Azithromycin for Child Survival in Niger: Mortality and Resistance Trial

NCT04224987 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: 19-28387A
• Study Type: interventional
• Target: 864,493
• Locations: 1 country
• Sites: 1

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.

Conditions

Mortality; Resistance Bacterial; Child, Only

Keywords

Mass Treatment; Azithromycin; Childhood Mortality Rate; Antimicrobial Resistance; Implementation and Cost Analysis

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  from 6 months up to 2.5 years

• 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 Outcomes (3)

• Mortality Rate by Subgroups: Anthropometric Indicators

  After 4 distributions (approximatively 24 month after first distribution)

• Prevalence of Resistance to Macrolides From Nasopharyngeal Swabs and Load of Genetics Determinants

  After 4 distributions (approximatively 24 month after first distribution)

• Program Costs Per Dose Delivered

  1 year

Study Arms (3)

Azithro 1-11

ACTIVE COMPARATOR

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; Other: Placebo

Azithro 1-59

ACTIVE COMPARATOR

Biannual age, weight- or height-based dose of oral azithromycin suspension to children 1-59 months old

Drug: Azithromycin

Placebo

PLACEBO COMPARATOR

Biannual weight- or height-based dose of oral placebo to children 1-59 months old

Other: Placebo

Interventions

Azithromycin DRUG

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

Also known as: Zithromax

Azithro 1-11; Azithro 1-59

Placebo OTHER

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

Azithro 1-11; Placebo

Eligibility Criteria

• Age: 1 Month - 59 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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:
• 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)
• Known allergy to macrolides
• Population-based sample collections
• At the community-level, eligibility includes:
• Location in Dosso
• Distinguishable from neighboring communities
• Verbal consent of community leader(s)
• Inaccessible or unsafe for the study team
• Included in MORDOR trials

Sponsors & Collaborators

• University of California, San Francisco: lead
• Bill and Melinda Gates Foundation: collaborator
• Ministry of Health, Niger: collaborator

Study Sites (1)

Programme national de santé oculaire

Niamey, Niger

Location

Related Publications (9)

• 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.

  PMID: 29694816 BACKGROUND

• 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.

  PMID: 31167060 BACKGROUND

• 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.

  PMID: 31167050 BACKGROUND

• 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/

  PMID: 32924384 BACKGROUND

• 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.

  PMID: 32067626 BACKGROUND

• Arzika AM, Amza A, Maliki R, Aichatou B, Bello IM, Beidi D, Galo N, Harouna N, Karamba AM, Mahamadou S, Abarchi M, Ibrahim A, Brandt C, Lebas E, Peterson B, Liu Z, Oldenburg CE, Doan T, Porco TC, Arnold BF, Lietman TM, O'Brien KS. Spillover of Azithromycin Mass Drug Administration and Child Survival: A Secondary Analysis of a Cluster-Randomized Clinical Trial. JAMA Netw Open. 2025 Jul 1;8(7):e2519693. doi: 10.1001/jamanetworkopen.2025.19693.

  PMID: 40638118 DERIVED

• Peterson B, Arzika A, Maliki R, Abdou A, Aichatou B, Bello IM, Beidi D, Galo N, Harouna N, Karamba AM, Mahamadou S, Abarchi M, Ibrahim A, Lebas E, Liu Z, Brandt C, Colby E, Oldenburg CE, Porco TC, Arnold B, Lietman TM, O'Brien KS. Mass distribution of azithromycin and child mortality among underweight infants in rural Niger: a subgroup analysis of the AVENIR cluster-randomised trial. BMJ Open. 2025 Mar 27;15(3):e097916. doi: 10.1136/bmjopen-2024-097916.

  PMID: 40147984 DERIVED

• O'Brien KS, Arzika AM, Amza A, Maliki R, Aichatou B, Bello IM, Beidi D, Galo N, Harouna N, Karamba AM, Mahamadou S, Abarchi M, Ibrahim A, Lebas E, Peterson B, Liu Z, Le V, Colby E, Doan T, Keenan JD, Oldenburg CE, Porco TC, Arnold BF, Lietman TM; AVENIR study group. Azithromycin to Reduce Mortality - An Adaptive Cluster-Randomized Trial. N Engl J Med. 2024 Aug 22;391(8):699-709. doi: 10.1056/NEJMoa2312093.

  PMID: 39167806 DERIVED

• 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.

  PMID: 33926403 DERIVED

MeSH Terms

Interventions

Azithromycin

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr Thomas Lietman
• Organization: UCSF Proctor foundation

tom.lietman@ucsf.edu

4154761442

Study Officials

• Tom M Lietman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Kieran S O'Brien, PhD, MPH

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In the mortality/resistance trial, we will use a matching placebo to mask study arm allocation. Placebo will be identical to azithromycin in appearance, smell, and packaging. Treatment assignment will be masked by assigning a series of upper- and lower-case letters to each trial, age group, and treatment arm. Those masked to study arm allocation include participants, investigators, most study personnel including study personnel administering treatment and collecting data on mortality outcomes, and laboratory personnel processing samples for resistance outcomes. Unmasked personnel include the trial biostatistician and data analyst responsible for implementing the randomization sequence and key members of Pfizer staff. In a subset of 80 communities, open-label azithromycin will be distributed with no masking of participants, implementors, or outcome assessors.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The AVENIR mortality/resistance trial is a large simple double-masked cluster-randomized trial with response-adaptive allocation in Niger.

Study Record Dates

• First Submitted: December 17, 2019
• First Posted: January 13, 2020
• Study Start: November 24, 2020
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: May 14, 2025
• Results First Posted: May 14, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Individual participant data will be made available after publication of the outcomes and will be made available indefinitely.
• Access Criteria: Once made available, the data will be open access.

Locations

NI (1)