Azithromycin for Child Survival in Niger: Mortality and Resistance Trial (AVENIR)

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Mortality; Child, Only; Resistance Bacterial
• Intervention / Treatment: Drug: Azithromycin; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 1106050
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Elodie Lebas, RN; Phone Number: 5104232245; Email: elodie.lebas@ucsf.edu

Study Locations

• Niger
  • Niamey, Niger
    • Recruiting
    • Programme national de santé oculaire
    • Contact: Amza Abdou, MD; Phone Number: 00227 96967009; Email: dr.amzaabdou@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 4 years (Child)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithro 1-11; 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; 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; Other Names: Zithromax; Other: Placebo; 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
Active Comparator: Azithro 1-59; Biannual age, weight- or height-based dose of oral azithromycin suspension to children 1-59 months old	Drug: Azithromycin; 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; Other Names: Zithromax
Placebo Comparator: Placebo; Biannual weight- or height-based dose of oral placebo to children 1-59 months old	Other: Placebo; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Bill and Melinda Gates Foundation; Ministry of Health, Niger
• Investigators: Principal Investigator: Tom M Lietman, MD, University of California, San Francisco; Principal Investigator: Kieran S O'Brien, PhD, MPH, University of California, San Francisco

Publications and helpful links

General Publications

• 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.
• 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/
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2020
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: January 8, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Azithromycin; Antimicrobial Resistance; Mass Treatment; Childhood Mortality Rate; Implementation and Cost Analysis
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: 19-28387A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data underlying outcomes publications will be made publicly available.
• IPD Sharing Time Frame: Individual participant data will be made available after publication of the outcomes and will be made available indefinitely.
• IPD Sharing Access Criteria: Once made available, the data will be open access.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes