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

Abstract

IntroductionIn many developing areas in the world, a high burden of enteric pathogens in early childhood are associated with growth deficits. The tryptophan-kynurenine-niacin pathway has been linked to enteric inflammatory responses to intestinal infections. However, it is not known in these settings whether scheduled antimicrobial intervention to reduce subclinical enteric pathogen carriage or repletion of the tryptophan-kynurenine-niacin pathway improves linear growth and development.Methods and analysisWe are conducting a randomised, placebo-controlled, factorial intervention trial in the rural setting of Haydom, Tanzania. We are recruiting 1188 children within the first 14 days of life, who will be randomised in a 2×2 factorial design to administration of antimicrobials (azithromycin and nitazoxanide, randomised together) and nicotinamide. The nicotinamide is administered as a daily oral dose, which for breast-feeding children aged 0–6 months is given to the mother and for children aged 6–18 months is given to the child directly. Azithromycin is given to the child as a single oral dose at months 6, 9, 12 and 15; nitazoxanide is given as a 3-day course at months 12 and 15. Mother/child pairs are followed via monthly in-home visits. The primary outcome is the child’s length-for-age Z-score at 18 months. Secondary outcomes for the child include additional anthropometry measures; stool pathogen burden and bacterial microbiome; systemic and enteric inflammation; blood metabolomics, growth factors, inflammation and nutrition; hydrogen breath assessment to estimate small-intestinal bacterial overgrowth and assessment of cognitive development. Secondary outcomes for the mother include breastmilk content of nicotinamide, other vitamins and amino acids; blood measures of tryptophan-kynurenine-niacin pathway and stool pathogens.Ethics and disseminationThis trial has been approved by the Tanzanian National Institute for Medical Research, the Tanzanian FDA and the University of Virginia IRB. Findings will be presented at national and international conferences and published in peer-review journals.Protocol version5.0, 4 December 2017.Protocol sponsorHaydom Lutheran Hospital, Haydom, Manyara, Tanzania.Trial registration numberNCT03268902; Pre-results.

Baseline Characteristics of Study Participants in the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) Trial

“…The ELICIT design and protocol is described in detail elsewhere. 6 In brief, the study is a randomized, placebo-controlled, interventional trial to determine whether administration of 1) antimicrobials (azithromycin and nitazoxanide) to reduce the subclinical carriage of enteric pathogens and/or 2) nicotinamide, a niacin vitamer, to reduce intestinal inflammation 14 has an effect on linear growth at 18 months. Mothers could provide informed consent during pregnancy, but mother/child dyads were enrolled within 14 days of the child’s birth from September 2017 to September 2018, when the inclusion and exclusion criteria were met.…”

“… 4 The prevalence of stunting in the Haydom MAL-ED cohort was found to be 70% at 18 months of age. 5 , 6 Although water, sanitation, and hygiene (WASH) interventions and micro- or macronutrient supplementation are widely thought to contribute to stunting, the efficacy of interventions to improve these factors has been inconsistent or limited. 7 – 11 There is evidence that recurrent enteric infections and micronutrient deficiencies, including deficiencies in the tryptophan–kynurenine–niacin pathway, are associated with environmental enteric dysfunction, which may contribute to poor child growth and stunting.…”

“… 2 , 5 , 12 – 15 We have previously described the rationale and design of the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) study, an ongoing interventional trial to determine the effect of antimicrobials and micronutrient supplementation on linear growth in children in Haydom. 6 …”

From Samples to Insights into Metabolism: Uncovering Biologically Relevant Information in LC-HRMS Metabolomics Data

“…There are several different experimental design types to consider. Amongst the more common are completely randomized, crossover, and factorial designs [18][19][20][21]. Although commonly used due to their fairly simple nature, completely randomized designs are limited in the fact that they study the effect of one primary factor without considering other factors.…”

Impact of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Plasma Biomarkers of Environmental Enteric Dysfunction among Rural Laotian Children: A Randomized Controlled Trial

“…During inflammation, the indoleamine 2,3-dioxygenase (IDO1) enzyme is upregulated by proinflammatory cytokines, such as tumor necrosis factor alpha, and tryptophan catabolism to kynurenine is increased, resulting in low tryptophan and high kynurenine concentrations and an elevated KT ratio. 23 Tryptophan availability for protein synthesis is decreased, and low tryptophan concentrations have been associated with decreased linear growth velocity. 24,25 Kynurenine itself can also have immunomodulatory activities, including decreasing proliferation and survival of T lymphocytes.…”