicotinamide metabolite concentration | Concentration of downstream metabolites of niacin and nicotinamide as tested by metabolomic analysis | 6, 12, 18 months | 
| Small intestinal bacterial overgrowth | Prevalence of SIBO as tested via exhaled hydrogen | 6, 12 and 18 months | 
| Malawi Developmental Assessment Tool score | The MDAT is a measure of child cognitive development | 18 months |