Community Health Azithromycin Trial in Burkina Faso

Study Overview
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Brief Summary
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An estimated 7.7 million pre-school aged children die each year, the majority from infectious diseases. Mass azithromycin distributions for trachoma may have the unintended benefit of reducing childhood mortality. We recently demonstrated the biannual mass azithromycin distribution significantly reduces all-cause child mortality in a cluster randomized trial (MORDOR I) conducted in three diverse regions of Sub-Saharan Africa. Our long-term goal is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood morbidity and mortality. We propose a cluster randomized trial designed to repeat the original study to confirm the original results in a different geographic study with similarly high child mortality, and to better understand the mechanism behind any effect of azithromycin on child mortality. We hypothesize that biannual mass azithromycin distribution will reduce child mortality compared to placebo, and that this effect will be primarily driven by a reduction in infectious burden. Objectives: Determine the efficacy of biannual mass azithromycin distribution versus placebo in children aged 1-59 months for reduction in all-cause mortality. Determine the efficacy of targeted azithromycin distribution to infants during an early infant healthcare visit (approximately 5th through 12th week of life) on infant mortality. Determine the mechanism behind the effect of biannual mass azithromycin distribution for reduction in child mortality. The study will be conducted in the Nouna District in northwestern Burkina Faso.

Detailed Description
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Although child health and mortality are improving worldwide, children in the Sahel and sub-Sahel regions of West Africa have the greatest risks of mortality.Burkina Faso's current under-5 mortality rate is estimated 110 per 1,000 live births. Similar to other countries in the region, the major causes of child mortality in Burkina Faso are malaria, respiratory tract infection, and diarrhea. Malnutrition acts as a major underlying contributor to mortality. Interventions that address these underlying causes may be particularly efficacious for reducing mortality. Younger children at are at a higher risk of mortality. Approximately 2/3rd of under-5 deaths occur during the first year of life. In general, the child mortality rate decreases as age increases. While some improvement has been observed, neonatal mortality is declining at a slower rate than post-neonatal childhood mortality. Many child health interventions are designed specifically for children over 6 months of age, such as vitamin A supplementation, seasonal malaria chemoprevention, and lipid-based nutritional supplementation. Identification of strategies that are safe and effective for the youngest children will be required to address persistently high rates of neonatal and infant mortality. The MORDOR I study demonstrated a significant reduction in all-cause child mortality following biannual mass azithromycin distribution. Across three diverse geographic locations in sub-Saharan Africa (Malawi, Niger, and Tanzania), biannual mass azithromycin distribution over a two-year period led to a 14% decrease in all-cause child mortality. In Niger, 1 in 5-6 deaths were averted. These results are qualitatively similar to those of a previous study of mass azithromycin distribution for trachoma control in Ethiopia, which found reduced odds of all-cause mortality in children in communities receiving mass azithromycin compared to control communities. In MORDOR I, the strongest effect of azithromycin was in the youngest cohort of children. Across all three countries, the strongest effect of azithromycin was consistently in children 1-5 months of age, with an approximately 25% reduction in all-cause mortality. However, MORDOR I was not optimized to target the youngest age groups. Although children as young as 1 month were eligible, biannual distributions might not reach some children until 7 months of age. On average, children were first treated at 4 months. Given that there may be a substantial benefit to treating children at younger ages, azithromycin strategies that are designed to target younger age groups may be even more beneficial for reducing child mortality. Here, we propose a randomized controlled trial designed to evaluate the efficacy of mass and targeted azithromycin strategies for child mortality. In the rural northwestern district of Nouna in Burkina Faso, we propose to randomize villages to biannual mass azithromycin distribution or placebo. This study was designed by CRSN and UCSF partners to confirm the results of MORDOR I, evaluate an alternative health systems distribution point (the vaccine visit) for delivery of azithromycin to young children, and to provide a platform for evaluation of potential mechanisms behind the effect of azithromycin by collecting and processing additional specimens and tests. Objectives: Determine the efficacy of biannual mass azithromycin distribution versus placebo in children aged 1-59 months for reduction in all-cause mortality. Determine the efficacy of targeted azithromycin distribution to infants during an early infant healthcare visit (approximately 5th through 12th week of life) on infant mortality. Determine the mechanism behind the effect of biannual mass azithromycin distribution for reduction in child mortality. Study Design: CRSN and UCSF (hereafter, we) will assess childhood mortality over three years, comparing communities where children aged 1-59 months receive biannual oral azithromycin and/or targeted azithromycin during the 5th-12th week of life in conjunction with the first Expanded Programme on Immunization (EPI) vaccine visit or biannual placebo and targeted placebo. All eligible communities in Nouna District will be randomized (278 communities). A random sample of 48 (12/arm) communities from within the HDSS will be selected to participate in the Mortality Plus study, which will entail an annual morbidity exam among 15 randomly selected children per community to monitor infectious disease morbidity, nutritional status, and macrolide resistance. All communities will contribute to the mortality outcome.

Official Title
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Community Health Azithromycin Trial in Burkina Faso

Conditions
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Childhood Mortality

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Communities: Inclusion Criteria: The community location in target district. The community leader consents to participation in the trial (this does not obviate the need for individual consent, but without overall leadership consent, the community as a whole cannot be part of the trial). Eligible communities estimated population of between 200-2,000 people The community is not in an urban area Exclusion criteria: - Refusal of village chief Individuals: Inclusion Criteria All children in the study communities aged 5 to 12 weeks old at the time of the vaccination visit are eligible to participate Ability to feed orally Appropriate consent from at least one caregiver Family intends to stay within the study area Exclusion Criteria: Individuals allergic to macrolides or azalides will not be given the study antibiotic azithromycin, but will be included in the outcome Refusal of parent or guardian Child unable to orally feed Family planning to move Children younger than 28 days old or older than 12 weeks Children in the bi annual drug administration group who weight less than 3.8kg.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: All eligible communities in Nouna District will be randomized in a 1:1 fashion to biannual azithromycin or placebo. Targeted treatment (vaccine visit) will be randomized 1:1 individually to azithromycin or placebo. Randomization will be conducted by T. Porco. Procedural and algorithmic details are provided in an appendix to the Statistical Analysis Plan.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Biannual mass oral azithromycin<br>Bi-annual Mass Azithromycin distribution to all children 1-60 months old in participating communities | Drug: Azithromycin<br>* biannual azithromycin in eligible communities to children 1 to 59 months old Targeted azithromycin to children aged 5 to 8 weeks old at the vaccine visit<br>|
| Placebo Comparator: Biannual mass oral placebo<br>Bi-annual Mass Placebo distribution to all children 1-60 months old in participating communities | Drug: Azithromycin<br>* biannual azithromycin in eligible communities to children 1 to 59 months old Targeted azithromycin to children aged 5 to 8 weeks old at the vaccine visit<br>Drug: Placebos<br>* biannual placebo in eligible communities to children 1 to 59 months old Targeted placebo to children aged 5 to 8 weeks old at the vaccine visit<br>|
| Placebo Comparator: Targeted oral placebo<br>Targeted placebo to children 5 to 12 weeks old at vaccine visit or other healthy child visit | Drug: Placebos<br>* biannual placebo in eligible communities to children 1 to 59 months old Targeted placebo to children aged 5 to 8 weeks old at the vaccine visit<br>|
| Active Comparator: Targeted oral azithromycin<br>Targeted azithromycin to children 5 to 12 weeks old at vaccine visit or other healthy child visit | Drug: Azithromycin<br>* biannual azithromycin in eligible communities to children 1 to 59 months old Targeted azithromycin to children aged 5 to 8 weeks old at the vaccine visit<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality Rate in children aged 1-59 months | All-cause mortality as determined by biannual census among children aged 1-59 months | 36 months | 
| All-cause Mortality Rate in individually randomized children at 4-12 weeks of age | All-cause mortality as determined by a follow-up visit for individually randomized children at healthy child visits | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight-for-height Z-score in individually randomized children at healthy child visits |  | 6 months | 
| Height-for-age Z-score in individually randomized children at healthy child visits |  | 6 months | 
| Mid-upper arm circumference in individually randomized children at healthy child visits |  | 6 months | 
| Linear growth in individually randomized children | Change in length from baseline to 6 months | 6 months | 
| Weight gain in individually randomized children | Change in weight from baseline to 6 months | 6 months | 
| Malaria parasitemia in children 1-59 months at 36 months | Malaria parasitemia as measured by thin and thick smears in a random sample of children at 36 months | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Childhood mortality, Azithromycin, Mass treatment, Vaccine Visit targeted treatment