Child, Only, Mortality, Resistance Bacterial
Conditions
Keywords
Mass Treatment, Azithromycin, Childhood Mortality Rate, Antimicrobial Resistance, Implementation and Cost Analysis
Brief summary
The MORDOR trial found that biannual distribution of azithromycin to children 1-59 months old reduced child mortality. The World Health Organization (WHO) released conditional guidelines for this intervention, which include targeting azithromycin distributions to children 1-11 months of age in high mortality settings.Targeting treatment to children 1-11 months old could reduce antimicrobial resistance by limiting antibiotic distributions while treating children at the highest mortality risk. However, this targeted intervention has not yet been tested. The AVENIR mortality/resistance trial aims to assess the efficacy of age-based targeting of biannual azithromycin distribution on mortality as well as determine the impact of age-based targeting on antimicrobial resistance.
Detailed description
In the Mortality/Resistance trial, 3,000 communities in the Dosso and Tahoua regions of Niger will be randomized to one of three arms: 1) azithro 1-11: biannual oral azithromycin to children 1-11 months old with biannual oral placebo to children 12-59 months old, 2) azithro 1-59: biannual oral azithromycin to children 1-59 months old, or 3) placebo: biannual oral placebo to children 1-59 months old. Interventions will be delivered biannually through a door-to-door census. Mortality will also be monitored through biannual census data collection, which will be used to adaptively allocate treatment assignments after the first year. Communities will retain an allocation for 4 distributions before being re-randomized. Antimicrobial resistance will be monitored using cluster sampling of treated and untreated children and adults in the Dosso region. To compare costs, coverage, and acceptability of treating 1-11-month-old children only vs children 1-59 months old, an additional 80 communities in the Dosso region will be selected. These communities will be randomized in a 1:1 fashion to either receive 1) distribution of open-label azithromycin to children 1-11 months old with no intervention to children 12-59 months old or 2) distribution of open-label azithromycin to children 1-59 months old. The primary outcome for this substudy will be community-level costs per dose delivered. Secondary outcomes include program costs, treatment coverage, and acceptability of the intervention according to community leaders, community health workers, and caregivers of eligible children.
Interventions
DRUGAzithromycin
Azithromycin will be administered as a directly observed dose in oral suspension form for children: 1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) 2. For children 1-11 months of age, weight or age-based dosing will be used 3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program
OTHERPlacebo
Placebo will be administered as a directly observed dose in oral suspension form for children: 1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g) 2. For children 1-11 months of age, weight-based dosing will be used 3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program
Sponsors
University of California, San Francisco
Bill and Melinda Gates Foundation
Ministry of Health, Niger
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
In the mortality/resistance trial, we will use a matching placebo to mask study arm allocation. Placebo will be identical to azithromycin in appearance, smell, and packaging. Treatment assignment will be masked by assigning a series of upper- and lower-case letters to each trial, age group, and treatment arm. Those masked to study arm allocation include participants, investigators, most study personnel including study personnel administering treatment and collecting data on mortality outcomes, and laboratory personnel processing samples for resistance outcomes. Unmasked personnel include the trial biostatistician and data analyst responsible for implementing the randomization sequence and key members of Pfizer staff. In a subset of 80 communities, open-label azithromycin will be distributed with no masking of participants, implementors, or outcome assessors.
Intervention model description
The AVENIR mortality/resistance trial is a large simple double-masked cluster-randomized trial with response-adaptive allocation in Niger.
Eligibility
Sex/Gender
ALL
Age
1 Months to 59 Months
Healthy volunteers
Yes
Inclusion criteria
1. Intervention At the community-level, eligibility includes: Inclusion Criteria: * Location in Dosso, Tahoua, Maradi, Zinder, or Tillabéri regions * Population 250 to 2,499\* * Distance \> 5 km from district headquarters town * Distinguishable from neighboring communities * Verbal consent of community leader(s)
Exclusion criteria
* Inaccessible or unsafe for study team * "Quartier" designation on national census \*Population size as estimated from the most recent national census or projections At the individual-level, eligibility includes: Inclusion criteria: * Age 1-59 months * Primary residence in a study community * Verbal consent of caregiver/guardian for study participation * Weight ≥ 3.0 kg (\*no weight limits in communities using age-based dosing)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality (1-59 Months Old) | from 6 months up to 2.5 years | Mortality rate (deaths per 1,000 person-years at risk) among children 1-59 months of age, comparing the azithro 1-59 and placebo arms. |
| All-cause Mortality (1-11 Months Old) | from 6 months up to 2.5 years | Mortality rate (deaths per 1,000 person-years at risk) among children 1-11 months of age, comparing the azithro 1-11 and placebo arms. |
| All-cause Mortality (12-59 Months Old) | from 6 months up to 2.5 years | Mortality rate (deaths per 1,000 person-years at risk) among children 12-59 months of age with rates compared between azithro 1-11 and azithro 1-59 communities. |
| Prevalence of Resistance to Macrolides - Nasopharyngeal Swabs (1-59 Months Old) | After 4 distributions (approximately 24 months) | Prevalence of macrolide resistance among pneumococcus-positive nasopharyngeal swabs collected from children aged 1-59 months after 4 distributions. Resistance was assessed among culture-positive pneumococcal isolates from nasopharyngeal swabs. |
| Load of Genetic Determinants of Resistance to Macrolides - Rectal Swabs (1-59 Months Old) | After 4 distributions (approximately 24 months) | Community-level load of macrolide antimicrobial resistance determinants in pooled rectal swabs collected from children aged 1-59 months after four biannual distributions. Rectal swabs from each community were pooled and analyzed using metagenomic DNA sequencing. Nonhost sequencing reads were aligned to an antimicrobial resistance reference database, and reads matching macrolide resistance determinants were summed and normalized to the total number of nonhost reads in the pooled sample. Values are reported as matched resistance reads per million nonhost reads (rM). Higher values indicate a greater abundance of macrolide resistance determinants. The values presented in the table are untransformed normalized counts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality Rate by Weight-for-age Z-score Subgroup Among Infants Aged 1-11 Months | After 4 distributions (approximatively 24 month after first distribution) | All-cause mortality incidence rate among children aged 1-11 months who had weight measured during at least one census round and had a valid weight-for-age z-score calculated using the World Health Organization Child Growth Standards. Nutritional status was assessed at the beginning of each census interval. This measure reports the overall mortality rate for this analysis population by randomized treatment arm and is not stratified by weight-for-age z-score subgroup. Mortality rates are reported as deaths per 1,000 person-years. |
| Load of Genetic Determinants of Resistance to Macrolides in Nasopharyngeal Swabs From Guardians | After 4 distributions (approximatively 24 month after first distribution) | Community-level loads of macrolide antimicrobial resistance determinants in nasopharyngeal swabs collected from guardians of children eligible for treatment after four biannual distributions. Nasopharyngeal swabs from each community were pooled and analyzed using DNA sequencing. Nonhost sequencing reads were aligned to an antimicrobial resistance reference database, and reads matching macrolide resistance determinants were summed and normalized to the total number of nonhost reads in the pooled sample. Values are reported as matched resistance reads per million nonhost reads (rM). Higher values indicate a greater abundance of macrolide resistance determinants. The values presented in the table are untransformed normalized counts; log-transformed values were used only for inferential statistical analyses. |
| Program Costs Per Dose Delivered | 1 year | Program cost per dose delivered was estimated using routine administrative data and micro-costing activities. Costs were calculated per dose delivered and were not stratified by randomized treatment arm. |
| Load of Genetic Determinants of Resistance to Macrolides in Nasopharyngeal Swabs From Children Aged 7-12 Years | After 4 distributions, approximately 24 months | Community-level loads of macrolide antimicrobial resistance determinants in nasopharyngeal swabs collected from children aged 7-12 years after four biannual distributions. Nasopharyngeal swabs from each community were pooled and analyzed using DNA sequencing. Nonhost sequencing reads were aligned to an antimicrobial resistance reference database, and reads matching macrolide resistance determinants were summed and normalized to the total number of nonhost reads in the pooled sample. Values are reported as matched resistance reads per million nonhost reads (rM). Higher values indicate a greater abundance of macrolide resistance determinants. The values presented in the table are untransformed normalized counts; log-transformed values were used only for inferential statistical analyses. |
Countries
Niger
Contacts
PRINCIPAL_INVESTIGATORTom M Lietman, MD
University of California, San Francisco
PRINCIPAL_INVESTIGATORKieran S O'Brien, PhD, MPH
University of California, San Francisco
Participant flow
Pre-assignment details
Please note number of participants in participant flow, baseline characteristics, and analyzed population will differ. A participant is included in the participant flow if they participated in the study in at least one round. However participants are only included in baseline collections if they participated in the first data collection for that community. Participants are only included in analyzed populations if they participated in at least two rounds of data collection.
Participants by arm
| Arm | Count |
|---|---|
| Azithro 1-11 Biannual weight- or height-based dose of oral azithromycin suspension to children 1-11 months old and oral placebo or no intervention to children 12-59 months old
Azithromycin: Azithromycin will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight or age-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program
Placebo: Placebo will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program | 41,064 |
| Azithro 1-11 Biannual weight- or height-based dose of oral azithromycin suspension to children 1-11 months old and oral placebo or no intervention to children 12-59 months old
Azithromycin: Azithromycin will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight or age-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program
Placebo: Placebo will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program | 431 |
| Azithro 1-59 Biannual age, weight- or height-based dose of oral azithromycin suspension to children 1-59 months old
Azithromycin: Azithromycin will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight or age-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program | 44,412 |
| Azithro 1-59 Biannual age, weight- or height-based dose of oral azithromycin suspension to children 1-59 months old
Azithromycin: Azithromycin will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight or age-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program | 463 |
| Placebo Biannual weight- or height-based dose of oral placebo to children 1-59 months old
Placebo: Placebo will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program | 43,702 |
| Placebo Biannual weight- or height-based dose of oral placebo to children 1-59 months old
Placebo: Placebo will be administered as a directly observed dose in oral suspension form for children:
1. Single-dose of 20mg/kg in children (up to the maximum adult dose of 1g)
2. For children 1-11 months of age, weight-based dosing will be used
3. For children 12-59 months of age, height-based dosing will be used via height-stick approximation as currently performed by Niger's trachoma program | 463 |
| Total | 130,535 |
Baseline characteristics
| Characteristic | Azithro 1-11 | Azithro 1-59 | Placebo | Total |
|---|---|---|---|---|
| Age, Customized Age in months categorical 1-11 months | 7569 Participants | 8220 Participants | 7981 Participants | 23770 Participants |
| Age, Customized Age in months categorical 12-23 months | 8452 Participants | 8922 Participants | 8773 Participants | 26147 Participants |
| Age, Customized Age in months categorical 24-59 months | 25043 Participants | 27270 Participants | 26948 Participants | 79261 Participants |
| Children per community | 95.28 children per community STANDARD_DEVIATION 71.36 | 95.92 children per community STANDARD_DEVIATION 67.48 | 94.39 children per community STANDARD_DEVIATION 61.65 | 95.19 children per community STANDARD_DEVIATION 66.79 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 41064 Participants | 44412 Participants | 43702 Participants | 129178 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Niger | 41064 participants | 44412 participants | 43702 participants | 129178 participants |
| Sex: Female, Male Female | 20605 Participants | 22078 Participants | 21582 Participants | 64265 Participants |
| Sex: Female, Male Male | 20459 Participants | 22334 Participants | 22120 Participants | 64913 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1,666 / 104,374 | 1,914 / 153,626 | 1,923 / 124,617 |
| other Total, other adverse events | 0 / 104,374 | 0 / 153,626 | 0 / 124,617 |
| serious Total, serious adverse events | 1 / 104,374 | 1 / 153,626 | 3 / 124,617 |
Outcome results
Primary
All-cause Mortality (1-11 Months Old)
Mortality rate (deaths per 1,000 person-years at risk) among children 1-11 months of age, comparing the azithro 1-11 and placebo arms.
Time frame: from 6 months up to 2.5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azithro 1-11 | All-cause Mortality (1-11 Months Old) | 22.3 deaths per 1,000 person years |
| Azithro 1-59 | All-cause Mortality (1-11 Months Old) | 18.5 deaths per 1,000 person years |
| Placebo | All-cause Mortality (1-11 Months Old) | 23.9 deaths per 1,000 person years |
Primary
All-cause Mortality (12-59 Months Old)
Mortality rate (deaths per 1,000 person-years at risk) among children 12-59 months of age with rates compared between azithro 1-11 and azithro 1-59 communities.
Time frame: from 6 months up to 2.5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azithro 1-11 | All-cause Mortality (12-59 Months Old) | 12.2 deaths per 1,000 person-years |
| Azithro 1-59 | All-cause Mortality (12-59 Months Old) | 10.7 deaths per 1,000 person-years |
| Placebo | All-cause Mortality (12-59 Months Old) | 12.0 deaths per 1,000 person-years |
Primary
All-cause Mortality (1-59 Months Old)
Mortality rate (deaths per 1,000 person-years at risk) among children 1-59 months of age, comparing the azithro 1-59 and placebo arms.
Time frame: from 6 months up to 2.5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azithro 1-11 | All-cause Mortality (1-59 Months Old) | 13.8 deaths per 1,000 person-years |
| Azithro 1-59 | All-cause Mortality (1-59 Months Old) | 11.9 deaths per 1,000 person-years |
| Placebo | All-cause Mortality (1-59 Months Old) | 13.9 deaths per 1,000 person-years |
Primary
Load of Genetic Determinants of Resistance to Macrolides - Rectal Swabs (1-59 Months Old)
Load of genetic determinants of resistance to macrolides including those determinants known to be found in Campylobacter spp, Salmonella spp, Shigella spp, and Escherichia coli from rectal swabs in children 1-59 months old, defined as read number per million base pairs, using DNA-seq (metagenomic deep sequencing)
Time frame: After 4 distributions (approximately 24 months)
Primary
Prevalence of Resistance to Macrolides - Nasopharyngeal Swabs (1-59 Months Old)
Prevalence of resistance to macrolides including those determinants known to be found in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus from nasopharyngeal swabs in children 1-59 months old.
Time frame: After 4 distributions (approximately 24 months)
Secondary
Mortality Rate by Subgroups: Anthropometric Indicators
Mortality rate compared by arm in subgroups based on weight in children 1-11 months over 2.5 years
Time frame: After 4 distributions (approximatively 24 month after first distribution)
Secondary
Prevalence of Resistance to Macrolides From Nasopharyngeal Swabs and Load of Genetics Determinants
Prevalence of resistance to macrolides from nasopharyngeal swabs and load of genetic determinants of resistance to macrolides from rectal swabs after 4 distributions in: * Children 7-12 years old at 24 months from baseline * Caregivers/guardians of eligible children at 24 months from baseline
Time frame: After 4 distributions (approximatively 24 month after first distribution)
Secondary
Program Costs Per Dose Delivered
Program costs as captured by routine administrative data collection during the substudy and by micro-costing activities, per doses delivered
Time frame: 1 year