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

Mark Daniel DeBoer, James A Platts-Mills, Rebecca J Scharf, Joann M McDermid, Anne W Wanjuhi, Jean Gratz, Erling Svensen, Jon R Swann, Jeffrey R Donowitz, Samwel Jatosh, Eric R Houpt, Estomih Mduma, Mark Daniel DeBoer, James A Platts-Mills, Rebecca J Scharf, Joann M McDermid, Anne W Wanjuhi, Jean Gratz, Erling Svensen, Jon R Swann, Jeffrey R Donowitz, Samwel Jatosh, Eric R Houpt, Estomih Mduma

Abstract

Introduction: In 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 analysis: We 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 dissemination: This 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 version: 5.0, 4 December 2017.

Protocol sponsor: Haydom Lutheran Hospital, Haydom, Manyara, Tanzania.

Trial registration number: NCT03268902; Pre-results.

Keywords: Tanzania; antibiotics; development; growth; niacin; stunting.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
The tryptophan-kynurenine-niacin pathway in the intestinal mucosa. Dietary tryptophan is metabolised to kynurenine by IDO—whose activity is increased in settings of inflammation. Adverse effects of elevated IDO activity relate to modulation of the immune response, decreased activity of mTOR in producing antimicrobial peptides and decreased tryptophan for protein synthesis. Intervention with nicotinamide ameliorates some of these effects in preclinical models; in the current study, we hypothesise that intervention with nicotinamide will increase linear growth via normalisation of the tryptophan-kynurenine-niacin pathway and restored enterocyte activity. Both nicotinic acid and nicotinamide are considered dietary forms of niacin. IDO, indoleamine 2,3-dioxygenase; NAD, nicotinamide adenine dinucleotide.
Figure 2
Figure 2
TAC schematic. Burden of intestinal pathogens will be assessed in stool samples from participants at multiple time points using TAC. TAC, Taqman Array Card.

References

    1. Grantham-McGregor S, Cheung YB, Cueto S, et al. . Child development in developing countries 1 - Developmental potential in the first 5 years for children in developing countries. Lancet 2007;369:60–70.
    1. Prendergast AJ, Humphrey JH. The stunting syndrome in developing countries. Paediatr Int Child Health 2014;34:250–65. 10.1179/2046905514Y.0000000158
    1. Kosek MN. MAL-ED Network Investigators. Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study. EBioMedicine 2017;18:109–17. 10.1016/j.ebiom.2017.02.024
    1. Mduma ER, Gratz J, Patil C, et al. . The etiology, risk factors, and interactions of enteric infections and malnutrition and the consequences for child health and development study (MAL-ED): description of the Tanzanian site. Clin Infect Dis 2014;59 Suppl 4(Suppl 4):S325–S330. 10.1093/cid/ciu439
    1. MAL-ED Network Investigators. Childhood stunting in relation to the pre- and postnatal environment during the first 2 years of life: The MAL-ED longitudinal birth cohort study. PLoS Med 2017;14:e1002408 10.1371/journal.pmed.1002408
    1. Scharf RJ, Rogawski ET, Murray-Kolb LE, et al. . Early childhood growth and cognitive outcomes: Findings from the MAL-ED study. Matern Child Nutr. In Press 2018:e12584 10.1111/mcn.12584
    1. Krebs NF, Lozoff B, Georgieff MK. Neurodevelopment: The Impact of Nutrition and Inflammation During Infancy in Low-Resource Settings. Pediatrics 2017;139(Suppl 1):S50–S58. 10.1542/peds.2016-2828G
    1. Platts-Mills JA, Babji S, Bodhidatta L, et al. . Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED). Lancet Glob Health 2015;3:e564–75. 10.1016/S2214-109X(15)00151-5
    1. MAL-ED Network Investigators. Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: findings from the MAL-ED birth cohort study. BMJ Glob Health 2017;2:e000370 10.1136/bmjgh-2017-000370
    1. Rogawski ET, Bartelt LA, Platts-Mills JA, et al. . Determinants and Impact of Giardia Infection in the First 2 Years of Life in the MAL-ED Birth Cohort. J Pediatric Infect Dis Soc 2017;6:153–60. 10.1093/jpids/piw082
    1. Gough EK, Moodie EE, Prendergast AJ, et al. . The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials. BMJ 2014;348:g2267 10.1136/bmj.g2267
    1. Porco TC, Gebre T, Ayele B, et al. . Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 2009;302:962–8. 10.1001/jama.2009.1266
    1. Amza A, Kadri B, Nassirou B, et al. . A cluster-randomized controlled trial evaluating the effects of mass azithromycin treatment on growth and nutrition in Niger. Am J Trop Med Hyg 2013;88:138–43. 10.4269/ajtmh.2012.12-0284
    1. Amadi B, Mwiya M, Musuku J, et al. . Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. Lancet 2002;360:1375–80. 10.1016/S0140-6736(02)11401-2
    1. Shi H, Enriquez A, Rapadas M, et al. . NAD Deficiency, Congenital Malformations, and Niacin Supplementation. N Engl J Med 2017;377:544–52. 10.1056/NEJMoa1616361
    1. Chen C, Mitchell NJ, Gratz J, et al. . Fumonisin, Not Aflatoxin, is Associated with Growth Impairment in Tanzanian Children. Environmental International. In Press 2018.
    1. Le Floc’h N, Otten W, Merlot E. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 2011;41:1195–205. 10.1007/s00726-010-0752-7
    1. Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect 2013;15:866–73. 10.1016/j.micinf.2013.08.003
    1. Hashimoto T, Perlot T, Rehman A, et al. . ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012;487:477–81. 10.1038/nature11228
    1. Wolf AM, Wolf D, Rumpold H, et al. . Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. Clin Immunol 2004;113:47–55. 10.1016/j.clim.2004.05.004
    1. Gupta NK, Thaker AI, Kanuri N, et al. . Serum analysis of tryptophan catabolism pathway: correlation with Crohn’s disease activity. Inflamm Bowel Dis 2012;18:1214–20. 10.1002/ibd.21849
    1. Favre D, Mold J, Hunt PW, et al. . Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2010;2:32ra36 10.1126/scitranslmed.3000632
    1. Mayneris-Perxachs J, Lima AA, Guerrant RL, et al. . Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children. Sci Rep 2016;6:19780 10.1038/srep19780
    1. Kosek MN, Mduma E, Kosek PS, et al. . Plasma Tryptophan and the Kynurenine-Tryptophan Ratio are Associated with the Acquisition of Statural Growth Deficits and Oral Vaccine Underperformance in Populations with Environmental Enteropathy. Am J Trop Med Hyg 2016;95:928–37. 10.4269/ajtmh.16-0037
    1. Allen LH, Hampel D, Shahab-Ferdows S, et al. . Antiretroviral therapy provided to HIV-infected Malawian women in a randomized trial diminishes the positive effects of lipid-based nutrient supplements on breast-milk B vitamins. Am J Clin Nutr 2015;102:1468–74. 10.3945/ajcn.114.105106
