Clinical trial NCT04224987: Azithromycin for Child Survival in Niger: Mortality and Resistance Trial
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Mortality
Resistance Bacterial
Child, Only
Keywords: Mass Treatment
Azithromycin
Childhood Mortality Rate
Antimicrobial Resistance
Implementation and Cost Analysis
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: Ministry of Health, Niger
First posted: 2020-01-13
Enrollment: 864493
Sex: ALL
Minimum age (years): 1
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The AVENIR mortality/resistance trial is a large simple double-masked cluster-randomized trial with response-adaptive allocation in Niger.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: All-cause Mortality (1-59 Months Old)
timeFrame: from 6 months up to 2.5 years
measure: All-cause Mortality (1-11 Months Old)
timeFrame: from 6 months up to 2.5 years
measure: All-cause Mortality (12-59 Months Old)
timeFrame: from 6 months up to 2.5 years
measure: Prevalence of Resistance to Macrolides - Nasopharyngeal Swabs (1-59 Months Old)
timeFrame: After 4 distributions (approximately 24 months)
measure: Load of Genetic Determinants of Resistance to Macrolides - Rectal Swabs (1-59 Months Old)
timeFrame: After 4 distributions (approximately 24 months)
Secondary outcomes:
measure: Mortality Rate by Subgroups: Anthropometric Indicators
timeFrame: After 4 distributions (approximatively 24 month after first distribution)
measure: Prevalence of Resistance to Macrolides From Nasopharyngeal Swabs and Load of Genetics Determinants
timeFrame: After 4 distributions (approximatively 24 month after first distribution)
measure: Program Costs Per Dose Delivered
timeFrame: 1 year
Other outcomes:
Locations:
city: Niamey
country: Niger
facility: Programme national de santé oculaire
Study officials:
affiliation: University of California, San Francisco
name: Tom M Lietman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Kieran S O'Brien, PhD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, Kalua K, Mrango Z, Ray KJ, Cook C, Lebas E, O'Brien KS, Emerson PM, Porco TC, Lietman TM; MORDOR Study Group. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018 Apr 26;378(17):1583-1592. doi: 10.1056/NEJMoa1715474.
citation: Doan T, Arzika AM, Hinterwirth A, Maliki R, Zhong L, Cummings S, Sarkar S, Chen C, Porco TC, Keenan JD, Lietman TM; MORDOR Study Group. Macrolide Resistance in MORDOR I - A Cluster-Randomized Trial in Niger. N Engl J Med. 2019 Jun 6;380(23):2271-2273. doi: 10.1056/NEJMc1901535. No abstract available.
citation: Keenan JD, Arzika AM, Maliki R, Boubacar N, Elh Adamou S, Moussa Ali M, Cook C, Lebas E, Lin Y, Ray KJ, O'Brien KS, Doan T, Oldenburg CE, Callahan EK, Emerson PM, Porco TC, Lietman TM. Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa. N Engl J Med. 2019 Jun 6;380(23):2207-2214. doi: 10.1056/NEJMoa1817213.
citation: WHO Guideline on Mass Drug Administration of Azithromycin to Children under Five Years of Age to Promote Child Survival [Internet]. Geneva: World Health Organization; 2020. No abstract available. Available from http://www.ncbi.nlm.nih.gov/books/NBK561641/
citation: Oldenburg CE, Arzika AM, Maliki R, Lin Y, O'Brien KS, Keenan JD, Lietman TM, For The Mordor Study Group. Optimizing the Number of Child Deaths Averted with Mass Azithromycin Distribution. Am J Trop Med Hyg. 2020 Sep;103(3):1308-1310. doi: 10.4269/ajtmh.19-0328.
citation: O'Brien KS, Arzika AM, Amza A, Maliki R, Ousmane S, Kadri B, Nassirou B, Mankara AK, Harouna AN, Colby E, Lebas E, Liu Z, Le V, Nguyen W, Keenan JD, Oldenburg CE, Porco TC, Doan T, Arnold BF, Lietman TM; AVENIR Study Group. Age-based targeting of biannual azithromycin distribution for child survival in Niger: an adaptive cluster-randomized trial protocol (AVENIR). BMC Public Health. 2021 Apr 29;21(1):822. doi: 10.1186/s12889-021-10824-7.