ELICIT: Early Life Interventions for Childhood Growth and Development In Tanzania

Sponsor

Haydom Lutheran Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT03268902

Collaborator

University of Virginia (Other), Bill and Melinda Gates Foundation (Other)

1,188

Enrollment

Location

Arms

30.7

Actual Duration (Months)

38.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Malnutrition Stunting Cognitive Development Enteric Pathogens	Drug: Azithromycin Oral Liquid Product Drug: Nitazoxanide Oral Suspension Dietary Supplement: Nicotinamide Drug: Placebos	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

1188 participants

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.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)

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.

Primary Purpose:

Treatment

Official Title:

Early Life Interventions for Childhood Growth and Development In Tanzania

Actual Study Start Date :

Sep 5, 2017

Actual Primary Completion Date :

Feb 28, 2020

Actual Study Completion Date :

Mar 26, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Height-for-age z-score (HAZ) at 18 months [18 months]

Secondary Outcome Measures

Weight-for-age z-score (WAZ) at 18 months [18 months]
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
Stool myeloperoxidase concentration [6, 12, 18 months]
Stool myeloperoxidase ELISA
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Days to 14 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).