Early Life Interventions for Childhood Growth and Development In Tanzania (ELICIT)

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

Study Overview

• Status: Completed
• Conditions: Malnutrition; Stunting; Cognitive Development; Enteric Pathogens
• Intervention / Treatment: Drug: Azithromycin Oral Liquid Product; Drug: Nitazoxanide Oral Suspension; Dietary supplement: Nicotinamide; Drug: Placebos

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 Type: Interventional
• Enrollment (Actual): 1188
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Tanzania
  • Manyara
    • Haydom, Manyara, Tanzania
      • Haydom Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Haydom Lutheran Hospital
• Collaborators: Bill and Melinda Gates Foundation; University of Virginia
• Investigators: Principal Investigator: Estomih Mduma, Haydom Lutheran Hospital

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2017
• Primary Completion (Actual): February 28, 2020
• Study Completion (Actual): March 26, 2020

Study Registration Dates

• First Submitted: August 29, 2017
• First Submitted That Met QC Criteria: August 29, 2017
• First Posted (Actual): August 31, 2017

Study Record Updates

• Last Update Posted (Actual): May 10, 2021
• Last Update Submitted That Met QC Criteria: May 5, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Malnutrition; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Anti-Infective Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Vitamins; Antiparasitic Agents; Vitamin B Complex; Nicotinic Acids; Azithromycin; Niacinamide; Niacin; Nitazoxanide
• Other Study ID Numbers: 19465

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes