Clinical trial NCT05288023
Conditions: Resistance Bacterial Morality Child Health Implementation
Sponsor: University of California, San Francisco
Start date: 2022-12-01; Completion date: 2024-01-15
Enrollment: 169707 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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. The proposed trial aims to demonstrate and evaluate large-scale implementation of azithromycin to children aged 1-11 months old in the context of a programmatic setting while monitoring mortality and resistance antimicrobial resistance.

Detailed description:
In the Programmatic Trial, community health centers (also known as "CSIs" or "Centres de Santé Intégrés") will be randomized to one of two arms: 1) programmatic azithro 1-11: biannual oral azithromycin administration to children aged 1-11 months distributed by community health workers or 2) no intervention: no distribution of azithromycin. A total of 2,490 communities within selected CSIs will be included .

All communities in both arms receive routine health services offered by community health workers working for the Niger Ministry of Health's community health program.

Mortality will be monitored through birth histories. Mortality and morbidity will also be monitored using routinely collected community and clinic visit data. Antimicrobial resistance will be monitored in a subset of eligible CSIs.

Arms: arm 1: Biannual oral azithromycin administration to children aged 1-11 months distributed by community health workers arm 2: No additional intervention.
Interventions: intervention 1: Azithromycin for Oral Suspension
Intervention descriptions: intervention 1: Azithromycin will be administered as a single dose in oral suspension form for children (up to the maximum adult dose of 1g).

Dosage will be calculated by age for children aged 1-5 months. For children 6-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program.

Protocol documents:
Prot_000.pdf: 
 
AVENIR Protocol 
Version 30.0, Last Revised September 2024 
 
1
Azithromycine pour la Vie des Enfants au Niger: Implémentation et Recherche  
(Azithromycin for Child Survival in Niger: Implementation and Research: AVENIR)  
Trial Protocol  
 
An adaptive cluster-randomized trial to determine the optimal age group for implementation of 
biannual oral azithromycin distribution to reduce child mortality in Niger 
 
Investigators and Study Personnel (in alphabetical order):   
 
Eric Adehossi3,4 
Abdou Amza*3,4  
Benjamin Arnold1 
Ahmed Arzika*2   
Nassirou Beido3,4   
Emily Colby1 
Adam Diori3,4 
Thuy Doan1 
Boubacar Kadri3,4 
Jeremy D. Keenan1 
Sandrine Kyane1 
Elodie Lebas1 
Thomas M. Lietman*1 
Zijun Liu1 
Boubacar Maidanda3,4 
Ramatou Maliki4 
Aissa Mamadou3,4 
Kamayé Moumouni3,4 
William Nguyen1 
Kieran S. O’Brien*1 
Catherine E. Oldenburg1 
Brittany Peterson1 
Travis C. Porco1 
Abba Kaka Yakoura3,4 
Amadou Zakari3 
 
Trial Registration: 
 
NCT04224987 (AVENIR Mortality and Resistance Trial) 
NCT04774991 (AVENIR Delivery Trials) 
NCT05288023 (AVENIR Programmatic Trial) 
 
Funding: 
 
Bill & Melinda Gates Foundation Planning Grant (OPP1210548); 
Bill & Melinda Gates Foundation (INV-002454) 
 
*Principal Investigator 
1Francis I. Proctor Foundation, San Francisco, California 
2Centre de recherche et interventions en santé publique (CRISP) 
3Ministère de la Santé Publique du Niger 
4Programme National de Santé Oculaire (PNSO) 


 
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List of Acronyms 
 
AE 
Adverse Event 
AMR 
Antimicrobial Resistance 
BUA 
Biological Use Authorization 
CDC 
Centers for Disease Control and Prevention 
CERMES Centre de recherche médicale et sanitaire 
CHW 
Community health worker 
CNERS 
Comité national ethique pour la recherche en santé 
CSI 
Centre de santé integré, (local health centers) 
DALY 
Disability-Adjusted Life Year 
DCC 
Data Coordinating Center 
DNA 
Deoxyribonucleic Acid 
DSC 
Division santé communautaire 
DSMC 
Data and Safety Monitoring Committee 
GPS 
Global Positioning System 
IHME 
Institute for Health Metrics and Evaluation 
IRB 
Institutional Review Board 
MOH 
Ministry of Health 
MUAC 
Mid-upper arm circumference 
PNSO 
Programme national de santé oculaire 
RDT 
Rapid diagnostic test (for malaria) 
SAE 
Serious Adverse Event 
SAP 
Statistical Monitoring Plan 
SMC 
Seasonal Malaria Chemoprevention 
TCC 
Trial Coordinating Center 
UCSF 
University of California, San Francisco 
WHO 
World Health Organization 
 
 
 


 
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Table of Contents 
1. 
Executive Summary ............................................................................................................ 5 
1.1. 
Administrative Information ......................................................................................... 5 
1.2. 
Trial Details .................................................................................................................. 6 
1.3. 
Revisions History ...................................................................................................... 10 
2. 
Background and Rationale ............................................................................................... 13 
3. 
Specific Aims ..................................................................................................................... 15 
4. 
Methods ............................................................................................................................. 16 
4.1. 
Trial Design ................................................................................................................ 16 
4.2. 
Study Setting ............................................................................................................. 16 
4.3. 
Timeline ...................................................................................................................... 18 
4.4. 
Mortality/Resistance Trial ......................................................................................... 20 
4.4.1. 
Trial Design ........................................................................................................ 20 
4.4.2. 
Eligibility ............................................................................................................ 20 
4.4.3. 
Randomization, Adaptation, and Masking ...................................................... 21 
4.4.4. 
Outcomes ........................................................................................................... 23 
4.4.5. 
Sample size ........................................................................................................ 25 
4.4.6. 
Recruitment ....................................................................................................... 26 
4.4.7. 
Adverse Events Monitoring .............................................................................. 26 
4.4.8. 
Data Collection, Management, Analysis, and Monitoring .............................. 27 
4.5. 
Delivery Trial .............................................................................................................. 29 
4.5.1. 
Trial Design ........................................................................................................ 29 
4.5.2. 
Eligibility ............................................................................................................ 30 
4.5.3. 
Randomization, Adaptation, and Masking ...................................................... 30 
4.5.4. 
Outcomes ........................................................................................................... 32 
4.5.5. 
Sample size ........................................................................................................ 33 
4.5.6. 
Recruitment ....................................................................................................... 33 
4.5.7. 
Adverse Events Monitoring .............................................................................. 33 
4.5.8. 
Data Collection, Management, Analysis, and Monitoring .............................. 33 
4.6. 
Programmatic Trial .................................................................................................... 38 
4.6.1. 
Trial Design ........................................................................................................ 38 
4.6.2. 
Eligibility ............................................................................................................ 38 
4.6.3. 
Randomization, Adaptation, and Masking ...................................................... 40 
4.6.4. 
Outcomes ........................................................................................................... 41 
4.6.5. 
Sample size ........................................................................................................ 42 
4.6.6. 
Recruitment ....................................................................................................... 43 
4.6.7. 
Adverse Events Monitoring .............................................................................. 43 


 
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4.6.8. 
Data Collection, Management, Analysis, and Monitoring .............................. 43 
5. 
Ethics and Dissemination ................................................................................................ 47 
5.1. 
Overview .................................................................................................................... 47 
5.2. 
Institutional Review Board Approval ....................................................................... 47 
5.3. 
Informed Consent ...................................................................................................... 47 
5.4. 
Potential Risks and Adequacy of Protection Against Risks ................................. 47 
5.5. 
Compensation for Participants ................................................................................ 48 
5.6. 
Dissemination Plan ................................................................................................... 48 
6. 
Organizational Structure and Responsibilities .............................................................. 49 
6.1. 
University of California, San Francisco Francis I. Proctor Foundation ............... 49 
6.2. 
Programme national de santé oculaire (PNSO) ...................................................... 49 
6.4 
Centre de recherche medical et sanitaire (CERMES) ............................................ 49 
6.5. 
Centre de recherche et interventions en santé publique (CRISP) ........................ 50 
6.6. 
Centres de santé intégré (CSI) ................................................................................. 50 
6.7. 
Executive Committee ................................................................................................ 50 
6.8. 
Trial Coordinating Center (TCC) .............................................................................. 50 
6.9. 
Niger Coordinating Center ....................................................................................... 50 
6.10. 
Data Coordinating Center (DCC) .............................................................................. 51 
6.11. 
Economic Consultants ............................................................................................. 51 
6.12. 
Duties and Responsibilities of Staff ........................................................................ 52 
6.13. 
Data Safety and Monitoring Committee .................................................................. 54 
6.14. 
Policy Matters ............................................................................................................ 56 
7. 
Appendices ........................................................................................................................ 58 
7.5. 
Informed Consent Forms .......................................................................................... 58 
7.6. 
Mortality/Resistance Trial: Training, Procedures, Data Collection Forms .......... 58 
7.7. 
Delivery Trial: Training, Procedures, Data Collection Forms ............................... 58 
7.8. 
Sample Collection: Training, Procedures, Data Collection Forms ....................... 58 
7.9. 
Laboratory Procedures ............................................................................................. 58 
7.10. 
Data Monitoring Plan ................................................................................................ 58 
7.11. 
Adverse Events Monitoring Plan ............................................................................. 58 
7.12. 
Integrated Management of Childhood Illness flowchart ........................................ 58 
References ................................................................................................................................. 59 
 
 
 


 
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1. Executive Summary 
1.1. 
Administrative Information  
 
Funding 
The Bill & Melinda Gates Foundation (OPP1210548, INV-002454) 
Pfizer donated azithromycin and placebo 
 
Data and Safety 
Monitoring Committee 
David Addiss, MD, MPH, Task Force for Global Health (chair)  
Mourtala Assao, MD, Niger Ministry of Health 
Julia Bielicki, MD, PhD, St. George’s University of London 
Allen Hightower, MS 
Brian Jackson, MD, Children’s Hospital of Colorado 
Fiona Russell, MPHTM, FRACP, PhD, University of Melbourne 
 
Medical Monitors 
Dr Amina Seyfoule, MD, Centre de santé mère et enfant, Dosso, Niger 
Jeremy Keenan, MD, MPH, University of California, San Francisco 
 
Principal Investigators 
Amza Abdou, MD 
Programme national de santé oculaire 
Email: dr.amzaabdou@gmail.com 
 
Ahmed Mamane Arzika, PhD 
Centre de recherche et interventions en santé publique 
Email: mamaneahmed@yahoo.fr 
 
Kieran O’Brien, PhD, MPH 
University of California San Francisco 
Email: Kieran.Obrien@ucsf.edu 
 
Tom Lietman, MD 
University of California San Francisco 
Email: tom.lietman@ucsf.edu 
 
Participating 
Institutions 
Francis I. Proctor Foundation, University of California San Francisco (UCSF) 
Ministère de la santé publique du Niger 
Programme national de la santé oculaire (PNSO) 
Centre de recherche et interventions en santé publique (CRISP) 
 
Trial Site 
Dosso, Tahoua, Maradi, Zinder, and Tillabéri regions in Niger 
 
Ethical Approval 
 
UCSF IRB Number: 19-28287 
Niger Ethics Approval Record: DELIBERATION N041/2020/CNERS 
 
Study Contacts 
Elodie Lebas 
Deputy Director of International Programs 
Francis I. Proctor Foundation, University of California San Francisco 
Email: elodie.lebas@ucsf.edu 
 
 
 
 
 


 
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1.2. 
Trial Details 
 
Background 
The MORDOR trial found that biannual distribution of 
azithromycin to children 1–59 months old reduced child 
mortality. 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. 
 
Objectives 
AVENIR has three main objectives: 
 
1) Mortality. To assess the efficacy of age-based 
targeting of biannual azithromycin distribution on 
mortality.  
2) Resistance. To determine the impact of age-based 
targeting on antimicrobial resistance by comparing the 
three arms. 
3) Implementation. To demonstrate and evaluate large-scale 
implementation. 
 
Trial Design 
Mortality/Resistance Trial: Large simple double-masked 
cluster-randomized trial with response-adaptive allocation. 
  
Delivery Trials: Cluster-randomized trial. 
 
Programmatic Trial: Cluster-randomized trial. 
 
Trial Setting 
Accessible rural and peri-urban communities in Niger. 
 
Summary of Methods 
Eligible communities in Niger will be randomly selected to 
participate in the three trials: 
 
In the Mortality/Resistance Trial, 3,000 communities will be 
randomized to one of three azithromycin distribution strategies: 
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.  
 
In Delivery Trial I, 80 communities will be randomized 
in a 1:1 allocation to door-to-door or fixed-point 
distribution of azithromycin by community health 
workers. Implementation outcomes, including 


 
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coverage, costs, feasibility, and acceptability, will be 
compared across delivery strategies. 
 
In Delivery Trial II, 80 communities will be randomized 
in a 1:1 allocation to one of two arms: 1) delivery 
azithro 1–11: biannual oral azithromycin administration 
to children aged 1–11 months distributed by community 
health workers or 2) delivery azithro 1–59: biannual 
oral azithromycin administration to children aged 1–59 
months distributed by community health workers. Costs 
and coverage will be compared across age-based 
strategies. 
 
In the Programmatic Trial, CSIs will be randomized in a 
2:1 allocation to one of two arms favoring the 
programmatic azithro 1–11 arm: 1) programmatic 
azithro 1–11: biannual oral azithromycin administration 
to children aged 1–11 months distributed by community 
health workers or 2) no intervention: no distribution of 
azithromycin. Approximately 1,500 communities from 
150 CSIs will be included. All communities still receive 
routine health services offered by community health 
workers working for the Niger Ministry of Health’s 
community health program. Antimicrobial resistance will 
be monitored using cluster sampling from a subset of 
20 eligible CSIs per arm (40 CSIs total). Sampling will 
take place within communities as well as CSIs.  
Mortality will be monitored through birth history 
surveys. All infectious cause and cause-specific clinic 
visits will be monitored through routine CSI data 
collection.  
 
 
Primary Outcomes 
Mortality/Resistance Trial  
• 
Mortality rate (deaths per 1,000 person-years 
at risk) among children 1- 59 months of age at 
2.5 years from the first enrollment, comparing 
the azithro 1–59 and placebo arms 
• 
Mortality rate (deaths per 1,000 person-years 
at risk) among children 1–11 months of age at 
2.5 years from the first enrollment, comparing 
the azithro 1–11 and placebo arms 
• 
Mortality rate (deaths per 1,000 person-years 
at risk) among children 12- 59 months of age at 
2.5 years from the first enrollment, comparing 
the azithro 1–11 and azithro 1–59 arms 
 
 Prevalence of genetic determinants of 
resistance to macrolides from nasopharyngeal 
swabs in children 1–59 months old after 2 
years of distributions 


 
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 Load of genetic determinants of resistance to 
macrolides from rectal swabs in children 1–59 
months old after 2 years of distributions 
 
Delivery Trial I 
• 
Treatment coverage as defined by the number of doses 
recorded by the community health workers and eligible 
population captured during the post-distribution census 
Delivery Trial II 
• 
Cost per dose delivered. Program costs will be captured by 
routine administrative data collection during the study period 
and by micro-costing activities. Doses delivered will be 
recorded by community health workers using paper data 
collection forms and entered electronically by the supervisor 
team. 
 
Programmatic Trial 
• 
Number of infectious clinic visits recorded by CSIs for 
children 1-59 months per month. 
• 
Prevalence of genetic determinants of macrolide 
resistance in nasopharyngeal swabs in children aged 
1–59 months after 2 years of distribution 
• 
Load of genetic determinants of macrolide resistance 
in rectal swabs among children aged 1–59 months 
after 2 years of distribution  
 
Sample Size 
Stage I of the study includes communities enrolled through the 
primary mortality outcome assessment at 2.5 years from the 
first region enrollment. Overall, approximately 4,660 
communities will be enrolled in Stage I from the Dosso, 
Tahoua and Maradi regions, with 3,000 communities included 
in the Mortality Trial, 160 communities in the Delivery Trial, and 
the remaining 1,500 communities in the Programmatic Trial.  
 
To monitor resistance in the Mortality Trial, 50 communities per 
arm (150 total) will be randomly sampled from Mortality Trial 
communities in the Dosso region. Within each sampled 
community, 30 children aged 1–59 months, 30 children aged 
7–12 years, and 30 caregiver/guardians of eligible children will 
be randomly selected for specimen collections.  
 
To monitor resistance in the Programmatic Trial, 40 CSIs (20 
per arm) will be randomly selected from Programmatic Trial 
CSIs. Of these 40 CSIs, 3 communities per CSI will be 
selected for sample collection. Within each selected 
community, 10 children aged 1–59 months will be selected for 
specimen collections.  
 
Recruitment 
Before implementation begins in a region, a sensitization 
campaign will inform local health authorities and community 
leaders of study design and nature of participation in the trial. 


 
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In addition to IRB and national, regional, and district approval, 
community-level approval will be obtained before study 
activities begin in any community.  
 
In the Mortality/Resistance and Delivery Trials, all households 
will be recruited for participation in the census. In the 
Mortality/Resistance Trial, all children 1–59 months of age will 
be recruited for the intervention. In the Delivery Trials, all 
children 1–59 months of age or 1–11 months of age will be 
recruited for the intervention, depending on arm allocation.  
 
In the Programmatic Trial, all eligible children aged 1–11 
months of age in communities in the catchment area of 
selected CSIs will be recruited for the intervention.  
 
Household-level consent will be obtained for the census and 
birth history activities, and caregiver/guardian consent will be 
obtained for interventions and sample collection. 
 
Data Management 
Most data will be collected electronically using a custom 
mobile application and uploaded regularly to secure, 
cloud-based servers. Data management teams in Niger and at  
UCSF will monitor data collection in real time daily, with 
progress and quality control reports prepared and distributed to 
investigators weekly. 
 
Sample Management 
During collection, samples will be stored at ambient 
temperature or on ice at 4°C. At the end of each collection 
period, samples will be transported to a location near the 
sampled community with facilities to store samples at -20°C as 
required or directly to CRISP each day. At the end of the 
collection period, all samples will be transferred to a central 
storage location at CRISP in Niamey stored at -20°C as 
required until processed or shipped to UCSF for processing. 
 
 
 
 
 


 
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1.3. 
Revisions History 
Date 
Version 
Edit 
13-5-20 
2 
Fixed adding error in Table 2 to reflect the correct grappe interval 
primary outcomes total of 12,300, Section 4 
19-5-20 
2 
Added Jeremy Keenan as additional US-based Medical Monitor, 
Section 1 
26-5-20 
2 
Added Elodie Lebas to list of study personnel in title page 
29-5-20 
2 
Added UCSF IRB study number to title page 
29-5-20 
2 
Updated mortality numbers to reflect most recent IHME data, Section 
4.2 
24-6-20 
2 
Removed Josette Vingon-Makong from list of Investigators and Study 
Personnel in title page 
30-Jun-20 
2 
Updated study design schematic, Section 4 (Figure 1) 
30-Jun-20 
2 
Updated sentence to indicate that AMR communities are included in 
the primary mortality outcome in the Mortality Trial, Section 4.5 
30-Jun-20 
2 
Add sentence about addition of parallel implementation trial with arm 
description and rationale sentence, Section 4.1 
1-Jul-20 
3 
Revised CRISP in list of collaborators, Section 1 
2-Jul-20 
4 
Added detail about implementation trial, Sections 1.2, 3, 4.1, 4.4.2, 
4.4.8, 4.5, 4.6, 4.10 
2-Jul-20 
4 
Updated formatting of table of contents 
15-Jul-20 
5 
Added detail about implementation trial, Sections 1.2, 3, 4.1, 4.4.2, 
4.4.8, 4.5, 4.6, 4.10 
31-Jul-20 
6 
Updated detail about implementation trial, Sections 1.2, 3, 4.1, 4.4.2, 
4.4.8, 4.5, 4.6, 4.10 and updated formatting 
3-Aug-20 
7 
Reordered outcomes to reflect hierarchical testing order, updated 
header and page numbers, added Ramatou Maliki to list of 
investigators, added CSI and CRISP to list of partnering 
organizations, Section 6, added interim analysis to study timeline, 
Section 4.6 
10-Aug-20 
8 
Updated list of appendices to include implementation trial 
procedures, Section 7 
12-Aug-20 
9 
Updated rollout table to include population numbers for all grappes. 
Section 4.6  
16-Sept-20 
10 
Updated design to reflect DSMC feedback: 
- 
Increased number of communities selected for Mortality Trial 
to 3,000, Section 4  
- 
Delayed start of remainder of communities until 1.5 years 
after the first enrollment (aligned with interim analysis), 
Section 4.6  
- 
Simplified the comparison of Delivery Trial approaches to a 2-
arm trial and removed mortality as an outcome, Section 4.5 
05-Oct-20 
11 
Updated with costing/cost-effectiveness protocol changes, Sections 
4.10 and 6.10 
09-0ct-20 
11 
Updated References Section to be consistent in formatting 
09-0ct-20 
11 
Added IRB numbers to the Executive Summary, Section 1.1 
09-0ct-20 
11 
Added the English study title to the title page, under the French title  
09-0ct-20 
11 
Updated timing language so that “period” is referred to as “round” 
and “phase” is referred to as “stage,” Section 4.6 (Tables 1 and 2), 


 
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07-Dec-20 
12 
Added information on the additional 40 MORDOR 54 communities to 
AMR baseline, Sections 4.10.3 and 4.7.2 
31-Jan-21 
13 
Outcome timepoints were clarified, Sections 1.2, 3, and 4.5 
6-May-21 
14 
Removed “biannual” from the Delivery Trial arms description, Section 
4.4.1  
6-May-21 
14 
Removed footnote from Proctor Implementation Outcomes 
Framework that describes using census data and satellite imagery 
as a data source for cost, Table 3, Section 4.10.4 
6-May-21 
14 
Changed “nutritional status” to “anthropometric indicators,” Section 
4.5.2 
6-May-21 
14 
Changed “serological outcomes” to “serological markers of pathogen 
infection,” Section 4.5.3 
6-May-21 
14 
Clarified that M54 grappes will remain untreated until after sample 
collection has concluded, Sections 4.7.2 and 4.10.3 
6-May-21 
14 
Updated intervention community-level eligibility inclusion criteria to 
specify that neighboring grappes must be distinguishable from one 
another, Section 4.3 
6-May-21 
14 
Updated population-based sample collection community-level 
eligibility inclusion criteria to specify that neighboring grappes must 
be distinguishable from one another, Section 4.3  
6-May-21 
14 
Updated population-based sample collection community-level 
eligibility exclusion criteria to specify that grappes treated in a given 
round prior to sample collection will be excluded from sample 
collection, Section 4.3 
6-May-21 
14 
Clarified the definition of treatment coverage in the Delivery Trial 
primary outcomes section as the number of doses recorded by 
community health workers and census workers, Section 4.5.1 
6-May-21 
14 
Clarified the definition of treatment coverage in the Delivery Trial 
secondary outcomes section as census projections and satellite 
imagery, Section 4.5.2 
25-
October-21 
15 
Updated footnote in table 2 to clarify distance-based exclusions for 
the Tahoua region: estimates exclude communities known to be 
within 5km of district headquarters or town, Section 4.6 
31-
January-22 
16 
Updated study design to incorporate details of the Programmatic 
Trial and the age-based comparison Delivery Trial (referred to as 
“Delivery Trial II” throughout this document): 
- 
Addition of Programmatic Trial specific aims 3a-3c, Section 3 
- 
Incorporated the Programmatic Trial and the age-based 
comparison Delivery Trial design description, Section 4.1 
- 
Modified Figure 1, “Stage I design summary” to include 
Programmatic Trial and Delivery Trial II data collection, 
Section 4 
- 
Updated individual-level eligibility criteria to specify no weight 
limits in the Programmatic Trial and Delivery Trials, Section 
4.3 
- 
Incorporated details on randomization, adaptation, masking, 
and dosing as they relate to the Programmatic and Delivery 
Trials, Section 4.4 
- 
Addition of primary and secondary outcomes for the 
Programmatic Trial, Section 4.5 


 
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- 
Included information on sample size in the and sample 
collections in the Programmatic Trial, Section 4.7 
- 
Added detail about data collection and measurement of 
outcomes in the Programmatic and Delivery Trials, Section 
4.10 
2-April-22 
17 
- 
Inclusion of CSI-based collections in the Programmatic Trial, 
Sections 1.2, 4.1, 4.3, 4.7.2, and 4.10.3 
- 
Addition of microbiome outcomes, Section 4.5.2 
- 
 Inclusion of additional 60 baseline AMR collections in Round 
4, Sections 4.7.2, and 4.10.3 
29-June-22 
18 
- 
Removal of grappe level eligibility restrictions in the 
Programmatic Trial eligibility, Section 4.6.2 
17-
November-
22 
19 
- 
Added detail on random selection of participants for AMR 
collections 
 
30-
November -
22 
20 
- 
Updated personnel  
3-February-
23 
21 
- 
Increased number of communities in programmatic AMR 
collections  
9-May-
2023 
22 
- 
Added a footnote to Figure 2: Stage I design Summary, that 
specifies that a random sample of 150 communities was 
selected for AMR monitoring, 60 of which contribute to the 
primary outcome 
10-May-
2023 
23 
- 
Updated Figure 1: Stage I design Summary and section 
4.4.5.1 Overview  to show that 3,000 grappes have been 
randomized 
19-May-23 
24 
- 
Updated section 4.4.8.2 to add a description of the random 
census verification and verbal autopsy to measure mortality 
outcomes 
13-Oct-23 
25 
- 
Reviewed for clarity and completeness and updated 
enrollment numbers  
27-Oct-23 
26 
- 
Primary outcome for programmatic trial changed to all 
infectious clinic visits 
21-Nov-23 
27 
- 
Updated Delivery II primary and secondary outcomes to 
match statistical analysis plan (Section 4.5.4) 
27-Nov-23 
28 
- 
Updated Mortality secondary outcome to include CSI data 
extraction to assess morbidity (Section 4.4.4.2) 
2-Feb-24 
29 
- 
Added paragraph to include the additional 60 communities 
(Section 4.4.5.2) 
- 
Added sentence stating all same procedures will be followed 
for the additional 60 communities (Section 4.4.8.3) 
26-Sept-24 
30 
- 
Update AMR analysis to include 150 communities 
 
 
 


 
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2. Background and Rationale  
 
Sub-Saharan African countries have drastically reduced under-5 mortality over the past 20 
years, yet in many areas, 10% of children still do not survive to the age of 5.1,2 Although some 
areas are well poised to achieve the Sustainable Development Goal (SDG) target to end 
preventable under-5 mortality by 2030, many settings in western and central Africa must 
achieve unprecedented rates of decline to meet the SDG goals.2,3 Under-5 mortality in Niger is 
among the highest globally, with estimates at 108 deaths per 1,000 livebirths,1 more than 4 
times the SDG target of 25 deaths per 1,000 livebirths.3 In high mortality settings like Niger, 
highly effective and feasible interventions are urgently needed. 
 
MORDOR I demonstrated that community-level biannual distribution of oral azithromycin to 
children 1–59 months of age reduced mortality by nearly 14% compared to placebo over 2 
years in Malawi, Niger, and Tanzania.4 The greatest effect was found in Niger, where 
communities receiving azithromycin experienced an 18% reduction in mortality compared to 
those receiving placebo.4 Subgroup analyses suggested that the youngest children might 
benefit the most, with reductions of approximately 23% in children 1–11 months old.4 In Niger, 
azithromycin distributions were associated with an increase in antimicrobial resistance (AMR) to 
macrolides after 2 years,5 though azithromycin remained similarly effective in reducing mortality 
after 3 years in MORDOR II.6 
 
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.7 The rationale for targeting this age group is that the youngest children 
experience the highest risk of mortality and limiting distributions to the youngest children could 
minimize selection for antimicrobial resistance. However, distributing azithromycin to children 1–
11 months alone remains untested, since MORDOR I treated children 1–59 months of age. A 
crude examination of relative mortality reductions by age group suggests a stronger effect in the 
younger age groups, but MORDOR was unable to demonstrate a differential effect by age group 
statistically (P = 0.20 for test of interaction of treatment and age).4 Moreover, a herd effect could 
have contributed to the apparent larger effect sizes in the younger groups; treating children 12–
59 months may protect children 1–11 months by reducing their exposure to infectious diseases 
causing mortality. Finally, beyond a possible differential effect by age group, in MORDOR I-
Niger there were 5 times as many children aged 12–59 months as children 1–11 months, 
resulting in nearly twice as many deaths averted in the older age group.8 The greatest societal 
gains may thus come from intervening on a population with a broader risk spectrum instead of 
targeting only the highest risk subgroups.9 More evidence is needed to determine the difference 
and magnitude of the benefit of targeting different age groups, and of the risk of inducing AMR 
when distributing to different age groups. 
 
The AVENIR trial was designed to test the effect of age-based targeting on mortality and 
resistance. Several design features allow for these assessments. First, as mortality is a rare 
event even in high mortality settings, a large sample size is required to detect modest 
intervention effects10. AVENIR thus uses a large simple trial design, with a simple intervention, 
simple data collection, and simple outcome assessment allowing for implementation in a very 
large population. Second, AVENIR is cluster randomized because of the community-based 
nature of the intervention as well as to address potential contamination within communities11. As 
the mechanism of azithromycin’s effect is likely through its impact on infectious disease, 
community-level randomization prevents an individual’s treatment assignment from affecting the 
outcomes of individuals with different assignments within a community. Finally, AVENIR will use 
response-adaptive allocation to achieve several aims. This approach allows for more ethical 


 
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allocation, as communities will have a higher probability of receiving the intervention that 
reduces mortality the most. By maintaining an allocation of at least 10% of communities to 
placebo, continued monitoring of efficacy is still possible. This includes the detection of waning 
effects over time which might indicate the appropriate duration of the intervention. The 
adaptive design also allows for greater flexibility, enabling the existing trial infrastructure to be 
used to evaluate other interventions. The study can adapt to changing guidelines by 
randomizing in new intervention arms, for example, rather than being constrained by the 
original design which could become irrelevant during the course of the trial. For example, 
unanticipated WHO recommendations could include changes to the target age range or 
distribution frequency. Finally, as countries consider implementation of this intervention for 
child survival, AVENIR provides an opportunity to demonstrate and rigorously assess large-
scale implementation of this program. 
 
 


 
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3. Specific Aims 
 
The overall objectives of trial are to determine the optimal age group to treat with biannual oral 
azithromycin distribution to reduce child mortality and to compare selection for antimicrobial 
resistance across different age-based strategies for azithromycin distribution. In a series of 
secondary outcomes and parallel studies, the trial will also evaluate large-scale implementation. 
We propose the following specific aims for the Mortality/Resistance trial: 
 
Specific Aim 1.  
 
1a. To compare efficacy of biannual oral azithromycin distribution to reduce mortality in children 
1–59 months old in communities distributing azithromycin to ages 1–59 months (azithro 1–59) 
compared to placebo. We hypothesize that the community-level mortality rate in children 1–59 
months old at 2.5 years from the first enrollment will be lower in the azithromycin arm. 
 
1b. To compare efficacy of biannual oral azithromycin distribution to reduce mortality in children 
1–11 months old in communities distributing azithromycin to ages 1–11 months (azithro 1–11) 
compared to placebo. We hypothesize that the community-level mortality rate in children 1–11 
months old at 2.5 years from the first enrollment will be lower in the azithromycin arm. 
 
1c. To compare efficacy of biannual oral azithromycin distribution to reduce mortality in children 
12–59 months old in communities distributing azithromycin to ages 1–11 months (azithro 1–11) 
compared to 1–59 months (azithro 1–59). We hypothesize that the community-level mortality 
rate in children 12–59 months old at 2.5 years from the first enrollment will be lower in the 
azithro 1–59 arm. 
 
Specific Aim 2.  
 
2a. To compare the community-level prevalence of genetic determinants of macrolide resistance 
in nasopharyngeal samples from children 1–59 months old in programs targeting azithromycin 
to 1–11 months, 1–59 months, or providing placebo. We hypothesize that the community-level 
prevalence of resistance determinants after 2 years of distributions will differ in these 3 arms. 
Specifically, we hypothesize that the community-level prevalence of resistance determinants will 
be greater in the azithromycin arms than the placebo arm. In addition, we hypothesize that the 
prevalence of resistance will be greater in the azithro 1–59 arm than the azithro 1–11 arm. 
 
2b. To compare the community-level load of genetic determinants of macrolide resistance in rectal 
samples from children 1–59 months old in programs targeting azithromycin to 1–11 months, 1–
59 months, or providing placebo. We hypothesize that the community-level load of resistance 
determinants after 2 years of distributions will differ in these 3 arms. Specifically, we 
hypothesize that the community-level load of resistance determinants will be greater in the 
azithromycin arms than the placebo arm. In addition, we hypothesize that the load of resistance 
determinants will be greater in the azithro 1–59 arm than the azithro 1–11 arm. 
 


 
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4. Methods 
 
4.1. 
Trial Design 
 
AVENIR uses a large simple cluster-randomized placebo-controlled adaptive platform design to 
conduct multiple studies. Eligible communities in Niger will be randomly selected for participation in 
the Mortality/Resistance Trial, the Delivery Trials, or the Programmatic Trial. Figure 1, Figure 2, 
Table 1, and Table 2 summarize the design, eligible population, and anticipated rollout of the 
platform. 
 
4.2. 
Study Setting 
 
The study will take place in accessible rural and peri-urban communities in the 5 regions of 
Niger with the largest under-5 populations. This includes communities in the Dosso, Tahoua, 
Maradi, Zinder, and Tillabéri regions (Figure 2). According to Institute for Health Metrics and 
Evaluation (IHME) projections to 202012, the average regional under-5 mortality rate (number of 
deaths per 1,000 livebirths) is 116 in Dosso, 101 in Tahoua, 110 in Maradi, 120 in Zinder, and 
116 in Tillabéri. Agadez, Diffa, and the capital area of Niamey have much smaller under-5 
populations than the other regions and some areas are currently inaccessible to study teams due 
to security concerns and thus are not included in the trial (see Section 4.3 Eligibility). 
 
Figure 1. Eligible regions in Niger with estimated total under-5 population and study timeline. 
 
 
 
 
 
 
 
 
Start Time 
Stage I: 2020 
Stage I: 2021 
Stage I: 2022 
Stage II: Future implementation 
Not eligible  


 
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Figure 2. Stage I design summary 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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2 
4.3. 
Timeline 
 
The study will take place over a 4-year period beginning Fall 2020 (Table 1). 
Implementation will be phased in by region. Study progress is defined in “census rounds” which 
refer to a single 6-month census data collection and treatment period, and “inter-census 
intervals”, which refer to the interval between two census rounds, required to assess the primary 
outcome of mortality in the Mortality Trial. Dosso will be enrolled in the first year and Tahoua in 
the second year. Parts of Tahoua and Maradi will be added to the Programmatic Trial in the second 
and third years.
 
 


 
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Table 1. Estimated eligible study population and communities with intervention roll out in Stage I and II. 
Region 
 
 
Stage I1 
Stage II2 
 
 
Year 1 
Year 2 
Year 3 
Year 3 
Year 4 
Estimated 
eligible 
under-5 
population3 
Estimated 
eligible 
communities 
Round 1 
Round 24 
Round 35 
Round 4 
Round 5 
Round 6 
Round 7 
Round 8 
Dosso 
271,273 
1,800 
X* 
X 
X 
X* 
X* 
X 
X 
X 
Tahoua (1) 
245,944 
1,225 
 
 
X 
X* 
X 
X 
X 
X 
Tahoua (2) 
245,944 
1,225 
 
 
 
X 
X 
X 
X 
X 
Maradi (1) 
342,889 
1,000 
 
 
 
 
X 
X 
X 
X 
Maradi (2) 
342,890 
2,000 
 
 
 
 
 
X 
X 
X 
Zinder  
452,241 
3,860 
 
 
 
 
 
 
X 
X 
Tillabéri 
440,791 
3,070 
 
 
 
 
 
 
 
X 
Total: 
2,341,972 
14,180 
 
 
 
 
 
 
 
 
X = census and/or treatment; X* = census and/or treatment + resistance collections in a sample of communities 
1Stage I through primary outcome analysis at 2.5 years from the first enrollment. 
2Stage II dependent upon primary outcome, resources, and security restrictions. 
3As estimated from projections by the Institute for Health Metrics and Evaluation multiplied by fraction of eligible grappes in each 
region. 
4Delivery trial will begin at the beginning of round 2 in year 1 
5Interim analysis at approximately 1.5 years (end of round 3). At this time, intervention will begin in Programmatic Trial Communities.  
 
Table 2. Estimated eligible population by trial and region for Stage I. 
Region 
Estimated eligible 
under-5 population1 
Estimated eligible 
communities2 
Mortality/Resistance trial 
communities3,4 
Delivery trial 
communities 
Programmatic 
communities 
Dosso 
271,273 
1,744 
1,584 
160 
0 
Tahoua 
491,888 
1,916 
1,416 
0 
500 
Maradi (1st half) 
342,889 
1,000 
0 
0 
1,000 
Total 
1,106,050 
4,660 
3,000 
160 
1,500 
1As estimated from projections by the Institute for Health Metrics and Evaluation multiplied by fraction of eligible grappes in each 
region. 
2Communities with total populations between 250 and 2,499 not designated as urban quartiers according to the 2012 Niger national 
census. Dosso and Tahoua region estimates further exclude communities known to be located within 5 km of district headquarters 
town. Distance-based exclusions pending for Maradi. 
3150 AMR communities will be selected from among the Dosso Mortality/Resistance Trial communities to undergo collections for 
resistance monitoring


 
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4.4. 
Mortality/Resistance Trial 
4.4.1. Trial Design 
 
In the Mortality Trial, communities in the Dosso region in Niger will be randomized in a 1:1:1 
fashion to: 1) azithro 1–11: biannual azithromycin to children 1–11 months old with placebo to 
children 12–59 months old, 2) azithro 1–59: biannual azithromycin to children 1–59 months old, 
or 3) placebo: biannual placebo to children 1–59 months old. For regions enrolled after the one-
year run-in period, the randomization allocation will be updated based on the probability of 
mortality in children 1–59 months in each arm. Communities will retain their allocation for 4 
distributions. A dedicated study team will conduct a biannual door-to-door census to deliver the 
intervention and monitor mortality. Within the Mortality Trial, 150 communities in the Dosso 
region will be randomly selected from among the eligible communities, similarly randomized 
1:1:1, and followed to monitor antimicrobial resistance (Figure 1).  
 
The initial design compares the efficacy of different age-based azithromycin distribution 
strategies to reduce child mortality. After the primary outcome analysis additional treatment 
arms may be added to the trial or arms may be dropped from the trial. With such changes, 
protocol details, power calculations, and analysis plans will be updated accordingly in the 
protocol and statistical analysis plan. 
 
4.4.2. Eligibility 
 
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  
 
Exclusion criteria: 
• 
Known allergy to macrolides 
 


 
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Population-based sample collections  
 
At the community-level, eligibility includes: 
 
Inclusion criteria: 
• 
Location in study region 
• 
Distinguishable from neighboring communities 
• 
Verbal consent of community leader(s) 
 
Exclusion criteria: 
• 
Inaccessible or unsafe for 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 
• 
Written consent of caregiver/guardian for study participation 
*7-12 years at baseline or under 12 years and not previously eligible for treatment at follow-up  
 
Exclusion criteria: 
• 
Not on list of randomly selected participants from the census 
 
4.4.3. Randomization, Adaptation, and Masking 
 
4.4.3.1. 
Randomization  
 
The randomization unit for the Mortality/Resistance Trial will be the grappe, which is the 
smallest health care unit administratively defined in Niger, hereafter referred to as “community.” 
 
Communities will be randomized to the following 3 arms: 
 
 Azithro 1–11: biannual weight- or height-based dose of oral azithromycin suspension 
to children 1–11 months old and oral placebo to children 12–59 months old 
 Azithro 1–59: biannual weight- or height-based dose of oral azithromycin suspension 
to children 1–59 months old 
 Placebo: biannual weight- or height-based dose of oral placebo to children 1–59 
months old  
 
4.4.3.2. Adaptation 
 
The randomization sequence will be generated by the trial biostatistician at UCSF.  
 
In the Mortality/Resistance Trial, Dosso communities will undergo the first randomization in a 
1:1:1 allocation to the 3 arms and will retain their allocation throughout the first stage of the 
study. For communities in other regions enrolled after Dosso, the allocation will adapt based on 
prior mortality outcomes from the Mortality Trial and each cluster’s assignment will be retained 


 
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through the primary outcome assessment. After the primary outcome assessment, allocation 
probabilities will be updated after every 4 distributions.  
 
After the Mortality Trial’s primary outcome analysis, the study team and key stakeholders will 
determine whether the Programmatic Trial continues. If the study continues, the Mortality Trial 
communities will be included in the Programmatic Trial and additional regions will be added over 
time (Figure 2). In this platform design, additional treatment arms may be added to the trial or 
arms may be dropped from the trial based on additional information from other studies, updates 
to the WHO guidelines, or preferences of programs or policymakers in Niger. With such 
changes, protocol details, power calculations, and analysis plans will be updated accordingly in 
the protocol and statistical analysis plan.  
 
Refer to the trial’s Statistical Analysis Plan (SAP) for complete details of the adaptive 
randomization algorithm. 
 
4.4.3.3. 
Masking 
 
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 census personnel administering treatment and 
collecting mortality outcome data and the data analysis team, 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. Key members of the Pfizer staff must be unmasked to implement 
the study drug treatment allocation, and to review SAE reporting. Masking will minimize bias 
introduced through knowledge of treatment assignment and will ensure that the census and 
outcome assessments are identical in all study communities.  
 
4.4.3.4. 
Interventions 
 
Description of Study Medicine 
 
Azithromycin (Zithromax®) for oral suspension is supplied in bottles containing azithromycin 
dehydrate powder equivalent to 1200 mg per bottle and the following inactive ingredients: 
sucrose; tribasic anhydrous sodium phosphate; hydroxypropyl cellulose; xanthan gum; FD&C 
Red #40; and flavoring including spray dried artificial cherry, crème de vanilla, and banana. 
After constitution, a 5 ml suspension contains 200 mg of azithromycin. 
 
Placebo is identical in appearance, with identical labeling, and contains no active ingredient. 
 
4.4.3.5. 
Dosage Information 
 
Azithromycin or placebo will be administered as a single dose, in oral suspension form for 
children, of 20 mg/kg in children (up to the maximum adult dose of 1 g). In the 
Mortality/Resistance Trial, weight-based dosing will be used via hanging scale for children 1–11 
months of age. 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. 
 
Both dosing cups and syringes will be used to administer treatment. For children too young to 


 
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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. 
 
4.4.3.6. 
Side Effects 
 
Azithromycin is usually well tolerated. The most common side effects are diarrhea, nausea, 
abdominal pain, and vomiting. These side effects occur in fewer than 5% of persons who 
receive azithromycin and have been rarely reported in studies of the mass distribution of 
azithromycin for trachoma or child mortality. Adverse events will be monitored as described in 
Section 4.10. 
 
There is a possibility of an increased risk of infantile hypertrophic pyloric stenosis in neonates, 
who are excluded from this trial.  
 
Pfizer, Inc. will provide the donation of azithromycin and placebo, which will be shipped directly 
to Niger and received by a representative of the Nigerien Ministry of Health, who will manage 
the customs process and transport the medication from the port to a storage site. The 
exemption of duties and taxes will be settled by the Nigerien Customs Authorities and the 
Nigerien Ministry of Health. 
 
4.4.3.7. 
Study Medication Storage and Accountability 
 
Azithromycin and placebo will be stored between 15° to 30°C (59° to 86°F), as recommended 
by Pfizer. A record of the exact quantity of oral suspension dispensed will be kept by the 
treatment distribution teams. 
 
4.4.3.8. 
Medication Quality Control 
 
Study medication will be stored in project offices prior to use. The study team will regularly 
check and record the temperature of the drug storage rooms and the study medication expiry 
dates. The expiration dates on the medication containers will be strictly monitored and all 
expired study medicine will be discarded appropriately. 
 
4.4.4. Outcomes 
 
4.4.4.1. 
Primary Outcomes 
 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children 1- 59 months of 
age at 2.5 years from the first enrollment with a window of up to 3 months, comparing 
the azithro 1–59 and placebo arms 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children 1- 11 months of 
age at 2.5 years from the first enrollment with a window of up to 3 months, comparing 
the azithro 1–11 and placebo arms 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children 12- 59 months of 
age at 2.5 years from the first enrollment with a window of up to 3 months, comparing 
the azithro 1–11 and azithro 1–59 arms 
 
• 
Prevalence of genetic determinants of resistance to macrolides from 
nasopharyngeal swabs in children 1–59 months old after 2 years of distributions  
• 
Load of genetic determinants of resistance to macrolides from rectal swabs in 


 
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children 1–59 months old after 2 years of distributions  
 
4.4.4.2. 
Secondary Outcomes 
 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children ages 12–59 
months over 2.5 years from the first enrollment with a window of up to 3 months, 
comparing the azithro 1–11 and placebo arms 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children ages 1–11 
months over 2.5 years from the first enrollment with a window of up to 3 months, 
comparing the azithro 1–11 and azithro 1–59 arms 
• 
Mortality rate over 2.5 years from the first enrollment with a window of up to 3 months 
by subgroups: 
o Region (Dosso, Tahoua, Maradi, Zinder, and Tillabéri) 
o Number of previous community distributions 
o Timing of distribution/seasonality 
o Other interventions 
▪ 
Participation in MORDOR trials 
▪ 
Participation in and coverage of Seasonal Malaria Chemoprevention 
(SMC) 
▪ 
Participation in trachoma distributions of azithromycin 
o Anthropometric indicators as defined by weight, MUAC, height interval 
o Distance to nearest healthcare facility 
 
• 
Prevalence of genetic determinants of resistance to macrolides from nasopharyngeal 
swabs and load of genetic determinants of resistance to macrolides from rectal swabs 
after two years of distributions in: 
o Children 7-12 years old  
o Caregivers/guardians of eligible children  
• 
Prevalence of genetic determinants of resistance to other antibiotic classes 
from nasopharyngeal swabs and rectal swabs in all samples after 2 years of 
distributions 
• 
Proportion of macrolide resistant pneumococcal isolates from nasopharyngeal 
swabs in children 1–59 months after 2 years of distributions 
• 
Prevalence of malaria as assessed by RDT during sample collections at 
baseline and after two years of distributions 
 
• 
Program costs as captured by routine administrative data collection during the study 
period and by micro-costing activities 
• 
Cost-effectiveness measured by estimated program costs and using measured 
mortality and estimated DALYs as the effectiveness outcome, compared across arms. 
 
• 
Change in anthropometric indicators over time as defined by weight, mid-upper 
arm circumference (MUAC), and height interval 
• 
All infectious clinic visits among children 1–59 months of age in the study area 
during the study period as assessed through passive surveillance of CSI 
records 
• 
Cause-specific clinic visits among children 1–59 months of age in the study area during 
the study period as assessed through passive surveillance of CSI records, including 
visits with diagnoses of respiratory infection, diarrheal disease, and malaria 
 
Microbiome outcomes for rectal swab collections 


 
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• 
Gamma diversity, estimated as the alpha diversity of the pooled community sample 
using the Shannon diversity index 
• 
Overall microbial structure using Manhattan distance 
• 
Relative abundance of individual microbial taxa at genus and species level  
 
4.4.4.3. 
Other Outcomes 
 
• 
Cause-specific mortality by treatment arm as defined by verbal autopsy* over 2.5 years 
from the first enrollment 
• 
Serological markers of pathogen infection as assessed by dried blood spots after 2 
years of distributions 
• 
Normalized read number of genetic determinants of resistance by antibiotic class in 
environmental samples after 2 years of distributions  
 
*Depending upon resources, verbal autopsy might be conducted by UCSF or another group 
 
4.4.5. Sample size 
 
4.4.5.1. 
Overview 
 
We estimate that there are approximately 14,180 eligible communities encompassing 
approximately 2.3 million children under 5 across the 5 eligible regions (Table 1). For the first 
stage of the study, we estimate we will include 4,660 eligible communities in Dosso, Tahoua, 
and part of Maradi, with a total of 1.1 million eligible children under 5 (Table 2).  
 
Stage I includes data collected through the primary outcomes. In Stage I, 3,000 communities 
will be selected for the Mortality/Resistance Trial, 160 for the delivery trials, and 1,500 will 
receive for the Programmatic Trial. The remaining eligible communities in Maradi, Zinder and 
Tillabéri will be included in the study during Stage II. Table 2 details the Stage I study population 
by region. 
 
Refer to SAP for details of power calculations based on this sample size.  
 
4.4.5.2. 
Sample Collections 
 
150 of the communities in the Mortality Trial in the Dosso region will be randomly selected to be 
followed to monitor antimicrobial resistance. In each community, 30 children aged 1–59 months, 
30 children 7-12 years, and 30 caregivers/guardians of eligible children will be randomly 
selected for sample collections at baseline and after 4 distributions. Samples will be collected in 
a random subset of 60 communities at baseline, and in all 150 AMR communities after 4 rounds 
(approximately 2 years). 
 
An additional 40 communities that participated in the MORDOR 54 trial will be randomly 
selected for inclusion in sample collections at baseline. Of these 40 communities, 20 will be 
randomly selected from among those who received 5 rounds of azithromycin during MORDOR, 
and the other 20 communities be randomly selected from among those who received 3 rounds 
of azithromycin and 2 rounds of placebo during MORDOR. In each community, 30 children 1–59 
months will be randomly selected to receive a rectal swab.  
 
Furthermore, 60 communities whose children aged 1-59 months have received ~11 biannual 


 
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distributions of azithromycin (as opposed to placebo) during the MORDOR trial will be selected 
randomly: 20 randomized in AVENIR to two more years of biannual azithromycin to 1-59 month 
olds, 20 randomized to biannual azithromycin to 1-11 month olds, and 20 randomized to 
biannual placebo. 40 children per grappe, aged 1-59 months, will be randomly selected from the 
prior census. Examiners will perform a nasopharyngeal swab on each child, stored in STGG 
media.  
 
In all communities selected for sample collections, treatment distribution for that round will be 
conducted after sample collections. 
 
Refer to SAP for details of power calculations. 
 
4.4.6. Recruitment 
 
Before implementation begins in a region, a sensitization campaign will inform local health 
authorities and community leaders of the study design and nature of participation in the trial. In 
addition to IRB and national-, regional-, and district-level approval, community-level approval will 
be obtained before study activities begin in any community. All households will be recruited for 
participation in the census, and all children 1–59 months of age will be recruited for the 
intervention. Household-level consent will be obtained for the census activities, and 
caregiver/guardian consent will be obtained for interventions and sample collection. Details of 
informed consent are found in Section 5.3. 
 
4.4.7. Adverse Events Monitoring 
 
During the consent process, the common adverse reactions that may occur will be explained to 
caregivers/guardians. At the time of treatment, caregivers will be instructed to report to the study 
team any adverse event experienced by the treated child within 28 days of treatment. Children 
will be referred for follow up care on a case-by-case basis. 
 
4.4.7.1. 
Adverse Events Reporting 
 
Serious adverse events (SAE) will be reported to Pfizer. An IIR SAE Form (Investigator-Initiated 
Research Serious Adverse Events Form) will be completed for each event. 
 
According to Pfizer, an SAE is any adverse event that: 
Results in death 
Is life-threatening (i.e., causes an immediate risk of death) 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Results in persistent or significant disability or incapacity 
Results in a congenital anomaly or birth defect or that is considered to be: 
An important medical event 
 
All caregivers will be advised to alert a community health worker or study team member if their 
child experiences an adverse event within 28 days of distribution. The study team will be trained 
to identify serious adverse events, which must be submitted to UCSF within 24 hours. UCSF will 
review and submit SAEs to Pfizer and the Medical Monitor, and to the DSMC as required. 
 
Deaths that are reported to the study team outside of the biannual census (primary Mortality 
Trial outcome) will be reported as an SAE to Pfizer. Note that deaths identified via the biannual 


 
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census, which constitute the primary outcome, will not be reported as SAEs. Deaths that are 
reported to the study team as part of the biannual census will be reported to Pfizer in aggregate, 
not by arm, quarterly. 
 
See the Adverse Events Reporting procedures for further details 
 
4.4.8. Data Collection, Management, Analysis, and Monitoring 
4.4.8.1. 
Data Collection Overview 
 
All Mortality/Resistance Trial data will be collected electronically on mobile devices with a 
custom-designed mobile application using the CommCare mobile data collection platform by 
Dimagi.  
 
4.4.8.2. 
Measurement of Mortality Outcomes 
 
Mortality will be monitored through biannual census data collection in the Mortality/Resistance 
Trial. Trained census workers will use a mobile application on smartphones to collect data. 
Census workers will visit each household in assigned study communities to obtain household 
consent for participation, and to collect demographic data on the head of household, all mothers 
in the household, and all children 1–59 months in the household. For eligible children, dose will 
be determined via weight using a hanging scale for children under 12 months of age or height-
stick approximation for children 12 months and older using the Niger trachoma program’s height 
stick. MUAC will also be assessed on all eligible children. The census worker will administer the 
dose and record the child’s treatment status. At subsequent census rounds, the census workers 
will return to each household and update the vital status of all children, indicating whether a 
child is alive, has died, has moved, or has an unknown status. New children and households will 
be added. The census will be updated at 6, 12, 18, 24, 30 and 36 months from baseline. A 
subset of communities will be randomly selected to receive a repeat census at the same time 
point to validate data collection. 
 
For Mortality Trial communities randomly sampled for additional monitoring, census data 
collection will include children 7-12 years of age (see Section 4.10.3). In these communities, 
treatment will be conducted after samples have been collected. 
 
Verbal and social autopsies may be conducted on deaths that occur during the study and are 
identified during the census, depending on the availability of resources. Verbal autopsies will be 
performed on children who were 1-2 months of age at the time of treatment and were recorded 
as died on the subsequent census.  
 
A subset of Mortality Trial communities will also receive a birth history survey in addition to the 
regular census. 
 
4.4.8.3. 
Measurement of Sample Based Outcomes 
 
In the Mortality and Resistance Trial, 150 AMR communities from the Dosso region will be 
randomly selected from the pool of eligible communities and followed to monitor antimicrobial 
resistance. Samples will be collected in a random subset of communities at baseline and in all 
150 AMR communities after 2 years of distributions. For primary outcomes, samples will be 
processed from a subset of 150 communities. 
 
In each of the selected Mortality/Resistance Trial communities, 30 children aged 1–59 months, 


 
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30 children aged 7–12 years, and 30 caregivers/guardians of eligible children will be randomly 
selected for additional monitoring. Nasopharyngeal samples will be collected from all sampled 
individuals. From children aged 1–59 months, rectal swabs, RDT, and dried blood spots will also 
be collected. In the sample of children aged 1–59 months, 10 children will be randomly selected 
for an additional nasopharyngeal swab which will be used for phenotypic testing. Samples will 
be collected at baseline and after 2 years of distributions. 
 
To randomly select individuals for population-based monitoring in the Mortality/Resistance Trial, 
census data will be used. In the 150 Dosso communities selected for additional monitoring, the 
baseline and 24-month census will be separate from treatment and will include data collection 
on children aged 7–12 years old. The random samples of children in both age groups and 
caregivers/guardians will be selected from the census. To ensure that samples are collected on 
30 individuals in each group, 50 children in both age groups and 50 caregivers/guardians will be 
randomly selected from the census data. 
 
60 previously untreated communities will be incorporated into the Mortality/Resistance Trial in 
Round 4 and will receive rectal swab baseline collections. This is to account for rectal swab 
baseline samples collected in Round 1 that were damaged and unusable. 1 rectal swab will be 
collected from 30 children aged 1–59 months per community. Samples from community latrines 
and chicken feces will also be collected when available from the homes of the 30 children 
selected for this sample collection.  
 
Environmental samples will be taken from communities and households from which participants 
were selected for data collection at baseline and 24 months. Latrine and water samples will be 
taken at the community level, and animal feces, stored water, and dirt samples will be taken at 
the household level. 
 
Once the census is complete and the sample is generated, the study team will work with a local 
mobilizer to invite the sampled group to a central location in the community for sample 
collection. Samples will be collected by trained personnel and linked to census data through bar 
codes. Once sample collection is complete, the census team or community health workers will 
visit the study community to complete treatment for that round. 
 
During collection, samples will be stored at ambient temperature or on ice at 4°C. At the end of 
each collection period, samples will be transported to a location near the sampled community 
with facilities to store samples at -20°C as required or directly to CRISP each day. At the end of 
the collection period, all samples will be transferred to a central storage location at CRISP in 
Niamey stored at -20°C as required until processed or shipped to UCSF for processing. Refer to 
Sample Collections Procedures and the Laboratory Procedures for full details. 
 
All the same procedures will be followed for the additional communities that will be added from 
MORDOR.  
 
4.4.8.4. 
Measurement of Additional Outcomes 
 
Data on other programs that include the distribution of antibiotics in the study area will be 
collected. Seasonal Malaria Chemoprevention (SMC) implementation and coverage data will be 
collected from SMC implementers at the district and community level during the study. 
Trachoma distributions will be tracked, and prior distributions recorded for each community 
through communications with PNSO. 
 


 
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4.4.8.5. 
Data Collection and Management 
 
All study personnel who assess outcomes will attend intensive, two-day training sessions prior 
to conducting study procedures. Training will include operation of the mobile device, data 
collection through the mobile application or on paper, and the study protocol and procedures. 
 
Where possible, data will be collected electronically using a custom-designed mobile census 
application (CommCare, Dimagi) on mobile devices and uploaded regularly to a secure, cloud-
based server. Where possible, data will be uploaded in real time using the cellular network, or 
weekly or monthly at a central site with strong Wi-Fi or cellular connection. In the Delivery Trial 
and Programmatic Trial communities, data on intervention administration will be recorded by 
community health workers on paper forms, and later entered electronically. 
 
Mobile devices will be accessed via unique usernames and passwords. Mobile devices will be 
stored in locked offices with electricity for charging. 
 
Validation will be used in development of the data collection forms to ensure to a large extent 
that there are no inconsistencies or invalid data. Data management teams in Niger and at UCSF 
will monitor data collection in real time daily. Progress and quality control reports will be 
prepared and distributed to investigators weekly. 
 
Study participants will be assigned unique identification numbers that do not contain identifying 
information, which will be used to link data across databases and will be the only identifier 
shared in de-identified datasets. 
 
The total number of all infectious and cause-specific CSI visits will be collected using data 
available from the Niger Ministry of Health.  
 
Refer to the Data Monitoring Plan for full details. 
 
4.4.8.6. 
Statistical Analysis Plan 
 
Refer to the trial’s Statistical Analysis Plan (SAP) for complete details 
 
4.4.8.7. 
Quality Control and Monitoring 
 
All study personnel will be trained on standardized study procedures for data collection before 
each round of study activities begin. A team of supervisors in Niger will monitor study personnel 
collecting data weekly, and the UCSF team will conduct biannual study monitoring visits. 
Weekly data monitoring reports will be distributed to the study team, with a detailed section on 
inconsistencies, errors, and missing data to be resolved by the data teams. 
 
4.5. 
Delivery Trial 
 
4.5.1. Trial Design 
From the same pool of eligible communities, 160 communities in Dosso will be randomly 
selected for participation in one of two Delivery Trials: 
 
In Delivery Trial I, 80 communities in Dosso will be randomly selected for participation in a 2-
arm trial that will compare coverage, costs, and other implementation outcomes between fixed-
point delivery and door-to-door delivery of azithromycin by community health workers to children 


 
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1–59 months of age.  
 
In Delivery Trial II, 80 communities in Dosso will be randomly selected for participation in a 2-
arm trial that will compare costs and other implementation outcomes between treating eligible 
children 1–11 months of age to treating eligible children 1–59 months of age. The intervention 
delivery method for all communities will be informed by Delivery Trial I.  
 
 
4.5.2. Eligibility 
 
Intervention  
 
At the community-level, eligibility includes: 
 
Inclusion criteria: 
• 
Location in Dosso 
• 
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 or 1–11 months depending on arm allocation 
• 
Primary residence in a study community 
• 
Verbal consent of caregiver/guardian for study participation 
 
Exclusion criteria: 
• 
Known allergy to macrolides 
 
4.5.3. Randomization, Adaptation, and Masking 
4.5.3.1. 
Randomization  
 
The randomization unit for these trials will be the grappe, which is the smallest health care unit 
administratively defined in Niger, hereafter referred to as “community.” 
 
Delivery Trial I communities will be randomized in a 1:1 fashion to the following 2 arms: 
 
• 
Azithro 1–59 fixed point: azithromycin distribution to children 1–59 months of age 
using a fixed-point delivery approach via existing community health workers 
• 
Azithro 1–59 door-to-door: azithromycin distribution to children 1–59 months of age 
using a door-to-door delivery approach via existing community health workers 


 
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Delivery Trial II communities will be randomized in a 1:1 fashion to the following 2 arms: 
 
• 
Delivery azithro 1–11: azithromycin distribution to children 1–11 months of age using 
a door-to-door delivery approach via existing community health workers 
• 
Delivery azithro 1–59: azithromycin distribution to children 1–59 months of age using 
a door-to-door delivery approach via existing community health workers  
 
4.5.3.2. Adaptation 
 
The randomization sequence will be generated by the trial biostatistician at UCSF.  
 
The Delivery Trial communities will not undergo adaptation during the Delivery Trial period and 
may be included in the adaptation or programmatic trial after the Delivery Trial is completed. 
 
Refer to the trial’s Statistical Analysis Plan (SAP) for complete details of the adaptive 
randomization algorithm. 
 
4.5.3.3. 
Masking 
 
In the Delivery Trial, participants, implementers, and outcome assessors will not be actively 
masked from the delivery approach given the nature of the intervention. Data analysts will be 
masked. 
 
4.5.3.4. 
Interventions 
 
Please refer to Section 4.4.3.4.  
 
4.5.3.5. 
Dosage Information 
 
Azithromycin or placebo will be administered as a single dose, in oral suspension form for 
children, of 20 mg/kg in children (up to the maximum adult dose of 1 g).  
 
In the Delivery Trials and Programmatic Trial, the dose will be calculated by age for children 
aged 1-11 months. Aged-based dosing will be implemented as follows: 
• 
2 ml of azithromycin for children aged 1-2 months 
• 
4 ml of azithromycin for children aged 3-11 months 
 
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. 
 
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. 
 
4.5.3.6. 
Side Effects 
 
Please refer to Section 4.4.3.6.  
 
4.5.3.7. 
Study Medication Storage and Accountability 


 
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Please refer to Section 4.4.3.7.  
 
4.5.3.8. 
Medication Quality Control 
 
Please refer to Section 4.4.3.8.  
 
4.5.4. Outcomes 
 
4.5.4.1. 
Delivery Trial I Primary Outcomes 
 
• 
Treatment coverage as defined by the number of doses of azithromycin administered 
and recorded by community health workers divided by the eligible population as 
determined by a post-distribution census in each community after a single distribution. 
 
4.5.4.2. 
Delivery Trial I Secondary Outcomes 
  
• 
Program costs as captured by routine administrative data collection during the study 
period and by micro-costing activities 
• 
Cost-effectiveness measured by estimated program costs and using measured 
mortality and estimated DALYs as the effectiveness outcome, compared across arms. 
• 
Estimated national-scale effects (health and cost) of scaling up each strategy.  
• 
Other implementation outcomes defined in the Proctor Outcomes Framework,13 
including feasibility and acceptability, as captured during routine administrative and 
monitoring data collection during the study period and by stakeholder interviews at the 
participant, community, and health system levels after one round of distributions (Table 
3) 
• 
Treatment coverage as defined by projections using national and study census data 
collection as well as satellite imagery 
 
4.5.4.3. 
Delivery Trial II Primary Outcomes 
• 
Cost per dose delivered. Program costs will be captured by routine administrative data 
collection during the study period and by micro-costing activities. Doses delivered will 
be recorded by community health workers using paper data collection forms and 
entered electronically by the supervisor team. 
 
4.5.4.4. 
Delivery Trial II Secondary Outcomes 
• 
Treatment coverage as defined by the number of doses of azithromycin administered in 
each community divided by the total eligible population, which will be determined in 
several ways: using the recorded number of eligible children from the community health 
workers, using a pre-treatment census of eligible children, using self-reported coverage 
recorded during the post-treatment survey, and the administrative estimates of the 
eligible population from the health centers. The number of eligible children recorded by 
community health workers will be used for the main analysis with the others included as 
sensitivity analyses, and a separate analysis will be done to compare the 4 methods. 
• 
Other implementation outcomes defined in the Proctor Outcomes Framework, including 
feasibility and acceptability, as captured during routine administrative and monitoring 
data collection during the study period and by stakeholder interviews at the participant, 
community, and health system levels after one round of distributions. 
 


 
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4.5.5. Sample size 
 
Please refer to Section 4.4.5.1.  
 
4.5.6. Recruitment 
 
Before implementation begins in a region, a sensitization campaign will inform local health 
authorities and community leaders of the study design and nature of participation in the trial. In 
addition to IRB and national-, regional-, and district-level approval, community-level approval will 
be obtained before study activities begin in any community. All households will be recruited for 
participation in the census, and all children 1–11 or 1–59 months of age will be recruited for the 
intervention depending on the study arm their community has been randomized to. Household-
level consent will be obtained for the census activities, and caregiver/guardian consent will be 
obtained for interventions and sample collection. Details of informed consent are found in 
Section 5.3. 
 
4.5.7. Adverse Events Monitoring 
 
Please refer to Section 4.4.7.  
 
4.5.8. Data Collection, Management, Analysis, and Monitoring 
 
4.5.8.1. 
Data Collection Overview 
 
Delivery trial data will be collected electronically and on paper as described below. 
 
4.5.8.2. 
Measurement of Implementation Outcomes 
 
In the Delivery Trial, existing community health workers will be trained to distribute azithromycin 
to children 1–59 months of age or 1–11 months of age every 6 months. In communities 
randomized to fixed-point delivery, community health workers (CHWs) will work with community 
leaders to identify a central location, date, and time for delivery. Mobilizers in each community 
will be engaged to publicize the intervention. In communities randomized to door-to-door 
delivery, CHWs will visit every household in the community. In both sets of communities, CHWs 
will determine eligibility, obtain informed consent, administer treatment, and record treatment 
administration on paper data collection forms. For eligible children in Delivery Trial I, the dose 
will be determined via weight using a hanging scale for children under 12 months of age or 
height-stick approximation for children 12 months and older using the Niger trachoma program’s 
height stick. For eligible children in Delivery Trial II, the dose will be determined via age for 
children under 6 months of age or height-stick approximation for children 6 months and older 
using the Niger trachoma program’s height stick. Treatment coverage will be monitored by 
tracking the total number of children treated in each community as recorded by CHWs during 
distributions. Denominators for treatment coverage will be estimated through a post-distribution 
census conducted by trained census workers.  
 
Program costs 
Program costs will be captured through micro-costing (units of resources used multiplied by the 


 
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unit costs thereof). The economic approach will assign value to all items used, regardless of the 
payer, and regardless of whether the resources consumed are fully monetized. A macro-costing 
approach will be used for reconciliation and for understanding cost efficiency: overall program 
spending and outputs will be compared to the totals found via micro-costing. Costs will be 
collected using both routine project administrative data collected for all study communities (e.g., 
expenditure reports for services delivered, operational reports for distances travelled) with 
“program costs” being defined as costs needed to deliver the program in the absence of any 
research efforts. Research costs will be measured as part of the overall project but removed 
when comparing different age and delivery options to more accurately reflect an azithromycin 
MDA program. The micro and macro approaches are described in turn below. Finally, ‘start-up’ 
costs will be distinguished from ongoing running costs.  
 
In addition to routine project administrative data collection, targeted additional data collection in 
the form of time and motion (T&M) studies for a small subset of communities will be 
implemented. As described below, the T&M studies will adapt and use forms that have been 
successfully used in other studies. Forms and data entry and analysis systems needed for 
routine program accounting, management and reporting purposes will be developed 
concurrently with the cost data collection needed for economic analysis and piloted using pre-
implementation expenditures.  
 
Program micro-costing  
 
Cost information collected through regular project records will include the following categories: 
 
• 
Personnel: Salaries and benefits (and any other emoluments, such as bonuses, etc.) 
for all staff, including service delivery (azithromycin distribution), program 
administration, transportation, etc. 
• 
Consumables: Medications, office supplies, dosing cups, syringes, water, scales, 
height sticks, fuel, and supplies needed for AMR surveillance, including swabs, tubes, 
media, storage, shipment, and processing, etc. 
• 
Services: Transportation, equipment maintenance, utilities, publicity, transport. 
• 
Equipment: Vehicles, laboratory equipment, and other significant capital items. 
• 
Training: Salaries, per diems, transport, food, etc. 
• 
Space: Rental cost and/or purchase depreciation. 
 
The last three items, equipment, training, and space will be appropriately amortized. 
 
Costs will be allocated appropriately in collaboration with local project staff in order to ensure 
accurate division of project and research costs. Should the economics team find discrepancies, 
in whether a cost is research or project oriented, the team alongside local project staff will 
discuss until consensus is achieved. Services-related, non-research costs will then be allocated 
to the categories listed above and cross–categorized by particular activities. These activities 
include direct service delivery excluding supervision; field supervision; transportation, and 
overhead, among others. Expenditure data will be allocated to these activities by recall via 
structured interviews and, for a small subset of sites, via T&M data. These costs can then be 
allocated to the community level according to a schema consistent with the one developed for 
the provisional cost model and which reflects current budget items. Cost allocation will 
distinguish payer (government / program, volunteer/contributed) and location (community, 
district, region). 
 


 
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Time & Motion (T&M) studies 
 
T&M will be conducted at least twice per region and distribution, for one week each time, for a 
sample of communities. The T&M activity has three purposes. First, it is one of the approaches 
we will use to compare the resources needed at the community level between the 1 – 11 month 
and 1 – 59-month distribution strategies and the fixed-point versus door-to-door strategies in the 
Delivery Trial. Second, the T&M data will inform modeling of intervention cost in settings with 
different characteristics. Third, the T&M data will help to disaggregate field costs associated with 
delivery of a real-world intervention from those related to the research setting. The T&M will 
quantify: 
 
• 
Time spent on program activities vs. other responsibilities (if any). 
• 
Within program activities, time spent at the community level (e.g. with a local leader), 
moving around the community, addressing household-level issues such as explanation 
and consent, and administering azithromycin to individual children. 
• 
At both the community and the household level it will allow us to distinguish between 
fixed and variable costs. 
 
Sampling for T&M will be conducted in order to provide robust estimates for important 
subgroups, including geographic regions, village size, difficult-to-reach villages, and other 
factors to be decided. 
 
Cost Differentiation 
 
Start-up costs. Large expenditures often occur in the early phases of a project when sizable 
one-time costs are incurred. This includes vehicle purchases, other equipment, and furniture 
purchases, building refurbishment, and some training costs. 
 
Focus on items contributing to majority of costs. Previous experience suggests that total costs 
are disproportionately attributable to a relatively small number of items. Data collection will 
therefore be calibrated via a formal “forest and trees” process of identifying the limited number 
of inputs constituting 90 - 95% of costs. We will reduce efforts to obtain high precision for items 
comprising the other 5 - 10%.  
 
Tracking costs over time. Unit costs may vary over time. For example, both administrative and 
field teams may become more efficient as they gain experience. We will generate graphs which 
display trends in major cost categories over time. We will also conduct structured interviews that 
aim to identify the proximate causes for observed changes in efficiency. 
 
Program macro-costing 
 
After removing research-related costs, program costs will be divided by the total number of 
outputs to arrive at a set of unit cost estimates. If these approximate the array of unit cost 
estimates obtained from the micro-costing approach described above, this would reconcile the 
micro-costing approach.  
 
Cost-effectiveness analyses  
Program costs and mortality outcomes will be used to develop incremental cost-effectiveness 
ratios (ICERs) for age group comparisons as detailed in the SAP.   
 
Table 3 summarizes the collection of additional process indicators to track key implementation 


 
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outcomes using the Proctor Implementation Outcomes and RE-AIM frameworks, which will be 
applied across work streams for program monitoring and evaluation. 


 
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Table 3. Proctor Implementation Outcomes and RE-AIM Frameworks Applied to AVENIR 
 
Outcome 
Definitions 
Sources of Data 
Acceptability/Appropriateness Perception of and satisfaction with 
intervention, facilitators and barriers to 
participation and implementation, 
relevance of intervention; at 
participant/community, implementer, and 
governmental levels 
Semi-structured 
interviews, 
surveys 
 
 
 
Reach/Penetration 
Census coverage 
Census, NSVRS 
 
Refusals and reasons for refusals 
Census, 
administrative 
data 
 
Treatment coverage, equity of coverage 
by sex, age, geography 
Census 
 
 
 
Cost 
Program costs 
Administrative 
data, micro-
costing 
 
Cost-effectiveness 
Administrative 
data, census, 
micro-costing 
 
 
 
Feasibility/Fidelity 
Timeliness and fidelity of intervention 
rollout 
Administrative 
data, site visits 
 
Training and supervision metrics, staff 
retention 
Administrative 
data, site visits 
 
Drug storage, temperature, inventory, 
delivery monitoring 
Administrative 
data 
 
AMR sample viability, rejection rates, 
processing speed 
Administrative 
data 
 
 
 
Sustainability 
Above metrics compared over time 
See above 
 
 
 
 
 


 
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4.5.8.3. 
Data Collection and Management 
 
Please refer to section 4.4.8.5. 
 
4.5.8.4. 
Statistical Analysis Plan 
 
Please refer to section 4.4.8.6. 
 
4.5.8.5. 
Quality Control and Monitoring 
 
Please refer to section 4.4.8.7.  
 
4.6. 
Programmatic Trial 
 
4.6.1. Trial Design 
The remaining 1,500 eligible communities will participate in a Programmatic Trial that utilizes 
existing community health workers working with the Niger Ministry of Health community health 
program. The distribution of biannual azithromycin will begin approximately 1.5 years after the 
first Mortality Trial enrollment and will be offered to children aged 1–11 months in selected CSIs. 
CSIs will be used as the randomization unit. CSIs will be randomized in a 2:1 allocation to 
azithromycin distribution to children aged 1–11 months by community health workers or no 
azithromycin distribution / usual care by community health care workers, with the allocation 
favoring azithromycin. AMR after 1 year will be monitored at the community level using similar 
methods to the Mortality/Resistance Trial as well as in children presenting to selected CSIs with 
diarrheal disease, respiratory infection, or for a well-child visit. Mortality will be monitored by 
birth histories after 2 years of treatment distribution. 
 
After 1 year of distributions, the results from the Mortality/Resistance trial will be available and 
will be used to inform the next steps for the Programmatic Trial. The trial may continue based on 
the Mortality trial results, the availability of funding, and stakeholder preferences. If the study 
continues, additional regions will be included in the Programmatic Trial (Figure 2), using 
adaptive randomization as described for the Mortality/Resistance Trial. The original 
Mortality/Resistance Trial communities would also be included in the Programmatic Trial during 
this expansion. Mortality, resistance, and clinic visits will be monitored every 2 years. In this 
platform trial, additional treatment arms may be added to the trial or arms may be dropped from 
the trial based on additional information from other studies, updates to the WHO guidelines, and 
preferences from programs and policymakers in Niger. With such changes, protocol details, 
power calculations, and analysis plans will be updated accordingly in the protocol and statistical 
analysis plan.  
 
4.6.2. Eligibility 
 
Intervention  
 
At the CSI-level, eligibility includes*: 
 
Inclusion criteria: 
• 
Location in Dosso, Tahoua, Maradi, Zinder, or Tillabéri regions 
• 
Verbal consent of community leader(s) 
 


 
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Exclusion criteria: 
• 
Inaccessible or unsafe for study team 
• 
“Quartier” designation on national census 
 
* Community-level eligibility for the programmatic trial will be based on Ministry of Health 
community health worker program guidelines and may change from what is currently listed 
above. 
 
At the individual-level, eligibility includes: 
 
Inclusion criteria: 
• 
Age 1–11 months 
• 
Primary residence in a study CSI 
• 
Verbal consent of caregiver/guardian for study participation 
 
Exclusion criteria: 
• 
Known allergy to macrolides 
 
Population-based sample collections  
 
At the community-level, eligibility includes: 
 
Inclusion criteria: 
• 
Location in study region 
• 
Distinguishable from neighboring communities 
• 
Verbal consent of community leader(s) 
 
Exclusion criteria: 
• 
Inaccessible or unsafe for study team 
• 
Not randomly selected 
• 
Received treatment prior to sample collection  
 
At the individual-level, eligibility includes: 
 
Inclusion criteria: 
• 
Age 1–59 months  
• 
Primary residence in a study community selected for sample collections 
• 
Written consent of caregiver/guardian for study participation 
 
Exclusion criteria: 
• 
Not on list of randomly selected participants from the census 
 
CSI-based sample collections 
 
At the CSI-level, eligibility includes*: 
 
Inclusion criteria:  
• 
Randomly selected CSI for inclusion within the Programmatic Trial 
• 
Verbal consent of CSI leader(s) 
 


 
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Exclusion criteria: 
• 
Not randomly selected for participation in the Programmatic Trial 
 
*CSI-level eligibility for the programmatic trial will be based on Ministry of Health community 
health worker program guidelines and may change from what is currently listed above. 
 
At the individual-level, eligibility includes: 
 
Inclusion criteria:  
• 
Presents to CSI with symptoms of diarrheal disease, respiratory illness, or visiting for routine 
healthcare (e.g. vaccination) 
• 
Verbal consent of caregiver/guardian for study participation 
 
Exclusion criteria: 
• 
Presents to CSI with disease symptoms not related to diarrheal or respiratory disease 
Received study treatment prior to sample collection 
 
4.6.3. Randomization, Adaptation, and Masking 
 
4.6.3.1. 
Randomization 
 
The randomization unit for these trials will be the CSI. Each CSI includes a catchment area of 
approximately 10 communities. 
 
CSIs will be randomized in a 2:1 allocation favoring azithromycin to the following 2 arms: 
 
• 
Programmatic azithro 1–11: all children aged 1–11 months will be offered a biannual 
dose of azithromycin. This distribution will be provided by existing community health 
workers as part of the Ministry of Health’s community health program.  
• 
Programmatic no intervention: All children aged 1–11 months will not receive 
azithromycin within the framework of this study. However, all children in this study will 
receive other health services provided by community health workers as part of the 
Ministry of Health’s community health program.  
 
4.6.3.2. 
Adaptation 
 
The randomization sequence will be generated by the trial biostatistician at UCSF  
 
The Programmatic Trial will use an adaptive allocation modeled after the adaptive allocation 
employed in the Mortality/Resistance Trial. Communities will undergo the first randomization in 
a 2:1 allocation favoring the Programmatic azithro 1–11 arm. If the program continues after the 
first year, new communities will be enrolled using the same adaptation methods used for the 
Mortality Trial. 
 
After the Mortality Trial’s primary outcome analysis, the study team and key stakeholders will 
determine whether the Programmatic Trial continues. If the study continues, the Mortality Trial 
communities will be included in the Programmatic Trial and additional regions will be added over 
time (Figure 2). In this platform design, additional treatment arms may be added to the trial or 
arms may be dropped from the trial based on additional information from other studies, updates 
to the WHO guidelines, or preferences of programs or policymakers in Niger. With such 


 
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changes, protocol details, power calculations, and analysis plans will be updated accordingly in 
the protocol and statistical analysis plan.  
 
Refer to the trial’s Statistical Analysis Plan (SAP) for complete details of the adaptive 
randomization algorithm. 
 
4.6.3.3. 
Masking 
 
In the Programmatic Trial, participants, and implementers will not be actively masked from the 
study arm allocation given that no placebo will be used. Outcome assessors and data analysts 
will be masked. 
 
4.6.3.4. 
Interventions 
 
In the Programmatic Trial, existing community health workers employed by the Minister of 
Health will be utilized. Community health workers from randomly selected, eligible communities 
will be trained to distribute azithromycin to children 1–11 months of age from within randomly 
selected CSIs every 6 months for a period of 1 year, with distributions potentially continuing 
beyond 1 year dependent on funding.  
 
In all communities in the Programmatic Trial, community health workers will continue to 
distribute routine care services, including prevention, screening, and treatment of diseases 
(such as malnutrition, malaria, diarrhea, and pneumonia), referral to the health center, nutritional 
advice, vaccination, or administration of vitamin A, as per the Ministry of Health community 
health program. 
 
Please refer to Section 4.4.3.4 for more details on the intervention.  
 
4.6.3.5. 
Dosage Information 
 
Please refer to Section 4.5.3.5. 
 
4.6.3.6. 
Side Effects 
 
Please refer to Section 4.4.3.6. 
 
4.6.3.7. 
Study Medication Storage and Accountability 
 
Please refer to Section 4.4.3.7.  
 
4.6.3.8. 
Medication Quality Control 
 
Please refer to Section 4.4.3.8.  
 
4.6.4. Outcomes 
 
4.6.4.1. 
Primary Outcomes* 
 
• 
Number of infectious cause CSI visits per month for children aged 1–59 months over 1 
year 
• 
Number of cause-specific CSI visits (diarrhea, respiratory infections, and malaria) per 


 
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month for children 1–59 months of age over 1 year 
 
*If the Programmatic Trial continues, outcomes will be assessed every 2 years 
 
4.6.4.2. 
Secondary Outcomes 
 
• 
Prevalence of genetic determinants of macrolide resistance in nasopharyngeal swabs in 
children aged 1–59 months from population-based samples after 2 years of distribution 
• 
Load of genetic determinants of macrolide resistance in rectal swabs among children 
aged 1–59 months from population-based samples after 2 years of distribution 
• 
Prevalence of genetic determinants of macrolide resistance in nasopharyngeal swabs in 
children aged 1–59 months with respiratory illness from CSI-based samples after 2 
years of distribution 
• 
Load of genetic determinants of macrolide resistance in rectal swabs among children 
aged 1–59 months with diarrheal disease from CSI-based samples after 2 years of 
distribution  
• 
Infant- and under-5 mortality rate (deaths per 1,000 livebirths) 2 years after the first 
treatment as assessed via birth history  
Program costs as captured by routine administrative data collection during the study 
period and by micro-costing activities 
• 
Estimated national-scale effects (health and cost) of scaling up each strategy.  
Other implementation outcomes defined in the Proctor Outcomes Framework,13 
including feasibility and acceptability, as captured during routine administrative and 
monitoring data collection during the study period and by stakeholder interviews at the 
participant, community, and health system levels after one round of distributions (Table 
3) 
• 
Treatment coverage as defined by projections using national and study census data 
collection as well as satellite imagery 
 
Microbiome outcomes for rectal swab collections  
• 
Gamma diversity, estimated as the alpha diversity of the pooled community sample 
using the Shannon diversity index 
• 
Overall microbial structure using Manhattan distance 
• 
Relative abundance of individual microbial taxa at genus and species level  
 
4.6.5. Sample size 
 
4.6.5.1. 
Overview 
 
Please refer to Section 4.4.5.1. 
 
4.6.5.2. 
Sample Collections 
 
In the Programmatic Trial, sample collection will take place in communities in the catchment 
area of 40 randomly selected CSIs (20 CSIs per arm) and at the same 40 selected CSIs 
themselves. Additional details about this collection can be found in Section 4.10.3, 
Measurement of Sample Based Outcomes. 
 
In all communities selected for sample collections, treatment distribution for that round will be 
conducted after sample collections. 


 
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Refer to SAP for details of power calculations. 
 
4.6.6. Recruitment 
 
Before implementation begins in a region, a sensitization campaign will inform local health 
authorities and community leaders of the study design and nature of participation in the trial. In 
addition to IRB and national-, regional-, and district-level approval, community-level approval will 
be obtained before study activities begin in any community or CSI. All children aged 1–11 
residing in a CSI catchment area randomized to receive treatment will be recruited for the 
intervention. Household-level consent will be obtained for the census activities, and 
caregiver/guardian consent will be obtained for interventions and sample collection. Details of 
informed consent are found in Section 5.3. 
 
4.6.7. Adverse Events Monitoring 
 
Please refer to Section 4.4.7. 
 
4.6.8. Data Collection, Management, Analysis, and Monitoring 
 
4.6.8.1. 
Data Collection Overview 
 
Programmatic Trial data will be collected electronically and on paper as described below. 
 
4.6.8.2. 
Measurement of Mortality Outcomes 
 
For communities randomized to participate in the Programmatic Trial, mortality will be monitored 
through an annual door-to-door birth history survey in a subset of randomly selected 
communities using trained census workers and following similar methods as described above. 
All women aged 12-65 will be invited to participate and asked about the status of each live birth 
they experienced over the past 10 years, including the name, age, sex, date of birth, current 
status, and as needed, date of death.  
 
4.6.8.3. 
Measurement of Sample Based Outcomes 
 
In the Programmatic Trial, sample collection will take place within communities in the catchment 
area of 40 selected CSIs (20 CSIs per arm) and at the same 40 selected CSI locations.  
• 
For samples collected within communities (population-based): 
o 3 communities per CSI from each of the 40 CSIs (120 communities total) will be 
randomly selected from the pool of eligible communities and followed to monitor 
antimicrobial resistance. In each community, 10 children aged 1–59 months will 
be selected to participate in nasopharyngeal and rectal swab sample collections. 
One rectal swab and one NP swab will be collected from each child. 
 
• 
For samples collected at CSI locations (CSI-based):  
o 1 rectal swab will be collected from the first 30 children who present to the CSI 
with symptoms of diarrheal disease. 
o 2 nasopharyngeal swabs will be collected from the first 30 children who present 
to the CSI with symptoms of respiratory disease. The second nasopharyngeal 
swab collected will be sent to the CERMES lab for processing. 


 
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o 1 rectal swab and 2 nasopharyngeal swabs will be collected from the first 30 
children who for routine medical care (e.g. vaccination) and present with no 
disease symptoms. The second nasopharyngeal swab collected will be sent to 
the CERMES lab for processing. 
 
In the Programmatic Trial, population-based sample collections will follow similar procedures to 
those described above for the Mortality/Resistance Trial. CSI-based collections will take place in 
the same month as the community-based collections for that CSI, with a window of + or – 1 
month. The presence of diarrheal or respiratory illness will be determined using the UNICEF 
Integrated Management of Childhood Illness flowchart currently used in Niger. Eligible children 
will be consecutively enrolled until the target sample sizes are achieved. A copy of the 
Integrated Management of Childhood Illness flowchart that will be used can be found in the 
Section 7.12 of the appendix.  
 
To randomly select individuals for population-based monitoring in the Programmatic Trial, a 
“random walk” approach will be used. 
 
Random walk selection protocol 
1. Start at the home of the chef du village. 
2. Use the application in CommCare to determine how many steps to go and in which 
direction to walk. 
3. Approach the household that is closest to you when you finish your steps. 
4. Ask the household if there are children 1-59 months of age and if the household is willing 
to participate. If not, choose the next closest household and repeat step 4. 
5. Enter the number of eligible children 1-59 months in the household into the app, and use 
the app to select which child from which to take samples. 
6. Take samples and complete data collection form. 
7. Repeat steps 2-6 until you have completed 10 households. 
 
For both trials with sample collections (the Mortality/Resistance Trial and Programmatic Trial), 
once the census is complete and the sample is generated, the study team will work with a local 
mobilizer to invite the sampled group to a central location in the community for sample 
collection. Samples will be collected by trained personnel and linked to census data through bar 
codes. Once sample collection is complete, the census team or community health workers will 
visit the study community to complete treatment for that round. 
 
During collection, samples will be stored at ambient temperature or on ice at 4°C. At the end of 
each collection period, samples will be transported to a location near the sampled community 
with facilities to store samples at -20°C as required or directly to CRISP each day. At the end of 
the collection period, all samples will be transferred to a central storage location at CRISP in 
Niamey stored at -20°C as required until processed or shipped to UCSF for processing. Refer to 
Sample Collections Procedures and the Laboratory Procedures for full details. 
 
4.6.8.4. 
Measurement of Clinic Visit Outcomes 
 
Clinic visits will be monitored through passive surveillance at CSIs in Programmatic Trial study 
regions. All infectious cause visits and cause-specific visits for diagnoses of respiratory 
infection, diarrheal disease, and malaria will be recorded among children under 5 based on the 
age groups routinely reported in Niger. Visits will be measured continuously by CSI staff using 
Niger’s DHIS2 national system for health information database. Records will be regularly 
reviewed for eligible entries and data including child age, community of residence, date of visit, 


 
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diagnosis at visit, and treatment given will be extracted electronically. 
 
The presence of respiratory infection, diarrheal disease, and malaria are determined using the 
UNICEF Integrated Management of Childhood Illness flowchart currently used in Niger. A copy 
of this Integrated Management of Childhood Illness flowchart can be found in the Section 7.12 
of the appendix.  
 
 
4.6.8.5. 
Measurement of Implementation Outcomes 
 
Implementation-focused outcomes include costs, cost-effectiveness, and the additional 
outcomes outlined in the Proctor Implementation Outcomes and RE-AIM frameworks (Table 3). 


 
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4.6.8.6. 
Data Collection and Management 
 
Please refer to Section 4.4.8.5. 
 
4.6.8.7. 
Statistical Analysis Plan 
 
Refer to the trial’s Statistical Analysis Plan (SAP) for complete details 
 
4.6.8.8. 
Quality Control and Monitoring 
 
Please refer to Section 4.4.8.7. 
 
 


 
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5. Ethics and Dissemination 
 
5.1. 
Overview 
 
The trial will be conducted according to Good Clinical Practice guidelines (ICH-GCP) and will 
adhere to the principles of the Declaration of Helsinki. Ethical approval will be obtained at all 
levels described below before study activities begin. 
 
5.2. 
Institutional Review Board Approval 
 
5.2.1. UCSF IRB 
 
The University of California, San Francisco Committee on Human Research will annually review 
the study protocol for ethical approval. The UCSF IRB number on record is, UCSF IRB 19-
28287 
 
5.2.2. Comité national éthique pour la recherche en santé (CNERS) 
 
The study protocol will be reviewed and granted ethical approval by CNERS before any study 
activities begin. The CNERS IRB number on record is DELIBERATION N041/2020/CNERS. 
 
5.3. 
Informed Consent 
 
In addition to IRB approval at the national-, regional-, district-, and community-level approval will 
be obtained before study activities begin. The study team will meet in person with regional, 
district, and community leaders to explain the nature of the study, answer questions, and obtain 
verbal or written consent, which will be documented electronically. 
 
After verbal consent from the regional, district, and community leaders is obtained, the study team 
will recruit participants by going door to door in each community enrolled in the study. The team 
will approach the head of household, explain the nature of the study, answer questions, and obtain 
verbal consent to perform the census. If the head of household agrees to participate, 
caregivers/guardians of children under 5 years old will be approached for verbal consent to treat 
the child. For children 30 to 42 days old, written consent will be obtained via caregiver thumbprint. 
The consent process will be conducted by trained personnel in relevant local languages and 
witnesses will be used to verify the process for illiterate community members. The consent 
process will also include the possibility for the household to be randomly selected for examination 
if the household resides in one of the randomly selected communities in Dosso region. 
 
5.4. 
Potential Risks and Adequacy of Protection Against Risks 
 
Azithromycin is usually well tolerated. The most common side effects are diarrhea, nausea, 
abdominal pain, and vomiting. These side effects occur in fewer than 5% of persons who receive 
azithromycin and have been rarely reported in studies of the mass distribution of azithromycin 
for trachoma or child mortality. Adverse events will be monitored as described in Section 4.10. 
 
Azithromycin is thought to be safe in children under 6 months of age and is recommended by the 
CDC as the treatment of choice for prophylaxis against whooping cough (Bordetella pertussis) in 
this young age group. There is a possibility of an increased risk of infantile hypertrophic pyloric 
stenosis in neonates. To mitigate this risk, the trial will exclude children under 1 month of age. 


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5.5. 
Compensation for Participants  
 
There is no cost to the participant and there is no reimbursement for overall participation in this 
study. 
 
5.6. 
Dissemination Plan 
 
Trial results will be presented at local and international meetings and submitted to peer- 
reviewed journals for publication. 
 
 


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6. Organizational Structure and Responsibilities  
 
6.1. 
University of California, San Francisco Francis I. Proctor Foundation 
 
The Proctor Foundation is an organized research unit at the University of California, San 
Francisco. Proctor has a 60-70-year history of research in ocular infectious and inflammatory 
diseases and runs one of the leading corneal and uveitis fellowship training programs in the United 
States. Proctor Foundation faculty have been involved in the prevention of blindness research in 
developing countries since the foundation’s inception. The impetus for establishing the foundation 
in 1947 was to eradicate trachoma in the American Southwest and other parts of the world. 
 
From this initial inception, the Foundation has expanded research efforts to include the other 
major causes of blindness worldwide, with a continuing emphasis on infectious and inflammatory 
eye diseases. The Proctor Foundation will be the main coordinating center for the study. Thomas 
Lietman, the Principal Investigator of this study at the Proctor Foundation, will be assisted by 
Kieran O’Brien, the co-Principal Investigator, several co-investigators, two biostatisticians, and 
several study coordinators, and data analysts. 
 
6.2. 
Programme national de santé oculaire (PNSO) 
 
Le Programme National de Santé Oculaire PNSO, was established in December of 2012. Before 
this time, the program existed under the name of the Programme National de Lutte Contre la 
Cécité (PNLCC), which was created in December of 2004 as part of the Direction de la lutte contre 
la maladie lié à la Direction Générale de la Santé Publique. PNSO is currently associated with 
the Direction des Etudes et de la Programmation, a part of the larger Ministry of Health in Niger 
(Secrétariat Général du Ministère de la Santé Publique [MSP]. 
 
PNSO is located in Niamey, Niger. However, it also has operations in the East under the 
Direction Nationale des Immunisations, in the West under the Lycée Bosso in the North under 
the quartier recasement and in the South under the Mairie Commune I. 
 
PNSO is tasked with the coordination and evaluation of Nigerien national ocular health and has 
support mass drug administration efforts for decades. 
 
6.3. 
Division santé communautaire (DSC) 
 
The goal of the DSC is to contribute to the reduction of infant, child and maternal mortality 
through health promotion, improved access to care for remote communities and improved 
utilization of health services with community participation. The DSC is currently associated with 
the Direction de l’organisation des soins, a part of the larger Ministry of Health in Niger. The 
current director is Dr. Amadou Zakari. 
 
The DSC will work with the study team to integrate the Programmatic Trial into the existing 
community health worker framework being implemented throughout Niger.  
 
6.4 
Centre de recherche medical et sanitaire (CERMES) 
 
The CERMES laboratory is a Nigerien public establishment for science and technology. It has 
been a part of the international network of Pasteur Institutes since 2003. The center has a three- 
fold mission of promoting research, public health and education. 
 


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6.5. 
Centre de recherche et interventions en santé publique (CRISP) 
 
CRISP is a business entity founded by Ahmed Arzika based in Niamey, Niger. CRISP will work 
with UCSF and PNSO to implement the study. 
 
6.6. 
Centres de santé intégré (CSI) 
 
CSIs are community health posts put in place by the Nigerien Ministry of Health. Agents 
employed by the CSIs will work at the grappe level to deliver treatment and record adherence in 
the delivery trial.   
 
6.7. 
Executive Committee 
 
The Executive Committee will consist of Thomas Lietman and Kieran O’Brien from the Proctor 
Foundation and Ahmed Arzika from CRISP. This committee will act as the administrative and 
executive arm of the clinical trial and will meet in person twice a year to provide overall oversight 
for the study and make decisions on day-to-day operation issues, including: 
• 
Monitor study progress and data collection progress 
• 
Discuss quality control issues that have arisen in the Trial Coordinating Center (TCC) and 
Data Coordinating Center (DCC) 
• 
Evaluate and adopt changes in study procedures as necessary 
• 
Communicate with and implement recommendations from the Data and Safety Monitoring 
Committee (DSMC) 
• 
Make executive decisions on the allocation of resources 
• 
Establish policies on publications and authorship 
• 
Approve and oversee ancillary studies 
 
6.8. 
Trial Coordinating Center (TCC) 
 
The TCC will be located at the Proctor Foundation. Thomas Lietman will lead the center, which 
will also include Kieran O’Brien (co-PI), Travis Porco (biostatistician), Benjamin Arnold 
(biostatistician), Jeremy Keenan (co-investigator), Catherine Oldenburg (co-investigator), Victoria 
Lee (data analyst), Zijun Liu (data analyst), and Catherine Cook (study coordinator). The role of 
the TCC will be to oversee and coordinate the overall implementation of the trial. Specifically, this 
includes maintaining an up-to-date study protocol and manual of procedures, obtaining ethical 
approvals from all involved parties (UCSF, Niger MOH), conducting training and certification of all 
study personnel, ensuring proper masking of outcome assessment, and monitoring to ensure that 
protocols of the study intervention are applied correctly in the field. The TCC will organize site 
visits at least once per year before each monitoring visit to conduct training sessions with outcome 
assessors and monitor the quality of data collection. The Proctor study coordinator(s), with 
assistance from the CRISP study coordinators, will organize the training sessions. The TCC will 
meet officially as a group at least four times per year. All members of the TCC are currently 
working on studies of childhood mortality in Niger and Burkina Faso. The group has close 
working relationships with the CRISP staff in Niger and expertise with cluster-randomized trials 
in resource- poor settings. 
 
6.9. 
Niger Coordinating Center 
 
The Niger Coordinating Center will be located at the CRISP headquarters in Niamey, Niger. The 
center will be led by the study site principal investigator, Ahmed Arzika, and also include the 
CRISP study coordinator. Ahmed Arzika will oversee the study activities that take place in Niger 


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and will manage the day-to-day activities of the study coordinator. He will also assist with 
obtaining ethical approval from appropriate federal, regional, and zonal agencies. The CRISP 
study coordinator will work with the local health officials to find census workers for the census 
activities and nurses to work as data collectors. This person will supervise all data collection 
activities and will be responsible for proper storage and transport of specimens. 
 
6.10. Data Coordinating Center (DCC) 
 
The DCC will be located at the Proctor Foundation and led by Benjamin Arnold and Travis Porco. 
The Proctor Foundation has served as a DCC for several other trials, including the cluster- 
randomized trials of trachoma in Ethiopia (TANA, NEI U10 EY016214) and Niger (MORDOR; 
Gates OPP 1032340), and individual- and cluster-randomized trials of corneal ulcer treatment 
and prevention in India (SCUT, NEI U10 EY015114; MUTT, NEI U10 EY018573) and Nepal 
(VIEW, NEI U10 EY022880). Ben Arnold and Travis Porco, along with Zijun Liu and Victoria Le 
(data analysts) will be responsible for data management, data quality control, event adjudication, 
and training and certification of enumeration personnel. The DCC will be responsible for drafting 
the trial’s statistical analysis plan, generating the trial’s randomization sequence, analyzing data 
according to the plan, and providing data requested for publications. The DCC will be responsible 
for coordinating and supervising the activities of the Data and Safety Monitoring Committee, 
including preparing interim and final data reports. The DCC will also be responsible for 
coordinating the use of the electronic data capture system, including maintenance of the software 
application and data backup monitoring visits. The DCC will meet monthly. The DCC will be in 
close contact with the Proctor study coordinator(s), who will help address any issues with 
counterparts in Niger. 
 
6.10.1. Data Safety and Monitoring Committee (DSMC) 
 
The DSMC is comprised of independent experts in bioethics, biostatistics, epidemiology, 
antimicrobial resistance, and global health. The DSMC will meet at least once per year. Ad hoc 
meetings may be convened as necessary. The DSMC will approve the trial protocol at the first 
meeting or recommend modifications to the protocol as necessary. At annual meetings, the 
DSMC will review data on efficacy and safety outcomes. They will also monitor for unanticipated 
events. 
 
 
6.11. Economic Consultants 
 
The AVENIR team will work with Dr. Meagan C. Fitzpatrick from the University of Maryland 
School of Medicine. Dr. Fitzpatrick will support the development of the sampling strategy, 


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protocol, data collection forms, and analysis plan for all economic-focused outcomes.  
 
6.12. Duties and Responsibilities of Staff 
 
6.12.1. Principal Investigator and Co-Principal Investigators (Proctor Foundation) 
• 
Develop study design and specific aims with help of biostatisticians, study 
coordinators, and partners 
• 
Obtain grant funding and develop grant budget with help of partners 
• 
Ensure execution of the study according to the protocol 
• 
Ensure that ethical approvals are maintained 
• 
Write or add major contributions to all study-related publications 
• 
Ensure proper masking is maintained 
• 
Supervise training and implementation of study procedures for all study staff 
• 
Assume responsibility for the study in the absence of the Principal 
Investigator (Co- Principal Investigators) 
 
6.12.2. Biostatisticians (Proctor Foundation) 
• 
With the Investigators, create the Statistical Analysis Plan (SAP) 
• 
Conduct all randomization allocations 
• 
Communicate randomization allocations to Pfizer 
• 
Receive all study data and review for quality control purposes 
• 
Ensure appropriate masking 
• 
Prepare data analysis plan for DSMC meetings; oversee analysis and 
prepare all presented data for DSMC meetings, DSMC reports, and all 
study publications 
 
6.12.3. Study Coordinators (Proctor Foundation) 
• 
Ensure the execution of the study per protocol 
• 
Coordinate with implementing partners, particularly with the CRISP Study 
Coordinators, in execution of the study 
• 
Manage correspondence between all collaborating organizations and parties 
• 
Maintain all ethical approvals for the study, including IRB renewals, the 
authorization of the CNERS, the authorization of the BUA and DSMC-
related approvals 
• 
Prepare all forms and documents necessary for fieldwork (training 
materials, data collection forms, etc) 
• 
Train census workers in the use of electronic data capture system 
• 
Train both Proctor and Nigerien teams for each site visit 
• 
Arrange logistics and itineraries for traveling team members in Niger 
• 
Purchase, maintain, and organize transport of all necessary study supplies to/within Niger 
• 
Maintain communication with Principal Investigators regarding all study 
activities and plans 
 
6.12.4. Study Coordinators (Niger) 
• 
Prior to the start of the study, secure support from the Ministry of Health 
and necessary ethical approvals in Niger 
• 
At baseline, obtain permission from the district health leaders; meet with 
and obtain permission/consent from all community leaders and local 
stakeholders 
• 
Supervise and train all study team members 


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• 
Charge all mobile devices and battery packs each night of the census 
• 
Maintain all fieldwork documents and records 
• 
Complete collection and intervention reports 
• 
Oversee transport of study samples 
• 
Assist Proctor Coordinators in coordinating logistics in Niger 
• 
Work with DCC and data teams to maintain database 
• 
Analyze and provide data when requested by co-investigators or staff from Proctor 
• 
Appropriately back up all data 
 
6.12.5. Data Analysts (Proctor Foundation) 
• 
Assist with preparation of the Statistical Analysis Plan 
• 
Develop data collection forms and database(s) 
• 
Assist with training of study teams on using data collection forms 
• 
Assist with training of Niger data team on monitoring data entry for quality and accuracy 
• 
Conduct daily review of incoming data to monitor for quality and completeness 
• 
Communicate with study coordinators and Niger data team about data discrepancies 
• 
Prepare weekly data monitoring and study progress reports to share with study team 
• 
Prepare reports summarizing data to be distributed to Data and 
Safety Monitoring Committee 
• 
Conduct analyses and prepare tables and figures for reports, 
publications, and presentations 
 
6.12.6. Data Analysts (Niger) 
• 
Conduct daily review of incoming data to monitor for quality and completeness 
• 
Work with Proctor Foundation study team to resolve discrepancies 
• 
Assist data collection team with preparation and maintenance of 
mobile devices and application for use in data collection and with 
troubleshooting the application 
 
6.12.7. Census and Treatment Team (PNSO) 
• 
Before each census and treatment round, complete training 
• 
During census and treatment rounds, travel to the enrolled communities for data collection 
• 
Obtain informed consent from households and caregivers for study participation 
• 
Administer study medications to eligible subjects according the the protocol 
• 
Record consent, census, and treatment data in the mobile application 
• 
Return to households until they have distributed study medications to at 
least 80% of individuals 
• 
Counsel and motivate participants for follow-up and monitoring visits 
• 
Inform participants of available health care facilities and procedures 
• 
Collect information on the nature of adverse events experienced by study 
participants, and report this information immediately to CRISP 
investigators 
 
6.12.8. Sample Collection Team 
• 
Before each collection, complete training 
• 
Prepare all study-related materials before travel to study sites 
• 
In each cluster, mobilize and identify all randomly selected participants 
• 
Obtain informed consent for enrollment from each participant or participant guardian 
• 
Under supervision of CRISP Study Coordinator and/or trained Proctor staff, collect all 


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participant study samples according to protocol; store and record all samples correctly for 
transport, organization, and processing 
• 
Counsel and motivate participants for follow-up and monitoring visits 
• 
Inform patients of available health care facilities and procedures 
• 
Collect information on the nature of any adverse events experienced by study participants, 
and immediately report to CRISP investigators 
 
 
6.12.9. Members of the Programme national de santé oculaire (PNSO) 
• 
Import study drug (azithromycin and placebo) 
• 
Import study supplies as a donation from the United States to Niger 
• 
Oversee a pre-study mapping activity for the purpose of determining the location of 
study communities 
• 
Support pre-study sensitization and obtain community consent for the trial 
• 
Assist with training and supervision of study staff located in Niger, including census 
workers and AMR sample collection team 
• 
Liaise with relevant regulatory bodies and stakeholders, including the Nigerien ethics 
committee (CNERS), including securing ethical approval to conduct study activities 
throughout the duration of the study 
• 
Oversee the building of study drug storage locations at the district level 
• 
Assist with training, supervision and implementation of pre-study and pilot activities 
including baseline community-based sample collection in Dosso Region 
• 
Oversee and provide administrative support for shipping of environmental sewage 
samples to test for antimicrobial resistance 
• 
Manage hiring of data analysts/managers and agents for pre-study and pilot activities 
 
6.13. Data Safety and Monitoring Committee 
 
6.13.1. Primary Responsibilities of the DSMC 
 
The DSMC will be responsible for safeguarding the interests of trial participants, assessing the 
safety and efficacy of the interventions during the trial, and monitoring the overall conduct of the 
trial. The DSMC will provide recommendations about stopping or continuing the trial. To contribute 
to the integrity of the trial, the DSMC may also formulate recommendations relating to the 
selection/recruitment/retention of participants, to the study protocol, and the procedures for data 
management and quality control. 
 
The DSMC will be advisory to the Executive Committee. The Executive Committee will be 
responsible for promptly reviewing the DSMC recommendations and determining whether to 
continue or terminate the trial, and whether amendments to the protocol are required. If needed, 
the DSMC may seek the advice of a content expert outside of the committee. 
 
6.13.2. DSMC Membership 
 
The DSMC is an independent multidisciplinary group consisting of epidemiologists, 
biostatisticians, bioethicists, and clinicians that collectively has experience in pediatric infectious 
diseases and mortality, antimicrobial resistance, and in the design, implementation, and analysis 
of randomized controlled trials. 
 
6.13.3. Conflict of Interest 
 


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55
The DSMC membership has been restricted to individuals free of apparent conflicts of interest. 
The source of these conflicts may be financial, scientific, or regulatory. Thus, neither study 
investigators nor individuals employed by the sponsor, nor individuals who might have regulatory 
responsibilities for the trial products, are members of the DSMC. 
 
The DSMC members will disclose to fellow members any consulting agreements or financial 
interests they have with the sponsor of the trial, with the contract research organizations, or with 
other sponsors having products that are being evaluated or that are competitive with those in the 
trial. The DSMC will be responsible for deciding whether these consulting agreements or financial 
interests materially impact their objectivity. 
 
The DSMC members will be responsible for advising fellow members of any changes in any of 
the membership requirements that occur during the course of the trial. It may be appropriate for 
DSMC members who develop significant conflicts of interest resign from the DSMC. 
 
DSMC membership is to be for the full duration of the trial. If any members leave the DSMC, the 
Executive Committee, in consultation with the DSMC, will promptly appoint a replacement. 
 
6.13.4. Timing and Purpose of DSMC Meetings 
 
The initial meeting of the DSMC will be held before study activities begin. The committee will 
provide an advisory review of scientific and ethical issues relating to study design and discuss the 
standard operating procedures and analysis plan, as well as the format and content of the reports 
that will be used to present trial results. 
 
The initial meeting will be attended by all DSMC members, lead trial investigators, and the trial 
biostatisticians. The DSMC will review drafts of the trial protocol, the Statistical Analysis Plan, and 
the DSMC Charter. At subsequent meetings, committee members will receive reports on study 
conduct, data collection, and adverse events. 
 
6.13.5. Procedures to Ensure Confidentiality and Proper Communication 
 
To enhance the integrity and credibility of the trial, procedures will be implemented to ensure the 
DSMC has access to emerging information from the trial regarding efficacy and safety as required. 
 
6.13.6. Closed Sessions 
 
Sessions involving only DSMC members (and, once primary outcome results become available, 
those unmasked trial investigators on the Data Coordinating Committee who will generate the 
unmasked reports), will be held to allow discussion of confidential data from the trial, including 
information about the efficacy and safety of interventions, as required. As this study uses an 
adaptive allocation design, there will be no interim unmasked data presented before primary 
outcome data become available. At each meeting after the initial meeting, at least two Closed 
Sessions will be scheduled. 
 
At the final Closed Session of each meeting, the DSMC will develop a consensus on its list of 
recommendations, including whether the trial should continue. 
 
6.13.7. Open Sessions 
 
The study team will review masked information relating to study progress and data collection with 


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56
the DSMC members between the Closed Sessions. 
 
6.13.8. Open and Closed Reports 
 
As needed, Open and Closed Reports will be provided for each DSMC meeting. Open Reports 
will include data on recruitment and baseline characteristics, eligibility, and completeness of 
follow-up and compliance in aggregate. The DCC will prepare these Open Reports. 
 
Closed Reports, available only to those attending the Closed Sessions of the meeting, will include 
analyses of primary and secondary efficacy endpoints, including subgroup and adjusted analyses, 
adverse events, and Open Report analyses that are displayed by intervention group. Closed 
Reports will be prepared by the unmasked study biostatistician and data analyst. No unmasked 
interim data will be reviewed during closed reports until primary analysis data has become 
available. 
 
The Open and Closed Reports should summarize data collection that has been completed by at 
most two months before the date of the DSMC meeting. The Reports should be provided to DSMC 
members at least three days prior to the date of the meeting. 
 
6.13.9. Minutes of the DSMC Meetings 
 
The research team will prepare minutes for the open portion of the meeting, including the DSMC’s 
recommendations. 
 
6.12.10. Recommendations to the Executive Committee 
 
At each meeting, the DSMC will make a recommendation to the Executive Committee to continue 
or terminate. This recommendation will be based primarily on safety and efficacy considerations 
and will be guided by statistical monitoring guidelines defined in this Charter. 
 
Recommendations to amend the protocol or conduct of the study made by the DSMC will be 
considered and accepted or rejected by the Executive Committee. The Executive Committee will 
be responsible for deciding whether to continue or to stop the trial based on the DSMC 
recommendations. 
 
The DSMC will be notified of all changes to the study protocol or to study conduct. The DSMC 
concurrence will be sought on all substantive recommendations or changes to the protocol or 
study conduct prior to implementation. 
 
The Executive Committee may communicate information in the Open Report to the sponsor and 
may inform them of the DSMC recommended alterations to study conduct or early trial termination 
in instances in which the Executive Committee has reached a final decision agreeing with the 
recommendation. The Executive Committee will maintain confidentiality of all information it 
receives other than that contained in the Open Reports until after the trial is completed or until a 
decision for early termination has been made. 
 
6.14. Policy Matters 
 
Any changes to the protocol made during the course of the study will be incorporated into the 
revised study protocol and procedures and recorded in a change log. Any new forms will be 
incorporated as an addendum. All protocol changes will be submitted and approved by the IRB 


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57
of both collaborating centers as required. Major changes will also be submitted to DSMC. 
 
6.14.1. Presentations and Publications 
 
All presentations and publications will include acknowledgement of funding sources and give 
credit to the collaborating organizations and/ individuals involved. 
 
Acknowledgements will include grant source(s) as well as the DSMC. 
 
 


AVENIR Protocol 
 
 
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58
7. Appendices 
 
Refer to Procedures for full documentation: 
 
7.5. 
Informed Consent Forms 
7.6. 
Mortality/Resistance Trial: Training, Procedures, Data Collection Forms 
7.7. 
Delivery Trial: Training, Procedures, Data Collection Forms 
7.8. 
Sample Collection: Training, Procedures, Data Collection Forms 
7.9. 
Laboratory Procedures 
7.10. Data Monitoring Plan 
7.11. Adverse Events Monitoring Plan 
7.12. Integrated Management of Childhood Illness flowchart 
 
 
 
 


AVENIR Protocol 
 
 
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59
References 
 
1. GBD 2016 Mortality Collaborators. Global, regional, and national under-5 mortality, adult 
mortality, age-specific mortality, and life expectancy, 1970-2016: a systematic analysis for the 
Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1084-1150. 
doi:10.1016/S0140-6736(17)31833-0. 
 
2. Golding N, Burstein R, Longbottom J, Browne AJ, Fullman N, Osgood-Zimmerman A, Earl L, 
Bhatt S, Cameron E, Casey DC, Dwyer-Lindgren L, Farag TH, Flaxman AD, Fraser MS, 
Gething PW, Gibson HS, Graetz N, Krause LK, Kulikoff XR, Lim SS, Mappin B, Morozoff C, 
Reiner RC, Sligar A, Smith DL, Wang H, Weiss DJ, Murray CJL, Moyes CL, Hay SI. Mapping 
under-5 and neonatal mortality in Africa, 2000-15: a baseline analysis for the Sustainable 
Development Goals. Lancet. 2017;390(10108):2171-2182. doi:10.1016/S0140- 6736(17)31758-
0. 
 
3. United Nations. Transforming our World: The 2030 Agenda for Sustainable Development .:. 
Sustainable Development Knowledge Platform. 
https://sustainabledevelopment.un.org/post2015/transformingourworld/publication. Accessed 
October 18, 2019. 
 
4. 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. Azithromycin to Reduce 
Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018;378(17):1583-1592. 
doi:10.1056/NEJMoa1715474. 
 
5. Doan T, Arzika AM, Hinterwirth A, Maliki R, Zhong L, Cummings S, Sarkar S, Chen C, Porco 
TC, Keenan JD, Lietman TM. Macrolide Resistance in MORDOR I — A Cluster- Randomized 
Trial in Niger. N Engl J Med. 2019;380(23):2271-2273. doi:10.1056/NEJMc1901535. 
 
6. 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;380(23):2207-2214. doi:10.1056/NEJMoa1817213. 
 
7. WHO, 2020. Guideline on Mass Drug Administration of Azithromycin to Children under Five 
Years of Age to Promote Child Survival. Available at: 
https://www.who.int/publications/i/item/9789240009585. Accessed October 9, 2020. 
 
8. Oldenburg CE, Arzika AM, Maliki R, Lin Y, O’Brien KS, Keenan JD, et al. Optimizing the 
Number of Child Deaths Averted with Mass Azithromycin Distribution. Am J Trop Med Hyg. 
February 2020:1-3. doi:10.4269/ajtmh.19-0328. 
 
9. Rose G. Sick individuals and sick populations. International Journal of Epidemiology. 
2001;30(3):427-432. doi:10.1093/ije/30.3.427. 
 
10. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med. 
1984;3(4):409-422. doi:10.1002/sim.4780030421. 
 
11. Hayes RJ, Moulton LH. Cluster Randomized Trials. Boca Raton: CRC/Taylor and Francis; 2009. 
 
12. Burstein R, Henry NJ, Collison ML, Marczak LB, Sligar A, Watson S, Marquez N, Abbasalizad-


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Farhangi M, Abbasi M, Abd-Allah F, Abdoli A, Abdollahi M, Abdollahpour I, Abdulkader RS, 
Abrigo MRM, Acharya D, Adebayo OM, Adekanmbi V, Adham D, Afshari M, Aghaali M, Ahmadi 
K, Ahmadi M, Ahmadpour E, Ahmed R, Akal CG, Akinyemi JO, Alahdab F, Alam N, Alamene 
GM, Alene KA, Alijanzadeh M, Alinia C, Alipour V, Aljunid SM, Almalki MJ, Al-Mekhlafi HM, 
Altirkawi K, Alvis-Guzman N, Amegah AK, Amini S, Amit AML, Anbari Z, Androudi S, 
Anjomshoa M, Ansari F, Antonio CAT, Arabloo J, Arefi Z, Aremu O, Armoon B, Arora A, 
Artaman A, Asadi A, Asadi-Aliabadi M, Ashraf-Ganjouei A, Assadi R, Ataeinia B, Atre SR, 
Quintanilla BPA, Ayanore MA, Azari S, Babaee E, Babazadeh A, Badawi A, Bagheri S, 
Bagherzadeh M, Baheiraei N, Balouchi A, Barac A, Bassat Q, Baune BT, Bayati M, Bedi N, 
Beghi E, Behzadifar M, Behzadifar M, Belay YB, Bell B, Bell ML, Berbada DA, Bernstein RS, 
Bhattacharjee NV, Bhattarai S, Bhutta ZA, Bijani A, Bohlouli S, Breitborde NJK, Britton G, 
Browne AJ, Nagaraja SB, Busse R, Butt ZA, Car J, Cárdenas R, Castañeda-Orjuela CA, Cerin 
E, Chanie WF, et al. Mapping 123 million neonatal, infant and child deaths between 2000 and 
2017. Nature. 2019;574(7778):353-358. doi:10.1038/s41586-019-1545-0 
 
13.  Proctor E, Hiie Silmere, Raghavan R, Hovmand P, Aarons G, Bunger A, Griffey R, Hensley 
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doi:10.1007/s10477-010-0319-7 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
L’azithromycine pour la vie des enfants au Niger: 
implémentation et recherche (AVENIR) 
An adaptive cluster-randomized trial to determine the optimal age 
group for implementation of biannual oral azithromycin distribution 
to reduce child mortality in Niger 
 
Statistical Analysis Plan — Mortality and Resistance Trial 
 
1.  Administrative Information 
 
Trial registration:   
NCT04224987 
Funder: 
Bill & Melinda Gates Foundation (grant OPP1210548) 
SAP Version: 
Version 15, Updated 2023-10-17 
A revision history for this document is included at the end. 
Protocol Version: 
Refers to Protocol Version 25 
Contributors: 
Persons contributing to the SAP:  
 
Zijun Liu 1, Victoria Le 1, William Nguyen 1, Brittany Peterson 1 
Statisticians responsible:  
 
Travis C. Porco 1, Benjamin F. Arnold 1  
Principal Investigators:  
 
Thomas M. Lietman 1, Kieran O’Brien 1, Abdou Amza 2,3, Ahmed 
Arzika4 
 
1 Francis I. Proctor Foundation for Research in Ophthalmology, 
University of California, San Francisco, USA 
2 Ministère de la Santé Publique du Niger 
3 Le Programme National de Santé Oculaire (PNSO) 
4 Centre de recherche et interventions en santé publique (CRISP) 
 
 
 
 
 
 
 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
SAP Table of Contents 
1.  ADMINISTRATIVE INFORMATION ......................................................................................................... 1 
4 CENTRE DE RECHERCHE ET INTERVENTIONS EN SANTÉ PUBLIQUE (CRISP)........................................................ 1 
2. OVERVIEW ................................................................................................................................................ 3 
Phase I Summary of the design ....................................................................................................................... 3 
Trial masking ....................................................................................................................................................... 3 
3. MORTALITY TRIAL .................................................................................................................................. 4 
3.1.  INTRODUCTION .................................................................................................................................................. 4 
3.1.1. Background and rationale ...................................................................................................................... 4 
3.1.2. Objectives ................................................................................................................................................. 4 
3.2.  STUDY METHODS .............................................................................................................................................. 4 
3.2.1. Trial design ............................................................................................................................................... 4 
3.2.2. Randomization ......................................................................................................................................... 5 
3.2.3. Sample size .............................................................................................................................................. 6 
3.2.4. Statistical framework ............................................................................................................................... 8 
3.2.5. Statistical interim analyses and stopping guidance ........................................................................... 8 
3.2.6. Timing of the primary analysis ............................................................................................................... 9 
3.2.7. Timing of outcome assessments .......................................................................................................... 9 
3.3.  STATISTICAL PRINCIPLES .................................................................................................................................. 9 
3.3.1. Confidence intervals and P-values ....................................................................................................... 9 
3.3.2. Protocol deviations ................................................................................................................................ 10 
3.3.3. Analysis Populations ............................................................................................................................. 10 
3.4.  TRIAL POPULATION ......................................................................................................................................... 11 
3.4.1. Screening data ....................................................................................................................................... 11 
3.4.2. Eligibility .................................................................................................................................................. 11 
3.4.3. Recruitment ............................................................................................................................................ 11 
3.4.4. Withdrawal/follow-up ............................................................................................................................. 11 
3.4.5. Baseline patient characteristics ........................................................................................................... 12 
3.5.  ANALYSIS ......................................................................................................................................................... 12 
3.5.1. Outcome definitions .............................................................................................................................. 12 
3.5.2. Analysis methods .................................................................................................................................. 16 
3.5.3. Missing data ........................................................................................................................................... 17 
3.5.4. Additional analyses ............................................................................................................................... 18 
Model Assessment ........................................................................................................................................... 18 
Subgroup Analyses .......................................................................................................................................... 18 
Bayesian Analysis ............................................................................................................................................ 19 
3.5.5. Harms ...................................................................................................................................................... 19 
3.5.6. Statistical software ................................................................................................................................ 20 
4.  REFERENCES ....................................................................................................................................... 20 
5.  REVISION HISTORY .............................................................................................................................. 22 
The content of this Statistical Analysis Plan meets the requirements stated by the US Food and 
Drug Administration and conforms to the American Statistical Association’s Ethical 
Guidelines.This SAP was organized following guidelines proposed by Gamble et al. [1] 
 
The companion computational notebook with underlying sample size calculations presented 
herein is entitled: AVENIR_Power_Calculation_v7.Rmd / .html; it is saved in the same directory as this 
document. 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
2. Overview 
The AVENIR study includes multiple different trials, each with different objectives (Figure 1). 
This Statistical Analysis Plan (SAP) includes details for the Mortality and Resistance Trial. 
Separate SAPs cover the Delivery and Programmatic trials.   
 
Phase I Summary of the design 
Figure 1. Phase I summary of design. 
 
 
 
*A random sample of 150 communities was selected for AMR monitoring, 60 of which contribute to the primary  
 
Trial masking 
The Mortality/Resistance trial is a double-masked, placebo controlled trial. All participants are 
masked to their treatement. Study investigators and field staff are masked to treatment with the 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
exception of the unmasked portion of the trial analysis team at UCSF. The unmasked portion of 
the analysis team will conduct the response adaptive allocation and pre-specified interim 
analyses. Unmasked members include one of the four PIs for the trial (Thomas Lietman), one of 
the two biostatisticians for the trial (Travis Porco), and one analyst (Zijun Liu). These members 
were designated in January 2022 before any adaptation or interim analyses would commence. 
The rationale for including this composition of the unmasked analysis team was to ensure 
sufficient statistical and subject matter expertise to guide the critical interim discussions and 
decisions for the response-adaptive trail, in coordination with the trial’s Data and Safety 
Monitoring Committee. 
 
The Delivery Trials and Programmatic Trial are unmasked and do not include a placebo.  
 
 
3. Mortality Trial 
 
3.1.  Introduction 
3.1.1. Background and rationale 
This document (Statistical Analysis Plan, SAP) describes the planned analysis and reporting 
for the clinical trial, L’azithromycine pour la vie des enfants au Niger: implémentation et 
recherche (AVENIR). It includes specifications for the statistical analyses and tables to be 
prepared for the final Clinical Study Report. This study is a Phase IV clinical trial to compare 
methods to reduce childhood mortality using mass administration of azithromycin (Pfizer, CAS 
83905-01-5) compared to placebo.  
 
3.1.2. Objectives 
AVENIR is designed to assess the efficacy of mass distribution of azithromycin to prevent 
mortality among children. 
The overall objectives of this study are to:  
1. Determine the optimal age group to treat with biannual oral azithromycin distribution to 
reduce child mortality  
2. To compare selection for antimicrobial resistance across different age-based strategies 
for biannual azithromycin distribution 
3. Demonstrate large-scale implementation of this program. 
 
3.2.  Study Methods 
3.2.1. Trial design 
AVENIR is designed as a large simple double-masked cluster-randomized trial with 
response-adaptive allocation (a platform, perpetual trial). The rationale for adaptive 
randomization is to allow all communities to have the opportunity to be treated, and to allow the 
program to evolve into the optimal treatment. If new treatment arms are added to AVENIR in the 
future, or if any of the current treatment arms are discontinued, the Protocol and SAP will reflect 
those updates. 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
Eligible communities in Niger will be randomly selected to participate in a 
mortality/resistance trial, a delivery trial or a delayed intervention.  
In the mortality/resistance trial, communities will be randomized to one of three azithromycin 
distribution strategies: 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. Mortality will be monitored through biannual census data collection, which will be 
used to adaptively allocation treatment assignments after the first year. Communities will keep 
their group assignment for 4 distributions. Antimicrobial resistance will be monitored in a random 
subsample of treated and untreated children and adults in the Dosso region. See Figure 1 for a 
summary of the deisgn. 
Details are provided in the Protocol document, INV_002454_2019. 
 
Mortality/Resistance Trial Interventions 
Communities will be randomized to the following 3 arms, with the allocation updated after a 
run-in period of 1 year according to the effect of each on the mortality rate among children aged 
1-59 months as determined by inter-census intervals: 
• 
Azithromycin 1-11: biannual weight- or height-based dose of oral azithromycin suspension 
to children 1-11 months old and oral placebo to children 12-59 months old 
• 
Azithromycin 1-59: biannual weight- or height-based dose of oral azithromycin suspension 
to children 1-59 months old 
• 
Placebo: biannual weight- or height-based dose of oral placebo to children 1-59 months old 
 
3.2.2. Randomization 
 
AVENIR includes two cluster randomized trials (mortality/resistance and delivery), with grappes 
as the unit of randomization. Throughout we will refer to grappes as “communities”. 
 
Mortality/Resistance Trial 
 
At the start of the trial, communities will be allocated equally across the three arms, 1:1:1. 
After a run-in period of 1 year, the trial will update allocation probabilities every 6 months, 
corresponding to each census. Allocation probabilities between the arms will adapt based on 
the probability of that arm being the superior arm with respect to the mortality rate among 
children 1-59 months, so that newly enrolled communities will have a higher probability of being 
allocated to the arm with the lowest mortality rate. To minimize the impact of a possible carry-
over effect of treatment in the event that a community changes arms through adaptive 
allocation, each community will stay with its randomized assignment for 4 distributions 
(approximately 2 years). Note that no community will be re-randomized by the time of the 
primary outcome. 
 
Response Adaptive Allocation Algorithm 
 
We will use the following algorithm for the adaptive allocation. Given all outcome 
measurements available at a given time, we will fit a negative binomial model to the data with 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
indicators for each arm (see section 6.2 for analysis details). From the model, we will estimate 
each arm’s log mortality rate and its standard error. We will then draw 10,000 replicates of log 
mortality rates from the estimated distributions, assuming they are normally distributed, and in 
each draw of the joint distribution we will determine which arm has the lowest mortality rate. We 
will estimate the probability that each arm has the lowest mortality rate as the proportion of 
10,000 replicates in which the arm has the lowest mortality rate. Following calculation of the 
probability that each arm has lowest mortality, we will then use a root transform of the 
probabilities to yield the allocation probabilities. Specifically, if 𝑝𝑖 is the probability that arm 𝑖 (𝑖=
1,2,3) yields the best outcomes, then compute the allocation probabilities 𝑎𝑖= 𝑝𝑖
𝛾/∑
𝑝𝑗
𝛾
3
𝑗=1
. 
We pre-specified a tempering value known only to the unmasked team to ensure masking: 𝛾 = 
1/4 or 1/6 or 1/8. This transformation will help mitigate violent swings in allocation due to chance 
alone. Finally, we will not allow any arm’s allocation probability to fall below 10% to preserve our 
ability to compare it against alternatives through the primary endpoint. 
 
3.2.3. Sample size 
We anticipate conducting the study in five regions of Niger: Dosso, Tahoua, Maradi, Zinder, 
Tillabéri; full details are given in the Protocol.  
For the first two years, we expect approximately 1,400 communities in Dosso to participate 
for two full years (4 inter-census intervals of six month duration) and approximately 975 
communities from Tahoua to participate for one year (2 inter-census intervals of six month 
duration) and 975 more communities from Tahoua to participate for half a year (1 inter-census 
interval). The sample size calculations below were informed by mortality rates and standard 
deviations measured in the MORDOR Niger trial [2]. 
Mortality rate measured as deaths per 1,000 person-years at risk will be the primary 
mortality outcome. The use of mortality rate protects against delays in start time across 
communities due to security or logistical issues, as person-time at risk naturally accounts for 
different follow-up times. Delayed implementation or exclusion of additional communities for 
security concerns could result in fewer inter-census intervals. The sample size calculation 
assumes 8,525 inter-census intervals and 1,116 communities per arm.  
 
Mortality primary outcomes 
 
Mortality primary outcome 1: mortality in 1-59 month olds, assessed at 2.5 years (based on at most 2 
years of follow-up per community), comparing the 1-59 month and the placebo arms. Assuming a 
standard deviation of approximately 0.023, we find that 1,116 communities per arm will provide 
approximately 80% power to detect a 10% relative reduction, assuming a baseline mortality rate of 27 per 
thousand person-years among children 1-59 months old and an alpha of 0.05. The absolute effect size is a 
mortality rate difference of 2.7 deaths per 1000 person-years. This calculation is based on the standard Z-
test formula for power (treating the mortality rate in each community as a continuous variable). The 
calculation does not involve a correction for multiple comparisons since the analysis uses a hierarchical 
testing approach for the three mortality outcomes, as described below. 
 
Mortality primary outcome 2: mortality in 1-11 month olds, assessed at 2.5 years (based on at 
most 2 years of follow-up per community), comparing the 1-11 month arm and the placebo arm. 
Assuming a standard deviation of approximately 0.074, we find that 1,116 communities per arm 
will provide approximately 80% power to detect a 19% relative reduction, assuming a baseline 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
mortality rate of 45 deaths per thousand person-years among children 1-11 months old and an 
alpha of 0.05. The absolute effect size is a mortality rate difference of 8.8 per 1000 person-
years. This calculation is based on the standard Z-test formula for power (treating the mortality 
rate in each community as a continuous variable). The calculation does not involve a correction for 
multiple comparisons since the analysis uses a hierarchical testing approach for the three mortality 
outcomes, as described below. 
 
Mortality primary outcome 3: mortality in 12-59 month olds, assessed at 2.5 years (based on at most 2 
years of follow-up per community), comparing the 1-11 month and 1-59 treatment arms. Assuming a 
standard deviation of approximately 0.022, we find that 1,116 communities per arm will provide 
approximately 80% power to detect a 11% relative reduction, assuming a baseline mortality rate of 24 
deaths per thousand person-years among children 12-59 months old and an alpha of 0.05. This 
corresponds to an absolute reduction of 2.7 in the death rate per 1000 person-years. This calculation is 
based on the standard Z-test formula for power (treating the mortality rate in each community as a 
continuous variable). 
 
Sensitivity analyses for primary outcomes based on reduced enrollment caused by security or logistical 
concerns: if only the first half of Tahoua communities are enrolled by 2.5 years, with 791 communities per 
arm, we anticipate the following detectable relative detectable effect sizes (respectively): 12%, 23% and 
13%, for 1-59 months, 1-11 months and 12-59 months. 
 
Mortality secondary outcomes 
 
Secondary outcome 1 : mortality rate among 12-59 months comparing the 1-11 and Placebo arms. The 
calculation is similar to Primary outcome 3. So assuming a standard deviation of approximately 0.022, we 
find that 1,116 communities per arm will provide approximately 80% power to detect a 11% relative 
reduction, assuming a baseline mortality rate of 24 per thousand person-years and an alpha of 0.05. This 
corresponds to an absolute reduction of 2.7 in the death rate per 1000 person-years. 
Secondary outcome 2: mortality rate among 1-11 months comparing the 1-11 month and 1-59 month 
arms. The calculation is similar to Primary outcome 2. So assuming a standard deviation of approximately 
0.074, we find that 1,116 communities per arm will provide approximately 80% power to detect a 19% 
relative reduction, assuming a baseline mortality rate of 45 per thousand person-years and an alpha of 
0.05. This corresponds to an absolute reduction of 8.8 in the death rate per 1000 person-years. 
Sensitivity analyses for secondary outcomes based on reduced enrollment caused by security or logistical 
concerns: With 791 communities per arm, we anticipate the following relative detectable effect sizes 
(respectively): 13% and 23%, for 12-59 month olds and 1-11 month olds. 
 
Antimicrobial Resistance (AMR) Monitoring Outcomes 
 
AMR primary outcome 1:  Prevalence of genetic determinants 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 
at 24 months from baseline. We anticipate inclusion of 50 communities per arm (150 total) 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
provides at least 80% power to detect an absolute difference of 8% in all age groups between 
any two arms, assuming:  
• 
Baseline resistance of 30% (from MORDOR I)  
• 
ICC of 0.045 (from multiple studies)  
• 
30 specimens from each of 50 communities from each arm  
• 
Alpha of 0.05/2 
AMR primary outcome 2: Load of genetic determinants of resistance to macrolides including 
those determinants known to be found in Campylobacter, Salmonella spp., Shigella spp., and 
Escherichia coli from rectal swabs in children 1-59 months old at 24 months from baseline. We 
anticipate inclusion of 50 communities per arm (150 total) provides approximately 80% power to 
detect a 1.4-fold difference in proportion of bacterial reads that are resistant all age groups 
between any two arms, assuming:  
• 
SD of resistance load (on log scale) equal to 3.1 (MORDOR I)  
• 
ICC of 0.02 (MORDOR I)  
• 
30 specimens from each of 50 communities from each arm  
• 
Alpha of 0.05/2 
AMR secondary outcome (as an example of detectable effects for other AMR secondary 
outcomes): For proportion of pneumococcal isolates from nasopharyngeal swabs in children 1-
59 months resistant to macrolides on phenotypic testing, we anticipate inclusion of 50 
communities per arm (150 total) provides approximately 80% power to detect a 8% absolute 
increase between any two arms, assuming: 
• 
Baseline resistance of 10% (from MORDOR I)  
• 
ICC of 0.045 (from multiple studies)  
• 
10 specimens from each of 20 communities from each arm (8 after accounting for 
specimen nongrowth) 
• 
Alpha of 0.05 
 
3.2.4. Statistical framework 
The overall analysis is divided into two aspects: 1) A single frequentist analysis, conducted 
at the time 2.5 years after enrollment, will test the hypothesis that azithromycin MDA reduces 
childhood mortality. The hypothesis tests will be superiority tests (as opposed to equivalence or 
noninferiority analyses) and will be two-sided. 2) Ongoing analyses beyond the primary 
endpoint, reflecting the perpetual nature of the trial, will be conducted using a Bayesian 
perspective. 
 
3.2.5. Statistical interim analyses and stopping guidance 
The adaptive design will naturally change allocation, evolving toward higher allocation 
probabilities for arms most likely to have lowest mortality. From a frequentist perspective, we 
propose a interim analysis at 18 months after the first enrollment (12 months of data in each 
community). The analysis will be based on the Haybittle-Peto boundary which results in an 
interim alpha of 0.001. The alpha of the final analysis will continue to be 0.05 according to the 
rule.[3] The Data and Safety Monitoring Committee will be notified of the results, and if the p-
value (hierarchical approach, same as primary outcome) is <0.001, then the DSMC and if 
appropriate, one or more PIs will meet to decide a course of action. Factors in any decision 
would include interest in both the 1-59 month and 1-11 month MDAs, and AMR. Early 


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discontinuation for other reasons (political, ethical, lack of resources, etc) would mandate final 
frequentist analysis at alpha of the full final prespecified value based on all available data 
(incorporating any alpha spending, as needed). We note that the DSMC may advise 
discontinuation based on evidence of harm, even in the absence of statistical significance. 
Bayesian inferences are unchanged by the application of interim analyses. Continuous 
Bayesian monitoring will be conducted.  
Interim reporting 
Reports will be planned for the Data and Safety Monitoring Committee. We will report the 
number of treatments delivered, the number of communities enrolled at each phase, and the 
coverage by community (i.e., process indicators). Overall mortality rates by age group (1-11, 12-
59, and 1-59) will be tabulated overall in open reports. 
We note that response adaptive randomization for the mortality trial will begin for 
communities enrolled at and after the one year mark.  
 
3.2.6. Timing of the primary analysis 
Mortality. The primary analysis will occur 2 years (rounded to the day) after the completion 
of enrollment. The analysis will use all the data available at that time; i.e., we do not propose to 
wait until phase completion for individuals enrolled and being currently followed at the 2-year 
mark, but rather, to use all complete data records at that moment. 
AMR. Analysis of resistance outcomes will occur after the 24-month community-based 
samples are analyzed in the lab. 
 
3.2.7. Timing of outcome assessments 
Mortaltiy outcomes are measured at the end of each prespecified inter-census interval, 
intended to be six months in duration. The primary analysis will include outcomes assessed up 
to 2.5 years after the first enrollment. AMR outcomes are assessed at baseline and after 24 
months of intervention.  
 
3.3.  Statistical Principles 
3.3.1. Confidence intervals and P-values 
The primary analysis for the mortality trial is prespecified to occur at alpha of 0.05, as 
follows. We propose to use a fixed-sequence, hierarchical testing approach for the three 
mortality primary outcomes [4]:  
 
The staged testing approach will maximize the trial’s power. Our rationale for a fixed-
sequence testing approach is if there is no benefit of treating all children 1-59 mo compared with 


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placebo, then the trial would be unlikely to demonstrate benefit between treatment in the 
narrower age subgroups. Note that the hypothesis testing in the mortality trial and 
implementation trial will proceed independently for primary outcomes along the same sequence 
of tests. Regardless of the hypothesis testing results, we will report 95% confidence intervals 
around estimates of the incidence rate ratio for the comparisons of the trial arms.   
In the mortality trial AMR substudy, we propose a second set of tests. There are two primary 
outcomes measured among children 1-59 months: prevalence of macrolide resistance 
measured in NP swabs, and load of genetic determinants of macrolide resistance measured in 
rectal swabs. Each primary outcome in the substudy will be examined separately at alpha of 
0.05. For each outcome, we propose three pair-wise comparisons between the study groups 
(Placebo v 1-59mo, Placebo v 1-11mo, 1-59mo v 1-11mo). We will compute P-values using a 
permutation test with a step-down minP approach to account for multiple testing [5,6]. Additional 
secondary comparisons between groups in the substudy will include prevalence of genetic 
determinants of resistance to non-macrolide antibiotics (NP swabs) and load of genetic 
determinants to non-macrolide antibiotics (rectal swabs). Within each outcome, we will report P-
values adjusted to control the false discovery rate at 5% the Benjamini-Hochberg approach [7]. 
For all AMR endpoints, we will additionally report unadjusted P-values, which will be less 
conservative to detect undesirable outcomes resulting from mass distribution of azithromycin. 
 
3.3.2. Protocol deviations 
The fraction of eligible censused children who accept the intervention will be reported. 
Communities for which this fraction falls below 60% at a specific census will be tabulated and 
reported. 
In addition, if the fraction of children identified on a subsequent census falls below 75%, an 
investigation will be conducted. The number of such communities will be tabulated and reported, 
and sensitivity analyses omitting such communities will be reported. 
Formal protocol deviations of two types are noted: (1) individual-level deviation, in which an 
ineligible individual is mistakenly treated, and (2) community-level deviation, in which a 
community is mistakenly treated with the wrong intervention. Any such events will be tabulated 
and reported. Note that any community which receives the wrong treatment will be analyzed 
according to the original randomization assignment (intention to treat).  
 
3.3.3. Analysis Populations 
Community-level data will be analyzed on an intention-to-treat basis, covering all inter-
census intervals for which follow-up data are available. The random sample of communities 
selected for the AMR substudy will contribute to the mortality analyses. 
Since AVENIR will randomize grappes before formal enrollment at baseline, the trial will 
analyze only grappes that are enrolled at baseline according to their assigned treatment. 
Grappes that are randomized but do not meet the trial’s enrollment criteria will not be included in 
the analysis. 
Modified per protocol analyses will be conducted that exclude communities with below 60% 
antibiotic coverage in the targeted age group. The number of such communities and their mean 
coverage will be reported, and such analyses will be sharply distinguished from the prespecified 
primary and secondary analyses. 


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3.4.  Trial Population 
3.4.1. Screening data 
AVENIR will report the number of communities screened by region and the reasons 
communities were not enrolled based on eligibility criteria described in the next section. 
 
3.4.2. Eligibility 
This information repeats Protocol v10 section 4.3 Eligibility - 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 
• 
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  
Exclusion criteria: 
• 
Known allergy to macrolides 
 
3.4.3. Recruitment  
The CONSORT flow diagram will follow the model of the MORDOR I trial [2] and will include 
a tabulation of the number of (a) available communities, (b) eligible communities, and (c) 
enrolled communities by arm. 
 
3.4.4. Withdrawal/follow-up  
Additional information will be provided. Specifically, (d) average number of individuals per 
community, (e) coverage and number of treatments given, and (f) number of individuals for 
whom end of intercensus mortality data are available. 


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As a large simple trial, AVENIR will not collect information regarding the specific reasons or 
timing for any loss to follow-up at the individual level. 
 
3.4.5. Baseline patient characteristics  
Since AVENIR is a large simple trial it will not collect extensive information about individual 
participants. We propose to summarize the community size (number of eligible children), child 
age distribution, and percentage female for enrolled communities. 
 
3.5.  Analysis 
3.5.1. Outcome definitions 
Mortality Trial Primary Outcomes 
The trial has three primary outcomes, each a different comparison of the mortality rate 
(deaths per 1,000 persons at risk) at 2.5 years from the first child enrolled, with a window of 3 
months. 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children 1-59 months of 
age compared between communities that receive azithromycin delivered to children 
ages 1-59 months and communities that receive placebo at 2.5 years  
• 
Mortality rate (deaths per 1,000 person-years at risk) among children 1-11 months of 
age compared between communities that receive azithromycin delivered only to children 
ages 1-11 months and communities that receive placebo at 2.5 years  
• 
Mortality rate (deaths per 1,000 person-years at risk) among children 12-59 months of 
age compared between communities that receive azithromycin delivered to children 
ages 1-11 months and communities that receive azithromycin delivered to children ages 
1-59 months at 2.5 years  
Mortality will be monitored through biannual census data collection. Trained census workers 
will use a custom-designed mobile application on smartphones to conduct the census. Census 
workers will visit each household in assigned study communities to obtain household consent 
for participation, and to collect demographic data on the head of household, all mothers in the 
household, and all children 1-59 months in the household. For eligible children, dose will be 
determined via weight or height and administered by the census worker. At subsequent census 
periods, the census workers return to each household and update the vital status of all children, 
indicating whether a child is alive, has died, has moved, or has an unknown status. New 
children and households will be added. 
A child will be included as a death in the primary outcome analysis if they are present on 
one census and absent on the subsequent census due to death (inter-census interval). Person-
time at risk will be calculated as time alive and eligible for treatment while living in the study 
area, with children who died contributing half of the person-time for their last inter-census 
interval. Children who moved, have an unknown status, or are missing from one census will 
contribute no person-time. 
If the study team fails to measure a community for a single census due to security or 
logistical reasons, but re-visits the community in the following census, then person-time and 
outcomes for the 1-year period (2 inter-census intervals) will be counted toward the primary 
outcome. In this case, as with the 6-month inter-census interval, person-time at risk will be 
calculated as time alive and eligible for treatment for the double inter-census interval 


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(approximately 12 months), and children who moved, have an unknown status, or are missing 
from one census contributing no person-time. Children who died will contribute half of the 
person-time between the first census date of the double inter-census interval and their death 
date. Death date will be used to determine to which inter-census interval the death will belong. 
 
Mortality Trial Secondary Outcomes 
Two secondary outcomes include mortality rate comparisons at 2.5 years (3 months) from 
the first child enrolled for the remaining comparisons between different age groups and arms 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children ages 12-59 
months, with rates compared between communities that receive azithromycin delivered 
only to children ages 1-11 months and communities that receive placebo 
• 
Mortality rate (deaths per 1,000 person-years at risk) among children ages 1-11 months, 
with rates compared between communities that receive azithromycin delivered only to 
children ages 1-11 months and communities that receive azithromycin delivered to 
children ages 1-59 months 
 
Antimicrobial Resistance Substudy Primary Outcomes 
The trial will have two primary outcomes for antimicrobial resistance (AMR): 
• 
Prevalence of genetic determinants 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 at 24 months from baseline 
• 
Load of genetic determinants of resistance to macrolides including those determinants 
known to be found in Campylobacter, Salmonella spp., Shigella spp., and Escherichia 
coli from rectal swabs in children 1-59 months old after 2 years of distributions 
 
Antimicrobial Resistance Substudy Secondary Outcomes 
• 
Prevalence of genetic determinants of resistance to macrolides from nasopharyngeal 
swabs collected from children 7-12 years old after 2 years of distributions 
• 
Prevalence of genetic determinants of resistance to macrolides from nasopharyngeal 
swabs collected from caregivers/guardians of eligible children after 2 years of distributions 
• 
Prevalence of genetic determinants of resistance to other antibiotic classes in all swabs 
and samples listed above 
• 
Proportion of macrolide resistant pneumococcal isolates from nasopharyngeal swabs 
collected from children 1-59 months  
• 
Load of genetic determinants of resistance to all antibiotic classes from stool samples in 
caregivers/guardians of eligible children after 2 years of distributions 
 
Microbiome Substudy Outcomes. 
Nasopharyngeal samples will be collected from children 1-59 months of age, children 7-12 
years of age, and caregivers/guardians of children 1-59 months of age as described above and 
in the protocol. Rectal swabs will be collected from children 1-59 months of age and stool 
samples will be collected from caregivers of these children as described above and in the 
protocol. Each age group and sample type will be used to assess the following outcomes: 


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• 
Overall microbial structure  after 2 years of distribution using Manhattan distance, adjusted 
for baseline and analyzed with PERMANOVA to compare by arm. Euclidean distance will 
be used in a secondary analysis. 
• 
Shannon’s diversity index (expressed as effective number) of the microbiome after 2 years 
of distribution, analyzed in a linear model with a covariate for arm and baseline numbers. 
Simpson’s index (expressed as effective number) will be used in a secondary analysis. 
• 
Relative abundance of individual microbial taxa at the genus and species level after 2 
years of distribution, adjusted for baseline and analyzed with DESeq2 to compare by arm 
with a Benjamini-Hochberg correction to account for the number of comparisons using a 
false discovery rate of 5%. 
 
Additional Secondary Outcomes 
• 
Mortality rate over 2.5 years by subgroups: 
o Region (Dosso, Tahoua, Maradi, Zinder, and Tillabéri) 
o Child age (1-11m, 12-24m, 24-59m) 
o Child sex 
o Community distance to the nearest Centre de Santé Intégré (CSI) 
o Number of previous community distributions 
o Timing of distribution/seasonality 
o Other interventions 
▪ 
Participation in MORDOR trials 
▪ 
Participation in and coverage of Seasonal Malaria Chemoprevention 
(SMC) 
▪ 
Participation in trachoma distributions of azithromycin 
o Nutritional status as defined by weight, MUAC, height interval 
 
• 
Program costs as captured by routine administrative data collection during the study 
period and by micro-costing activities (T&M) 
o Measured cost per dose of azithromycin MDA in Niger for the two age groups (1 
– 11 months of age and 1 – 59 months of age) 
o Variation in measured cost per dose of azithromycin MDA as a function of 
community characteristics. 
o Modeled cost per dose of an azithromycin MDA in new but similar settings. 
Values will be assigned to each input cost category (personnel, consumables, 
equipment, services, training, space), activity (eg, publicity, transport), and level 
(communities / household / child) using a fixed and variable cost perspective 
adjusted to the level, and adjusted for community-level characteristics.   
o Total observed azithromycin MDA program costs, by age group (1 – 11 month 
versus 1 – 59 month) 
 
• 
Cost-effectiveness measured by estimated program costs and using measured mortality 
and estimated DALYs as the effectiveness outcome, compared across arms. 
o ICER for administering azithromycin to the different age groups, comparing the 
cost and effectiveness of 1 – 59 month vs. 1-11 month. 
 


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• 
Estimated 10 year national-scale effects (health and cost) of scaling up each 
strategy.  
 
• 
Other implementation outcomes defined in the Proctor Outcomes Framework,[8]2 
including feasibility and acceptability, as captured during routine administrative and 
monitoring data collection during the study period and by stakeholder interviews at the 
participant, community, and health system levels at 2.5 years (Table 3). 
 
• 
Change in nutritional status over time as defined by weight, mid-upper arm 
circumference (MUAC), and height interval 
 
• 
All-cause clinic visits among children 1-59 months of age in the study area during 
the study period as assessed through passive surveillance of Centre de Santé 
Integré records. 
 
• 
Cause-specific clinic visits among children 1-59 months of age in the study area 
during the study period as assessed through passive surveillance of Centre de 
Santé Integré records, including visits with diagnoses of respiratory infection, 
diarrheal disease, and malaria. 
 
• 
Respiratory microbiome by arm in all age groups (children 1-59 month old, 
children 7-12 year old and caregivers/guardians) as specified microbiome 
substudy primary outcomes 
 
 
Other Outcomes 
• 
Cause-specific mortality by treatment arm as defined by verbal autopsy* over 2.5 years 
• 
Serology outcomes as assessed by dried blood spots during sample collections at 
baseline and 24 months 
• 
Normalized read number of genetic determinants of resistance by antibiotic class in 
environmental samples at baseline and 24 months 
 
*Depending upon resources, verbal autopsy might be conducted by UCSF or another group 
 
MORDOR trial subgroup continuation outcomes 
 
The AVENIR trial will include the 594 villages in Dosso region that were previously enrolled in 
the MORDOR I, II and III trials. This creates an opportunity to study the longer-term effects of 
mass azithromycin treatment on and on antimicrobial resistance. 
 
• Longer-term carry-over effects on mortality 
o MORDOR III, beginning at month 42, re-randomized villages to receive bi-annual mass 
distribution of azithromycin or placebo to children 1-59 months, and followed the 
communities for 18 additional months (in three inter-census intervals 42-48m, 48-54m, 
54-60m). From MORDOR communities allocated to the placebo arm of AVENIR, we will 
compare the mortality rate among children ages 1-59 months over 2.5 years in 
communities that received azithromycin during MORDOR III versus those that received 
placebo during MORDOR III. Our primary comparison of interest is among communities 
allocated to AVENIR’s placebo arm because it will enable us to study longer-term carry-
over effects of previous azithromycin treatment after discontinuation. We hypothesize 


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that communities that previously received azithromycin during MORDOR phase 3 will 
have lower mortality compared to communities that continually received placebo for the 
entire period. The analysis approach will follow the primary analysis, estimating 
incidence rate ratios using a negative binomial regression. Comparisons within 
additional AVENIR arms (1-59m, 1-11m) could be estimated as an exploratory analysis. 
 
• Longer-term carry-over effects on antimicrobial resistance 
o During MORDOR III, 160 communities were tested for genetic determinants of 
antimicrobial resistance at month 54. This creates the opportunity to study effects of 
treatment history on longer-term effects for antimicrobial resistance selection. From the 
160 communities in the MORDOR trial with resistance measures, the AVENIR trial will 
randomly select 40 communities, evenly distributed (20/20) between two treatment 
histories (AAAAA, AAAPP, each letter refers to a year of Azithromycin or Placebo). 
Within each community, we will collect a rectal swab from 30 children 1-59 months, 
and test the samples for genetic determinants of antimicrobial resistance using 
metagenomic deep sequencing, as in the resistance primary analysis. This additional 
substudy will enable two analyses of primary interest: 
▪ At enrollment in AVENIR, approximately 1 year after the end of MORDOR, we will 
compare the load of genetic determinants of antimicrobial resistance to 
macrolides (primary) and other classes of antibiotics (secondarily) between the 
two treatment histories.  We hypothesize that load of genetic determinants will be 
higher among communities with the AAAAA history compared with AAAPP 
history. The analysis approach will follow the primary analysis for the antimicrobial 
resistance substudy 
▪ Among the 20 communities with AAAPP treatment history in MORDOR, we will 
compare the the load of genetic determinants of antimicrobial resistance to 
macrolides (primary) and other classes of antibiotics (secondarily) longitudinally 
over time from MORDOR 54 to AVENIR enrollment (approximately 1 year later), 
and again to the final measurement in AVENIR phase 1 (approximately 3 years 
after discontinuation of azithromycin). We hypothesize that load of genetic 
determinants will decline with time from last treatment. 
 
3.5.2. Analysis methods 
Mortality in the mortality/resistance trial 
Our parameter of interest for comparisons of mortality between arms is the relative reduction 
in mortality measured by the incidence rate ratio (IRR). The primary analysis will be a Poisson 
regression that includes the count of deaths as the outcome and the community-level person-
time at risk as an offset, with observations for each community’s inter-census interval. The 
model will include an indicator variable for each active treatment arm. The adaptive allocation 
will be accounted for using pooled regression, including in the model additional indicator 
variables for each of three allocations in the trial (the initial, equal allocation plus 2 adaptations). 
For community i and randomization j (j = 1, 2, 3), the model will be: 
log(𝑌𝑖𝑗) −log(𝑇𝑖𝑗) = 𝛼+ 𝛽𝐴𝑖𝑗+ ∑
𝛾𝑗𝑃𝑗
3
𝑗=2
, 
where 𝑌𝑖𝑗 is the number of deaths and 𝑇𝑖𝑗 is the person-time at risk in that community; 𝐴𝑖𝑗 is 
a treatment indicator that will vary by each comparison (details below), and 𝑃𝑗 is an indicator for 
the two adaptive random allocations (the first equal allocation is the omitted category). We will 


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estimate 95% confidence intervals for the IRRs using bootstrap resampling (10,000 replicates) 
that resamples communities with replacement and re-estimates the IRRs.  
For primary outcome 1 that compares mortality among 1-59 month olds, we will include in 
the analysis children ages 1-59 months in the 1-59 month treatment arm and placebo arm. 𝐴𝑖𝑗 
will be an indicator of allocation to the 1-59 month treatment arm, and exp⁡(𝛽̂) will estimate the 
IRR.  
For primary outcome 2 that compares mortality among children ages 1-11 months, we will 
subset the analysis to children ages 1-11 months enrolled in the 1-11 month treatment arm and 
placebo arm. 𝐴𝑖𝑗 will be an indicator of allocation to the 1-11 month treatment arm, and exp⁡(𝛽̂) 
will estimate the IRR. 
Similarly, for primary outcome 3 that compares mortality among children ages 12-59 
months, we will subset the analysis to children ages 12-59 month in the 1-11 month treatment 
arm and 1-59 month treatment arm. 𝐴𝑖𝑗 will be an indicator of allocation to the 1-59 month 
treatment arm, and exp⁡(𝛽̂) will estimate the IRR.  
Secondary mortality analyses will be estimated similarly from the model subset to the 
appropriate age range.  
We will estimate permutation P-values for each comparison using a randomization test that 
permutes community treatment labels within each adaptive allocation group according to the 
probabilities used in each allocation, holding community outcomes fixed, and will assess 
statistical significance using the fixed sequence, hierarchical testing procedure described above 
in section 3.3.  
We will examine effect heterogeneity by pre-specified effect modifiers on additive and 
multiplicative scales [10]. We will do so by including interaction terms between effect modifiers 
and treatment indicators in the regression models.  
 
Antimicrobial Resistance Substudy 
The primary analysis for resistance outcomes from nasopharyngeal swabs will be ANOVA to 
compare the community-level proportion of individuals with any macrolide resistant genetic 
determinants across the three arms. The primary analysis for rectal swabs will be ANOVA to 
compare community-level mean load of macrolide resistant genetic determinants across the 
three arms. For both sets of swabs, secondary analyses examining resistance in other classes 
of antibiotics and other age groups will be conducted similarly. P-values for all resistance 
analyses will be computed using a permutation test, using a step down minP procedure to 
control for three pairwise comparisons in each primary outcome, and using a Benjamini-
Hochberg correction to control the false discovery rate across additional (non-macrolide) 
endpoints, described above in section 4.1. 
 
3.5.3. Missing data 
Individuals with missing outcome data are assumed to contribute one half of one phase of 
person time to the denominator, and no counts to the numerator. Individuals are counted for 
each phase in which they are confirmed present at the beginning of that phase. 
Communities that completely drop out during a phase will be reported, but their 
measurements in that phase will not contribute to the primary analysis. Earlier inter-census 


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intervals to which communities contributed complete data will be included in the primary 
analysis. 
 
3.5.4. Additional analyses 
 
Model Assessment 
The results of additional regressions will be reported and will be clearly labeled as such and 
will be sharply distinguished from the primary prespecified outcome. These analyses serve two 
purposes: (a) assessment of how sensitive the final analytic result is to the prespecified analytic 
choices, and (b) facilitation of future meta-analytic or review studies. In particular, results will be 
reported in both absolute and relative scales. Model adequacy will be checked by examination 
of residuals or other goodness of fit tests as needed. Inadequate model fit will prompt us to 
report alternative models. As a supplemental, sensitivity analysis, we will estimate permutation 
P-values for each comparison using a randomization test proposed by Simon and Simon, which 
re-estimates the allocation probabilities within each permutation rather than treating them as 
fixed [9]. 
 
Subgroup Analyses 
Pre-specified subgroup analyses for mortality constitute secondary outcomes for the trial. They 
include: 
• 
Region (Dosso, Tahoua, Maradi, Zinder, Tillaberi). Rationale: examine effect 
heterogeneity by geographic region. 
• 
Child age (1-11m, 12-24m, 24-59m). Rationale: examine effect heterogeneity by age 
within each treatment regimen 
• 
Child sex. Rationale: consistent with US NIH reporting of sex as a biological variable. 
• 
Community distance to the nearest Centre de Santé Intégré (CSI). Rationale: previous 
analysis of the MORDOR trial in Dosso, Niger found larger mortality reductions in 
communities further from CSIs. 
• 
Number of previous community distributions. Rationale: examine whether effects wane 
with number of treatments. 
• 
Timing of distribution / seasonality. Rationale: examine effect heterogeneity by season, 
as mortality could vary by season.  
• 
Other Interventions 
o Participation in the MORDOR trials (Dosso region) 
o Seasonal Malaria Chemoprevention (SMC) in the most recent malaria season if it 
occurred within the three months prior to the current treatment period. Rationale: 
examine if there is effect heterogeneity depending on co-delivery with SMC. SMC 
coverage. Rationale: examine if there is effect heterogeneity depending on co-
delivery with high coverage SMC. 
o Trachoma distributions of azithromycin: any distribution received by other 
programs during the AVENIR trial. Rationale: effect could be attenuated among 
communities that receive additional treatment. Number of distributions received 
before and during the AVENIR trial. Rationale: examine effect heterogeneity by 
the quantity of past and concurrent azithromycin treatments outside of the trial.   


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o Nutritional status as defined by weight, mid-upper arm circumference (MUAC), 
height interval. Rationale: determine if there is effect heterogeneity by child 
nutritional status measured by anthropometry. 
 
Bayesian Analysis 
To complement the primary Frequentist analysis, a Bayesian analysis of the trial will be 
conducted. Ongoing analyses beyond the primary endpoint, reflecting the perpetual nature of 
the trial, will be conducted using a Bayesian perspective. The details of the Bayesian analyses 
will be added to a future update of this SAP. 
Costing and Cost-Effectiveness 
 
 Cost-effectiveness analysis will assess the added net costs, added health outcomes (e.g. 
deaths and DALYs averted), and the ICER (incremental cost-effectiveness ratio): cost per 
health outcome achieved by going from no intervention to 1 – 11 months, and then to 1 – 59 
months as well as comparing the ICERs for census door to door, CHW door to door and CHW 
fixed point distribution strategies using cost estimates from the Delivery Trials described below. 
The health outcomes will be mortality (measured in the trial) and DALYs (calculated from 
mortality). Cost-effectiveness will be assessed from different perspectives: households, 
community, government health system, and society. Analyses will produce measures of 
incremental cost-effectiveness: net cost per dose delivered, per death averted, and net cost per 
DALY averted. The economic analysis will include two-time frames: the study period of 1 – 4 
years and a longer time frame highlighting potential long-term effects such as morbidity, 
mortality and antimicrobial resistance. All results will be subject to sensitivity analyses: one-way 
(deterministic), two-way, and multi-way (probabilistic) to assess dependence of outcomes on 
uncertainties in input values. 
 
The cost-effectiveness analysis will incorporate costs and effectiveness as described above. 
Determination of cost-effectiveness will be according to a Willingness to Pay criterion, e.g. 
$150/DALY averted. Costs and DALYs will be discounted at 3% per year. The study will have 
two time frames: the observed study period (1 – 4 years) and a longer time frame highlighting 
expected downstream effects and out-of-study effects (see Protocol for further discussion). 
 
Strategies that are more costly but less or equally effective as the next alternative will be 
considered “dominated”, and removed from consideration, as per best practices.  Strategies will 
be compared by cost from “no intervention” as the base case, going forward by increasing cost. 
Projected potential benefits in the second time frame may include delayed benefits in the 
intermediate term based on an observed decay curve, and potentially long-term benefits of the 
improved health observed during the trial (e.g., nutrition, disease episodes). 
 
To ensure that the model and comparisons are robust, comprehensive sensitivity analyses will 
be conducted, including one-way, two-way, scenario, threshold and multivariate/stochastic. 
 
3.5.5. Harms 
Passive reporting of adverse effects has been used in the past for azithromycin trials. More 
than 800 million doses have been distributed as part of the trachoma program, and this study 
will be unlikely to unveil new side effects. We intend to be vigilant, and serious adverse events 
suspected of being drug-related will be reported to the DSMC within 24 hours of our notification.  


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
We propose no formal statistical analysis of safety events but will report adverse events by 
arm. 
3.5.6. Statistical software 
Statistical analysis will be conducted using R (R Foundation for Statistical Computing, Vienna, 
Austria). 
 
4.  References 
1.  Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Doré C, et al. Guidelines for the 
Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017;318: 2337–2343. 
doi:10.1001/jama.2017.18556 
2.  Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, et al. Azithromycin to 
Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018;378: 1583–1592. 
doi:10.1056/NEJMoa1715474 
3.  Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol. 1971;44: 793–797. doi:10.1259/0007-1285-44-526-793 
4.  Dmitrienko A, D’Agostino RB. Multiplicity Considerations in Clinical Trials. N Engl J Med. 
2018;378: 2115–2122. doi:10.1056/NEJMra1709701 
5.  Westfall PH, Young SS. Resampling-based multiple testing: examples and methods for P-
value adjustment. New York: Wiley; 1993.  
6.  Ge Y, Dudoit S, Speed TP. Resampling-based multiple testing for microarray data analysis. 
Test. 2003;12: 1–77. doi:10.1007/BF02595811 
7.  Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful 
Approach to Multiple Testing. J R Stat Soc Ser B Methodol. 1995;57: 289–300. 
doi:10.1111/j.2517-6161.1995.tb02031.x 
8.  Proctor E, Hiie Silmere, Raghavan R, Hovmand P, Aarons G, Bunger A, et al. Outcomes for 
implementation research: conceptual distinctions, measurement challenges, and research 
agenda. Adm Policy Ment Health. 2011;38: 65–76. doi:10.1007/s10477-010-0319-7 
9.  Simon R, Simon NR. Using randomization tests to preserve type I error with response 
adaptive and covariate adaptive randomization. Stat Probab Lett. 2011;81: 767–772. 
doi:10.1016/j.spl.2010.12.018 
10.  VanderWeele TJ, Knol MJ. A Tutorial on Interaction. Epidemiol Method. 2014;3: 33–72. 
doi:10.1515/em-2013-0005 
11.  Hayes RJ, Moulton LH. Cluster randomised trials. 2nd Edition. Boca Raton, FL: Taylor & 
Francis Group; 2017.  
12.  Park JJH, Detry MA, Murthy S, Guyatt G, Mills EJ. How to Use and Interpret the Results of a 
Platform Trial: Users’ Guide to the Medical Literature. JAMA. 2022;327: 67. 
doi:10.1001/jama.2021.22507 


AVENIR Mortality Trial, Statistical Analysis Plan  
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13.  Goodrich B, Gabry J, Ali I, Brilleman S. rstanarm: Bayesian applied regression modeling via 
Stan. 2022. Available: https://mc-stan.org/rstanarm 
14.  Gabry J, Simpson D, Vehtari A, Betancourt M, Gelman A. Visualization in Bayesian 
workflow. J R Stat Soc Ser A Stat Soc. 2019;182: 389–402. doi:10.1111/rssa.12378 
15.  Doan T, Arzika AM, Hinterwirth A, Maliki R, Zhong L, Cummings S, et al. Macrolide 
Resistance in MORDOR I - A Cluster-Randomized Trial in Niger. N Engl J Med. 2019;380: 
2271–2273. doi:10.1056/NEJMc1901535 
 
 
 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
5.  Revision history 
 
 
Version 
Date 
Summary of Changes, Justification, and Timing vis-à-vis key 
trial events (enrollment completion, interim analyses, 
unmasking, etc) 
1 
2020-03-10 
 
• 
First draft 
2 
2020-03-30 
• 
Revision to sample size calculations (harmonization across 
work to date) 
• 
Revision to adaptive allocation algorithm text 
• 
Revision to analysis details (phase-stratified estimator) 
 
3 
2020-05-01 
• 
Harmonized the order of outcomes, and list of secondary 
outcomes with protocol v1.  Added a complete list of pre-
specified secondary analyses. 
• 
Added language to allow for communities to contribute to the 
primary outcome if they were missed in a single census but 
revisited after ~12 months from the last census. 
4 
2020-07-27 
• 
Added implementation trial to the SAP 
• 
Updated sample size and detectable effect calculations based 
on the revised design, which now includes a mortality trial and 
a parallel implementation trial.  
• 
Described the resistance monitoring as nested within the 
mortality trial.  
• 
Changed the hypothesis testing framework from Bonferroni-
Holm to a fixed sequence, hierarchical testing framework to 
maximize study power. 
• 
Added birth history outcome measurement for the 
implementation trial. 
5 
2020-07-31 
• 
Added Figure 1 (design overview) 
6 
2020-08-05 
• 
Added interim analysis (3.5) 
7 
2020-09-24 
Updated the design to reflect DSMC feedback, align with the 
Protocol: 
• 
Increased number of communities selected for mortality trial 
to 3,350  
• 
Delayed start of remainder of communities until 1.5 years 
after the first enrollment (aligned with interim analysis) 
• 
Simplified the comparison of delivery trial approaches to a 2-
arm trial and removed mortality as an outcome 
8 
2020-10-08 
Updated outcomes and additional analyses with relevant 
clarifications for costing and cost-effectiveness. 
9 
2021-04-06 
• 
Added MORDOR continuation substudies to the outcomes 
definitions in section 6.1 
• 
Updated the multiple testing procedure planned for AMR 
substudy in section 4.1 
• 
Clarified the ITT analysis will only include enrolled grappes 
10 
2022-02-04 
• 
Added sensitivity analyses to Delivery Trial treatment 
coverage outcome in section 6.2 


AVENIR Mortality Trial, Statistical Analysis Plan  
Version 16, 2024-09-25 
11 
2022-05-24 
• 
Updated the format to include 3 different sections for the 3 
different trials. 
• 
Added in the Programmatic Trial section. 
12 
2022-05-27 
• 
Removed details of CSI clinic visit outcome measurement and 
analyses until those details can be confirmed vis-à-vis field 
measurement and logistics. 
13 
2022-10-21 
• 
Updated wording of person-time calculations for Mortality trial 
14 
2023-07-24 
• 
Included in the trial overview details of study team masking 
(membership, timing, rationale), section 2. 
• 
Updated Figure 1 and included footnote 
• 
Updated the language of tempering roots from 1/3 or 1/4 to 
1/4 or 1/6 or 1/8, section 3.2.2.  
• 
Removed redundant paragraph for masking in the section of 
interim Analysis, section 3.2.5 
• 
Clarified the timing of the primary analysis, to be exactly 2 
years after completion of enrollment, section 3.2.6 
• 
Revised Mortality trial primary analysis to align notation with 
the final adaptive randomization schedule, including the 
model specification and permutation test, section 3.5.2 
• 
Moved Delivery Trial and Programmatic Trial analysis plans to 
separate SAPs to make the SAP easier to navigate. 
15 
2023-10-17 
• 
Updated Figure 1 to reflect the final count of communities 
screened and enrolled in the programmatic trial.  
16 
2024-09-25 
• 
Updated AMR sample size and power calculations. The lab is 
going to be processing all 150 communities for the AMR 
outcomes, so we can include the full 150 communities in the 
primary AMR analyses, as opposed to the 60 that we listed 
originally.