    1. Obradović J, Yousafzai AK, Finch JE, et al. . Maternal scaffolding and home stimulation: Key mediators of early intervention effects on children’s cognitive development. Dev Psychol 2016;52:1409–21. 10.1037/dev0000182
    1. Walker SP, Wachs TD, Grantham-McGregor S, et al. . Inequality in early childhood: risk and protective factors for early child development. Lancet 2011;378:1325–38. 10.1016/S0140-6736(11)60555-2
    1. Rasheed MA, Yousafzai AK. The development and reliability of an observational tool for assessing mother-child interactions in field studies- experience from Pakistan. Child Care Health Dev 2015;41:1161–71. 10.1111/cch.12287
    1. Gladstone M, Lancaster GA, Umar E, et al. . The Malawi Developmental Assessment Tool (MDAT): the creation, validation, and reliability of a tool to assess child development in rural African settings. PLoS Med 2010;7:e1000273 10.1371/journal.pmed.1000273
    1. Bayley N. Bayley Scales of Infant and Toddler Development. San Antonio, TX: The Psychological Corporation, 2006.
    1. Murray-Kolb LE, Rasmussen ZA, Scharf RJ, et al. . MAL-ED Network Investigators. The MAL-ED cohort study: methods and lessons learned when assessing early child development and caregiving mediators in infants and young children in 8 low- and middle-income countries. Clin Infect Dis 2014;59:S261–72. 10.1093/cid/ciu437
    1. Donowitz JR, Petri WA. Pediatric small intestine bacterial overgrowth in low-income countries. Trends Mol Med 2015;21:6–15. 10.1016/j.molmed.2014.11.001
    1. Donowitz JR, Haque R, Kirkpatrick BD, et al. . Small Intestine Bacterial Overgrowth and Environmental Enteropathy in Bangladeshi Children. MBio 2016;7:e02102-15–15. 10.1128/mBio.02102-15
    1. Trammell SA, Schmidt MS, Weidemann BJ, et al. . Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016;7:12948 10.1038/ncomms12948
    1. Buchanan AM, Fiorillo SP, Omondi MW, et al. . Establishment of biochemistry reference values for healthy Tanzanian infants, children and adolescents in Kilimanjaro Region. Trop Med Int Health 2015;20:1569–77. 10.1111/tmi.12580
    1. Coghlan RF, Oberdorf JA, Sienko S, et al. . A degradation fragment of type X collagen is a real-time marker for bone growth velocity. Sci Transl Med 2017;9:eaan4669 10.1126/scitranslmed.aan4669
    1. Inagaki T, Moschetta A, Lee YK, et al. . Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 2006;103:3920–5. 10.1073/pnas.0509592103
    1. Claus SP, Swann JR. Nutrimetabonomics: Applications for Nutritional Sciences, with Specific Reference to Gut Microbial Interactions : Doyle MP, Klaenhammer TR, Annual Review of Food Science and Technology. 4 Palo Alto: Annual Reviews, 2013:381–99.
    1. Ghodsi M, Liu B, Pop M. DNACLUST: accurate and efficient clustering of phylogenetic marker genes. BMC Bioinformatics 2011;12:271 10.1186/1471-2105-12-271
    1. Liu J, Gratz J, Amour C, et al. . A laboratory-developed TaqMan Array Card for simultaneous detection of 19 enteropathogens. J Clin Microbiol 2013;51:472–80. 10.1128/JCM.02658-12
    1. Liu J, Gratz J, Amour C, et al. . Optimization of Quantitative PCR Methods for Enteropathogen Detection. PLoS One 2016;11:e0158199 10.1371/journal.pone.0158199
    1. Liu J, Platts-Mills JA, Juma J, et al. . Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet 2016;388:1291–301. 10.1016/S0140-6736(16)31529-X
    1. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 27 ed Wayne, Pennsylvania: Clinical and Laboratory Standards Institute, 2017.
    1. Ikehara Y, Nishihara S, Yasutomi H, et al. . Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer Epidemiol Biomarkers Prev 2001;10:971–7.
    1. McGovern DP, Jones MR, Taylor KD, et al. . Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum Mol Genet 2010;19:3468–76. 10.1093/hmg/ddq248
    1. Marionneau S, Airaud F, Bovin NV, et al. . Influence of the combined ABO, FUT2, and FUT3 polymorphism on susceptibility to Norwalk virus attachment. J Infect Dis 2005;192:1071–7. 10.1086/432546
    1. Yusuf S, Lonn E, Pais P, et al. . Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med 2016;374:2032–43. 10.1056/NEJMoa1600177
    1. Locks LM, Manji KP, McDonald CM, et al. . Effect of zinc and multivitamin supplementation on the growth of Tanzanian children aged 6-84 wk: a randomized, placebo-controlled, double-blind trial. Am J Clin Nutr 2016;103:910–8. 10.3945/ajcn.115.120055
    1. Soofi S, Cousens S, Iqbal SP, et al. . Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet 2013;382:29–40. 10.1016/S0140-6736(13)60437-7

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