Azithromycin for Child Survival in Niger: Mortality and Resistance Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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In the Mortality/Resistance trial, 3,350 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.

Official Title
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Azithromycine Pour la Vie Des Enfants au Niger - Implémentation et Recherche: Essai mortalité et résistance (Azithromycin for Child Survival in Niger: Mortality Trial and Resistance Trial)

Conditions
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Mortality, Resistance Bacterial, Child, Only

Intervention / Treatment
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* Drug: Azithromycin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The AVENIR mortality/resistance trial is a large simple double-masked cluster-randomized trial with response-adaptive allocation in Niger.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithro 1-11<br>Biannual weight- or height-based dose of oral azithromycin suspension to children 1-11 months old and oral placebo or no intervention to children 12-59 months old | Drug: Azithromycin<br>* Azithromycin will be administered as a directly observed dose in oral suspension form for children: Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) For children 1-11 months of age, weight or age-based dosing will be used 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<br>* Other names: Zithromax;Other: Placebo<br>* Placebo will be administered as a directly observed dose in oral suspension form for children: Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) For children 1-11 months of age, weight-based dosing will be used 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<br>|
| Active Comparator: Azithro 1-59<br>Biannual age, weight- or height-based dose of oral azithromycin suspension to children 1-59 months old | Drug: Azithromycin<br>* Azithromycin will be administered as a directly observed dose in oral suspension form for children: Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) For children 1-11 months of age, weight or age-based dosing will be used 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<br>* Other names: Zithromax;|
| Placebo Comparator: Placebo<br>Biannual weight- or height-based dose of oral placebo to children 1-59 months old | Other: Placebo<br>* Placebo will be administered as a directly observed dose in oral suspension form for children: Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) For children 1-11 months of age, weight-based dosing will be used 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2.5 years from the first enrollment | 
| 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. | 2.5 years from the first enrollment | 
| 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. | 2.5 years from the first enrollment | 
| Prevalence of resistance to macrolides - nasopharyngeal swabs (1-59 months old) | Prevalence of resistance to macrolides including those determinants known to be found in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus from nasopharyngeal swabs in children 1-59 months old. | After 4 distributions (approximately 24 months) | 
| Load of genetic determinants of resistance to macrolides - rectal swabs (1-59 months old) | Load of genetic determinants of resistance to macrolides including those determinants known to be found in Campylobacter spp, Salmonella spp, Shigella spp, and Escherichia coli from rectal swabs in children 1-59 months old, defined as read number per million base pairs, using DNA-seq (metagenomic deep sequencing) | After 4 distributions (approximately 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality (12-59 months old) | Mortality rate (deaths per 1,000 person-years at risk) among children ages 12-59 months over 2.5 years, comparing the azithro 1-11 and placebo arms. | 2.5 years from first enrollment | 
| All-cause mortality (1-11 months old ) | Mortality rate (deaths per 1,000 person-years at risk) among children ages 1-11 months over 2.5 years, comparing the azithro 1-11 and azithro 1-59 arms. | 2.5 years from first enrollment | 
| Mortality rate by subgroups: anthropometric indicators | Mortality rate compared by arm in subgroups based on weight in children 1-11 months over 2.5 years | After 4 distributions (approximatively 24 month after first distribution) | 
| Prevalence of resistance to macrolides from nasopharyngeal swabs and load of genetics determinants | Prevalence of resistance to macrolides from nasopharyngeal swabs and load of genetic determinants of resistance to macrolides from rectal swabs after 4 distributions in: Children 7-12 years old at 24 months from baseline Caregivers/guardians of eligible children at 24 months from baseline | After 4 distributions (approximatively 24 month after first distribution) | 
| Program costs per dose delivered | Program costs as captured by routine administrative data collection during the substudy and by micro-costing activities, per doses delivered | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mass Treatment, Azithromycin, Childhood Mortality Rate, Antimicrobial Resistance, Implementation and Cost Analysis