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

• ClinicalTrials.gov Identifier: NCT04224987
• Recruitment Status: Recruiting
• First Posted: January 13, 2020
• Last Update Posted: September 7, 2022
• Sponsor: University of California, San Francisco
• Collaborators: Bill and Melinda Gates Foundation; Ministry of Health, Niger
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Mortality; Resistance Bacterial; Child, Only	Drug: Azithromycin; Other: Placebo	Phase 4

Detailed Description:

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 determine the costs of treating 1-11-month-old children only, 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 distribution to children 12-59 months old or 2) distribution of open-label azithromycin to children 1-59 months old.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1106050 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The AVENIR mortality/resistance trial is a large simple double-masked cluster-randomized trial with response-adaptive allocation in Niger.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description

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.

• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: November 24, 2020
• Estimated Primary Completion Date: March 2026
• Estimated Study Completion Date: March 2026

Arms and Interventions

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 Name: 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 Name: 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

Outcome Measures

Primary Outcome Measures :

1. All-cause mortality (1-59 months old) [ Time Frame: 2.5 years from the first enrollment ]
   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. All-cause mortality (1-11 months old) [ Time Frame: 2.5 years from the first enrollment ]
   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.
3. All-cause mortality (12-59 months old) [ Time Frame: 2.5 years from the first enrollment ]
   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.
4. Prevalence of resistance to macrolides - nasopharyngeal swabs (1-59 months old) [ Time Frame: 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.
5. Load of genetic determinants of resistance to macrolides - rectal swabs (1-59 months old) [ Time Frame: 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 :

1. All-cause mortality (12-59 months old) [ Time Frame: 2.5 years from first enrollment ]
   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. All-cause mortality (1-11 months old ) [ Time Frame: 2.5 years from first enrollment ]
   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.
3. Mortality rate by subgroup: anthropometric indicators [ Time Frame: Over 2.5 years ]
   Mortality rate compared by arm in subgroups based on weight in children 1-11 months
4. Prevalence of resistance to macrolides from nasopharyngeal swabs and load of genetic determinants of resistance to macrolides from rectal swabs [ Time Frame: After 4 distributions (approximately 24 months) ]

   Prevalence of resistance to macrolides from nasopharyngeal swabs and load of genetic determinants of resistance to macrolides from rectal swabs in:

   • Children 7-12 years old at 24 months from baseline
   • Caregivers/guardians of eligible children at 24 months from baseline
5. Program costs [ Time Frame: 2.5 years ]
   Program costs as captured by routine administrative data collection during the study period and by micro-costing activities.

Eligibility Criteria

• Ages Eligible for Study: 1 Month to 59 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Contacts

Contact: Elodie Lebas, RN; 5104232245; elodie.lebas@ucsf.edu

Locations

Niger

Programme national de santé oculaire; Recruiting

Niamey, Niger

Contact: Amza Abdou, MD 00227 96967009 dr.amzaabdou@gmail.com

Sponsors and Collaborators

University of California, San Francisco

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

More Information

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.

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.

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/

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT04224987
• Other Study ID Numbers: 19-28387A
• First Posted: January 13, 2020
• Last Update Posted: September 7, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified data underlying outcomes publications will be made publicly available.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (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.

• 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

Keywords provided by University of California, San Francisco:

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

Additional relevant MeSH terms:

Azithromycin; Anti-Bacterial Agents; Anti-Infective Agents