Azithromycin for Child Survival in Niger: Mortality and Resistance Trial

University of California, San Francisco864,493 enrolled

Overview

The MORDOR trial found that biannual distribution of azithromycin to children 1-59 months old reduced child mortality. The World Health Organization (WHO) released conditional guidelines for this intervention, which include targeting azithromycin distributions to children 1-11 months of age in high mortality settings.Targeting treatment to children 1-11 months old could reduce antimicrobial resistance by limiting antibiotic distributions while treating children at the highest mortality risk. However, this targeted intervention has not yet been tested. The AVENIR mortality/resistance trial aims to assess the efficacy of age-based targeting of biannual azithromycin distribution on mortality as well as determine the impact of age-based targeting on antimicrobial resistance.

In the Mortality/Resistance trial, 3,000 communities in the Dosso and Tahoua regions of Niger will be randomized to one of three arms: 1) azithro 1-11: biannual oral azithromycin to children 1-11 months old with biannual oral placebo to children 12-59 months old, 2) azithro 1-59: biannual oral azithromycin to children 1-59 months old, or 3) placebo: biannual oral placebo to children 1-59 months old. Interventions will be delivered biannually through a door-to-door census. Mortality will also be monitored through biannual census data collection, which will be used to adaptively allocate treatment assignments after the first year. Communities will retain an allocation for 4 distributions before being re-randomized. Antimicrobial resistance will be monitored using cluster sampling of treated and untreated children and adults in the Dosso region. To compare costs, coverage, and acceptability of treating 1-11-month-old children only vs children 1-59 months old, an additional 80 communities in the Dosso region will be selected. These communities will be randomized in a 1:1 fashion to either receive 1) distribution of open-label azithromycin to children 1-11 months old with no intervention to children 12-59 months old or 2) distribution of open-label azithromycin to children 1-59 months old. The primary outcome for this substudy will be community-level costs per dose delivered. Secondary outcomes include program costs, treatment coverage, and acceptability of the intervention according to community leaders, community health workers, and caregivers of eligible children.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Interventions

AzithromycinDRUG

Azithromycin will be administered as a directly observed dose in oral suspension form for children: 1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) 2. For children 1-11 months of age, weight or age-based dosing will be used 3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program

PlaceboOTHER

Placebo will be administered as a directly observed dose in oral suspension form for children: 1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) 2. For children 1-11 months of age, weight-based dosing will be used 3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program

Eligibility

Sex: ALLMin age: 1 MonthMax age: 59 MonthsHealthy volunteers:

Medical Language ↔ Plain English

1. Intervention At the community-level, eligibility includes: Inclusion Criteria: * Location in Dosso, Tahoua, Maradi, Zinder, or Tillabéri regions * Population 250 to 2,499\* * Distance \> 5 km from district headquarters town * Distinguishable from neighboring communities * Verbal consent of community leader(s) Exclusion criteria: * Inaccessible or unsafe for study team * "Quartier" designation on national census \*Population size as estimated from the most recent national census or projections At the individual-level, eligibility includes: Inclusion criteria: * Age 1-59 months * Primary residence in a study community * Verbal consent of caregiver/guardian for study participation * Weight ≥ 3.0 kg (\*no weight limits in communities using age-based dosing) Exclusion criteria: • Known allergy to macrolides 2. Population-based sample collections At the community-level, eligibility includes: Inclusion Criteria: * Location in Dosso * Distinguishable from neighboring communities * Verbal consent of community leader(s) Exclusion criteria: * Inaccessible or unsafe for the study team * Included in MORDOR trials * Not randomly selected * Received treatment prior to sample collection At the individual-level, eligibility includes: Inclusion Criteria: * Age 1-59 months or 7-12 years or caregiver/guardian of a child eligible for treatment * Primary residence in a study community selected for sample collections * Verbal consent of caregiver/guardian for study participation Exclusion criteria: • An individual is not on the list of randomly selected participants from the census

Outcomes

Primary Outcomes

All-cause Mortality (1-59 Months Old)

Mortality rate (deaths per 1,000 person-years at risk) among children 1-59 months of age, comparing the azithro 1-59 and placebo arms.

