Azithromycin for Child Survival in Niger: Mortality and Resistance Trial

Phase 4

Completed

Conditions: Resistance Bacterial
Child, Only
Mortality

Interventions: Drug: Azithromycin
Other: Placebo

Registration Number: NCT04224987

Lead Sponsor: University of California, San Francisco

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 864493

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Azithro 1-11	Placebo	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
Placebo	Placebo	Biannual weight- or height-based dose of oral placebo to children 1-59 months old
Azithro 1-11	Azithromycin	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
Azithro 1-59	Azithromycin	Biannual age, weight- or height-based dose of oral azithromycin suspension to children 1-59 months old

Primary Outcome Measures

Name	Time	Method
All-cause Mortality (1-59 Months Old)	from 6 months up to 2.5 years	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.
Prevalence of Resistance to Macrolides - Nasopharyngeal Swabs (1-59 Months Old)	After 4 distributions (approximately 24 months)	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.
All-cause Mortality (1-11 Months Old)	from 6 months up to 2.5 years	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.
All-cause Mortality (12-59 Months Old)	from 6 months up to 2.5 years	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.
Load of Genetic Determinants of Resistance to Macrolides - Rectal Swabs (1-59 Months Old)	After 4 distributions (approximately 24 months)	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)

Secondary Outcome Measures

Name	Time	Method
Mortality Rate by Subgroups: Anthropometric Indicators	After 4 distributions (approximatively 24 month after first distribution)	Mortality rate compared by arm in subgroups based on weight in children 1-11 months over 2.5 years
Prevalence of Resistance to Macrolides From Nasopharyngeal Swabs and Load of Genetics Determinants	After 4 distributions (approximatively 24 month after first distribution)	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
Program Costs Per Dose Delivered	1 year	Program costs as captured by routine administrative data collection during the substudy and by micro-costing activities, per doses delivered