Azithromycin for Child Survival in Niger II (AVENIR II)

Azithromycine Pour la Vie Des Enfants au Niger II

Several randomized controlled trials have demonstrated that azithromycin mass drug administration (MDA) reduces child mortality, but increases antimicrobial resistance (AMR). The World Health Organization (WHO) guidelines for this intervention specify that implementation must be accompanied by continued monitoring of mortality and AMR. Niger is expanding the azithromycin MDA program nationwide. To establish monitoring of mortality and AMR as part of this program as well as to leverage the infrastructure to evaluate other child health interventions, AVENIR II is designed as an adaptive platform trial with monitoring and re-randomization every 2 years.

Study Overview

• Status: Not yet recruiting
• Conditions: Mortality; Antimicrobial Resistance
• Intervention / Treatment: Drug: Azithromycin for Oral Suspension

Detailed Description

AVENIR II is a cluster-randomized adaptive platform trial designed to evaluate community health interventions in Niger. The initial focus is to monitor under-5 mortality and antimicrobial resistance as the azithromycin MDA for child survival program expands in Niger, with the following specific aims:

1. Mortality.

   1. To conduct surveillance of mortality over time compared to the Sustainable Development Goal targets for under-5 mortality reduction. As this intervention is not intended to continue indefinitely, surveillance against a target is needed to determine when to stop.
   2. To continue to evaluate the effectiveness of azithromycin MDA to reduce under-5 mortality. Given the risk of AMR, the effectiveness of the intervention over time is needed to fully weigh the risks against the benefits.
2. Antimicrobial Resistance. To determine the impact of azithromycin MDA on AMR in population- and clinic-based samples.

• Study Type: Interventional
• Enrollment (Estimated): 3300000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Andrea R Picariello, MPH; Phone Number: 609-865-4532; Email: andrea.picariello@ucsf.edu
• Study Contact Backup: Name: Elodie Lebas; Email: elodie.lebas@ucsf.edu

Study Locations

• Niger
  • Niamey, Niger
    • Program National de Santé Oculaire

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

CSI-level for mortality and AMR monitoring:

• Located in a region participating in the program
• Designated as rural by local study team
• Selected for participation in monitoring activities
• Safe and accessible for study teams
• Verbal approval from community leaders

Individual level for mortality monitoring:

• Residing in the catchment area of an eligible CSI
• Selected for participation in monitoring activities
• Female
• Age between 12 and 55 years old
• Verbal approval from participant

Individual-level for AMR monitoring:

• Residing in the catchment area of an eligible CSI
• Selected for participation in monitoring activities
• Age between 1 and 59 months old
• Verbal approval from a caregiver or guardian

Exclusion Criteria:

At the community-level:

• Designated as urban by local study team
• Inaccessible or unsafe for study team

At the individual-level:

• Known allergy to macrolides

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Continuous Distribution; Azithromycin distribution to children 1-59 months of age for four years using a door-to-door delivery approach via existing community health workers	Drug: Azithromycin for Oral Suspension; Azithromycin will be administered as a single dose, in oral suspension form for children. The dose will be calculated by age or height depending on the child's age Both dosing cups and syringes will be used to administer treatment. For children too young to drink out of a dosing cup, a 1 ml or 5 ml syringe will be used, and the calculated dose will be rounded upwards to the nearest 0.2 ml.; Other Names: Zithromax
Active Comparator: Delayed Distribution; Delayed, by two years, azithromycin distribution to children 1-59 months of age using a door-to-door delivery approach via existing community health workers	Drug: Azithromycin for Oral Suspension; Azithromycin will be administered as a single dose, in oral suspension form for children. The dose will be calculated by age or height depending on the child's age Both dosing cups and syringes will be used to administer treatment. For children too young to drink out of a dosing cup, a 1 ml or 5 ml syringe will be used, and the calculated dose will be rounded upwards to the nearest 0.2 ml.; Other Names: Zithromax
Active Comparator: Stop Distribution; Stopping azithromycin distribution after two years to children 1-59 months of age using a door-to-door delivery approach via existing community health workers	Drug: Azithromycin for Oral Suspension; Azithromycin will be administered as a single dose, in oral suspension form for children. The dose will be calculated by age or height depending on the child's age Both dosing cups and syringes will be used to administer treatment. For children too young to drink out of a dosing cup, a 1 ml or 5 ml syringe will be used, and the calculated dose will be rounded upwards to the nearest 0.2 ml.; Other Names: Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	Under-5 mortality rate (U5MR, deaths per 1,000 live births) assessed by pregnancy history at 2 years from the first treatment distribution, comparing the intervention and delayed arms	2 years
All-cause mortality	Under-5 mortality rate (U5MR, deaths per 1,000 live births) assessed by pregnancy history at 4 years, comparing the continue and stop arms	4 years
Prevalence of resistance to macrolides - nasopharyngeal swabs	Prevalence of macrolide-resistant pneumococcus from nasopharyngeal swabs in children 1-59 months old after 2 years of distributions, comparing the intervention and delayed arms	2 years
Load of genetic determinants of resistance to macrolides - rectal swabs	Load of genetic determinants of resistance to macrolides from rectal swabs in children 1-59 months old after 2 years of distributions, comparing the intervention and delayed arms	2 years
Load of genetic determinants of resistance to macrolides - rectal swabs	Load of genetic determinants of resistance to macrolides from rectal swabs in children 1-59 months old after 4 years of distributions, comparing the continue and stop arms	4 years
Prevalence of resistance to macrolides - nasopharyngeal swabs	Prevalence of macrolide-resistant pneumococcus from nasopharyngeal swabs in children 1-59 months old after 4 years of distributions, comparing the continue and stop arms	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of clinic visits - infectious	All infectious clinic visits among children 1-59 months of age in the program catchment area during the distribution period as assessed through passive surveillance of CSI records	2 years
Number of clinic visits - infectious	All infectious clinic visits among children 1-59 months of age in the program catchment area during the distribution period as assessed through passive surveillance of CSI records	4 years
Prevalence of Genetic Determinants of resistance - Nasopharyngeal swabs	Prevalence of genetic determinants of resistance from nasopharyngeal swabs in children 1-59 months old after 2 years of distributions, comparing the intervention and delayed arms	2 years
Prevalence of Genetic Determinants of resistance - Nasopharyngeal swabs	Prevalence of genetic determinants of resistance from nasopharyngeal swabs in children 1-59 months old after 4 years of distributions, comparing the continue and stop arms	4 years
Program Cost Per Dose Delivered	Program costs will be tracked using routine expenditure reporting and micro-costing activities.	2 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Bill and Melinda Gates Foundation; Ministère de la Santé Publique du Niger; Centre de Recherche Médicale et Sanitaire; Centre de recherche et interventions en santé publique (CRISP); Le Programme National de Santé Oculaire
• Investigators: Principal Investigator: Kieran S O'Brien, PhD, University of California, San Francisco