Time frame: from 6 months up to 2.5 years

All-cause Mortality (1-11 Months Old)

Mortality rate (deaths per 1,000 person-years at risk) among children 1-11 months of age, comparing the azithro 1-11 and placebo arms.

Time frame: from 6 months up to 2.5 years

All-cause Mortality (12-59 Months Old)

Mortality rate (deaths per 1,000 person-years at risk) among children 12-59 months of age with rates compared between azithro 1-11 and azithro 1-59 communities.

Time frame: from 6 months up to 2.5 years

Prevalence of Resistance to Macrolides - Nasopharyngeal Swabs (1-59 Months Old)

Prevalence of macrolide resistance among pneumococcus-positive nasopharyngeal swabs collected from children aged 1-59 months after 4 distributions. Resistance was assessed among culture-positive pneumococcal isolates from nasopharyngeal swabs.

Time frame: After 4 distributions (approximately 24 months)

Load of Genetic Determinants of Resistance to Macrolides - Rectal Swabs (1-59 Months Old)

Community-level load of macrolide antimicrobial resistance determinants in pooled rectal swabs collected from children aged 1-59 months after four biannual distributions. Rectal swabs from each community were pooled and analyzed using metagenomic DNA sequencing. Nonhost sequencing reads were aligned to an antimicrobial resistance reference database, and reads matching macrolide resistance determinants were summed and normalized to the total number of nonhost reads in the pooled sample. Values are reported as matched resistance reads per million nonhost reads (rM). Higher values indicate a greater abundance of macrolide resistance determinants. The values presented in the table are untransformed normalized counts.

Time frame: After 4 distributions (approximately 24 months)

Secondary Outcomes

Mortality Rate by Weight-for-age Z-score Subgroup Among Infants Aged 1-11 Months

All-cause mortality incidence rate among children aged 1-11 months who had weight measured during at least one census round and had a valid weight-for-age z-score calculated using the World Health Organization Child Growth Standards. Nutritional status was assessed at the beginning of each census interval. This measure reports the overall mortality rate for this analysis population by randomized treatment arm and is not stratified by weight-for-age z-score subgroup. Mortality rates are reported as deaths per 1,000 person-years.

Time frame: After 4 distributions (approximatively 24 month after first distribution)

Load of Genetic Determinants of Resistance to Macrolides in Nasopharyngeal Swabs From Guardians

Community-level loads of macrolide antimicrobial resistance determinants in nasopharyngeal swabs collected from guardians of children eligible for treatment after four biannual distributions. Nasopharyngeal swabs from each community were pooled and analyzed using DNA sequencing. Nonhost sequencing reads were aligned to an antimicrobial resistance reference database, and reads matching macrolide resistance determinants were summed and normalized to the total number of nonhost reads in the pooled sample. Values are reported as matched resistance reads per million nonhost reads (rM). Higher values indicate a greater abundance of macrolide resistance determinants. The values presented in the table are untransformed normalized counts; log-transformed values were used only for inferential statistical analyses.

Time frame: After 4 distributions (approximatively 24 month after first distribution)

Program Costs Per Dose Delivered

Program cost per dose delivered was estimated using routine administrative data and micro-costing activities. Costs were calculated per dose delivered and were not stratified by randomized treatment arm.

Time frame: 1 year

Load of Genetic Determinants of Resistance to Macrolides in Nasopharyngeal Swabs From Children Aged 7-12 Years

Community-level loads of macrolide antimicrobial resistance determinants in nasopharyngeal swabs collected from children aged 7-12 years after four biannual distributions. Nasopharyngeal swabs from each community were pooled and analyzed using DNA sequencing. Nonhost sequencing reads were aligned to an antimicrobial resistance reference database, and reads matching macrolide resistance determinants were summed and normalized to the total number of nonhost reads in the pooled sample. Values are reported as matched resistance reads per million nonhost reads (rM). Higher values indicate a greater abundance of macrolide resistance determinants. The values presented in the table are untransformed normalized counts; log-transformed values were used only for inferential statistical analyses.

Azithromycin for Child Survival in Niger: Mortality and Resistance Trial

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes