ELICIT Randomized Controlled Trial

Background: Childhood growth and thriving remain sub-optimal in low-resource settings worldwide, underscoring the need to better understand underlying etiologies and to identify interventions toward improving outcomes. Children living in the area around Haydom, Tanzania were found in the MAL-ED study to have a high burden of infection with intestinal pathogens starting early in life. High carriage of enteropathogens, even in the absence of diarrhea, was associated with a 1.36 increased odds of having lower length for age. A prior meta-analysis of randomized controlled trials reported that childhood antibiotic use was associated with a 0.04 cm/month increase in height.

Another potential means of improving growth is by targeting the tryptophan-kynurenine-niacin pathway, in which dietary tryptophan is absorbed and then metabolized by indoleamine 2,3-dioxygenase (IDO) to kynurenine and later to nicotinic acid, a key precursor to NAD+. In MAL-ED, children at the Haydom site with higher ratios of kynurenine:tryptophan were noted to have poorer linear growth. Children in the Haydom area have a maize-based diet low in tryptophan, a key precursor to niacin/nicotinamide and NAD+.

We hypothesized that among children with a high degree of stunting and enteric pathogen burden in this region, intervention with 1) antimicrobials and/or 2) nicotinamide would increase linear growth. We further set out to interrogate the potential mechanisms behind these effects. In the case of antimicrobial intervention, we hypothesize that intervention with azithromycin and nitazoxanide (relative to placebo) would result in a decrease in enteropathogen burden that would be associated with an increase in growth. In the case of nicotinamide (relative to placebo), we hypothesize that intervention will result in a reduction in the kynurenine:tryptophan ratio, an increase in availability of nicotinamide for NAD+ synthesis and associated increases in growth.

Objectives: The primary objectives of this randomized factorial, double-blind, placebo-controlled trial are to determine if interventions with 1) antimicrobials and 2) nicotinamide are associated with increased length-for-age z-score (LAZ, relative to placebo-treated children) by age 18 months.

Methodology:

Geographic Location/Study Sites: Area around Haydom, Tanzania (a rural, semi-arid area with a high degree of poverty)

Dates of Data Collection: September 2017 - March 2020

Study Design: Factorial randomized controlled trial with treatment between 2 weeks and 18 months of age

Eligibility Criteria: The participants must have met the following

Inclusion criteria:

Mother is >18 years
Child is age <14 days
Born in the Haydom catchment area (defined for study purposes as 25 km radius of Haydom Lutheran Hospital)

Exclusion criteria:

Maternal inability to adhere to the protocol
Multiple gestation
Significant birth defect or neonatal illness
Weight <1,500 g at enrollment (age < 14 days)
Lack of intent to breastfeed infant
Plan to move from area within the next 18 months

Study Arms: The nicotinamide intervention consists of nicotinamide 250 mg daily administered by mouth to the child's mother during breast feeding 0-6 months (and thus passed on to the child via breast milk) and then 100 mg administered daily by mouth to the child during months 6-18.

The antimicrobial intervention consists of azithromycin administered as a single dose (20 mg/kg of 200 mg/5 mL suspension) at age 6, 9, 12, and 15 months and nitazoxanide as a 3-day course (100 mg twice daily of 100 mg/5 mL suspension) at age 12 and 15 months (with both antimicrobials randomized together).

These interventions were delivered in a factorial manner such that children received both interventions, either intervention alone, or neither intervention.

Data Collection: Study visits occurred in the family's home at enrollment and monthly from age 1 through 18 months, occurring within a 7-day window around these dates.

Study staff use standardized questionnaires designed for the study, including questions asked monthly regarding breastfeeding, use of complementary foods, childhood illness and treatment (including whether an antibiotic was used and if so which one), types of food sources given, and food insecurity. Additional questionnaires completed at the first month's visit collected data related to the child's home environment.

Child length, weight, mid-upper-arm circumference (MUAC) and head circumference were measured every three months starting at enrollment. Weight was assessed monthly.

Cognitive testing using the Malawi Developmental Assessment Test (MDAT) was performed at month 18.

For laboratory analysis, the following specimens were collected:

Breast milk at months 1 and 5
Stool at months 3, 6, 9, 12, 15, and 18
Urine at months 6, 12 and 18
Blood at months 12 and 18

ClinEpiDB Data Integration: Data files were provided to ClinEpiDB as flat csv files. Redundant or administrative columns were dropped from presentation on ClinEpiDB.org. All dates were obfuscated per participant through the application of a random number algorithm that shifted dates no more than seven days to comply with the ethical conduct of human subjects research.

Acknowledgements: We would like to thank the families in the Haydom area who participated in this trial.

Financial Support: This work was supported by the Bill and Melinda Gates Foundation, OPP1141342.

Ethics Statement: The study protocol was approved by the National Institute for Medical Research (NIMR) of Tanzania and the Tanzanian Food and Drug administration (TFDA) and the Institutional Review Board at the University of Virginia. Study oversight was provided by FHI360 (North Carolina, USA). Mothers gave written informed consent to participate either during pregnancy or at the time of enrollment.

Last updated: March 8, 2021The Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) study was a randomized controlled trial evaluating the efficacy of antimicrobials and nicotinamide in increasing growth. Infants aged 0-14 days old with no significant birth defects or neonatal illness were enrolled with their mothers and assigned to one of 4 intervention arms in a 2 x 2 factorial trial design. Participants were followed for 18 months.