Publications and helpful links

General Publications

• Keenan JD, Ayele B, Gebre T, Zerihun M, Zhou Z, House JI, Gaynor BD, Porco TC, Emerson PM, Lietman TM. Childhood mortality in a cohort treated with mass azithromycin for trachoma. Clin Infect Dis. 2011 Apr 1;52(7):883-8. doi: 10.1093/cid/cir069.
• 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, Hinterwirth A, Worden L, Arzika AM, Maliki R, Abdou A, Kane S, Zhong L, Cummings ME, Sakar S, Chen C, Cook C, Lebas E, Chow ED, Nachamkin I, Porco TC, Keenan JD, Lietman TM. Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution. Nat Med. 2019 Sep;25(9):1370-1376. doi: 10.1038/s41591-019-0533-0. Epub 2019 Aug 12.
• Oldenburg CE, Ouattara M, Bountogo M, Boudo V, Ouedraogo T, Compaore G, Dah C, Zakane A, Coulibaly B, Bagagnan C, Hu H, O'Brien KS, Nyatigo F, Keenan JD, Doan T, Porco TC, Arnold BF, Lebas E, Sie A, Lietman TM. Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial. JAMA. 2024 Feb 13;331(6):482-490. doi: 10.1001/jama.2023.27393.
• Sie A, Ouattara M, Bountogo M, Boudo V, Ouedraogo T, Compaore G, Dah C, Bagagnan C, Lebas E, Hu H, Rice J, Porco TC, Arnold BF, Lietman TM, Oldenburg CE. Azithromycin during Routine Well-Infant Visits to Prevent Death. N Engl J Med. 2024 Jan 18;390(3):221-229. doi: 10.1056/NEJMoa2309495.
• Chao DL, Arzika AM, Abdou A, Maliki R, Karamba A, Galo N, Beidi D, Harouna N, Abarchi M, Root E, Mishra A, Lebas E, Arnold BF, Oldenburg CE, Keenan JD, Lietman TM, O'Brien KS. Distance to Health Centers and Effectiveness of Azithromycin Mass Administration for Children in Niger: A Secondary Analysis of the MORDOR Cluster Randomized Trial. JAMA Netw Open. 2023 Dec 1;6(12):e2346840. doi: 10.1001/jamanetworkopen.2023.46840.
• O'Brien KS, Cotter SY, Amza A, Kadri B, Nassirou B, Stoller NE, Zhou Z, West SK, Bailey RL, Keenan JD, Porco TC, Lietman TM. Childhood Mortality After Mass Distribution of Azithromycin: A Secondary Analysis of the PRET Cluster-randomized Trial in Niger. Pediatr Infect Dis J. 2018 Nov;37(11):1082-1086. doi: 10.1097/INF.0000000000001992.
• Keenan JD, Arzika AM, Maliki R, Elh Adamou S, Ibrahim F, Kiemago M, Galo NF, Lebas E, Cook C, Vanderschelden B, Bailey RL, West SK, Porco TC, Lietman TM; MORDOR-Niger Study Group. Cause-specific mortality of children younger than 5 years in communities receiving biannual mass azithromycin treatment in Niger: verbal autopsy results from a cluster-randomised controlled trial. Lancet Glob Health. 2020 Feb;8(2):e288-e295. doi: 10.1016/S2214-109X(19)30540-6.
• Doan T, Worden L, Hinterwirth A, Arzika AM, Maliki R, Abdou A, Zhong L, Chen C, Cook C, Lebas E, O'Brien KS, Oldenburg CE, Chow ED, Porco TC, Lipsitch M, Keenan JD, Lietman TM. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. N Engl J Med. 2020 Nov 12;383(20):1941-1950. doi: 10.1056/NEJMoa2002606.

Study record dates

Study Major Dates

• Study Start (Estimated): April 29, 2024
• Primary Completion (Estimated): April 29, 2028
• Study Completion (Estimated): April 29, 2028

Study Registration Dates

• First Submitted: April 3, 2024
• First Submitted That Met QC Criteria: April 8, 2024
• First Posted (Actual): April 11, 2024

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 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: 23-39839

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: 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