Early Life Interventions for Childhood Growth and Development In Tanzania
Condition: Malnutrition; Stunting; Cognitive Development; Enteric Pathogens
MeSH terms: Malnutrition
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Azithromycin Oral Liquid Product; Nitazoxanide Oral Suspension; Nicotinamide; Placebos
Intervention type(s): Drug; Drug; Dietary Supplement; Drug
Intervention description(s): Azithromycin 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months; Nitazoxanide 100 mg given twice daily for 3 days at 12 and 15 months; 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; 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
Other intervention name(s): Throza DPS; Alinia; Vitamin B3
Intervention MeSH terms: Niacinamide; Niacin; Nicotinic Acids; Azithromycin; Nitazoxanide
Allocation: Randomized
Intervention model: Factorial Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment