Clinical trial NCT03676764: Community Health Azithromycin Trial in Burkina Faso
Official title: Community Health Azithromycin Trial in Burkina Faso
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Childhood Mortality
Keywords: Childhood mortality
Azithromycin
Mass treatment
Vaccine Visit targeted treatment
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Centre de Recherche en Sante de Nouna, Burkina Faso
name: Bill and Melinda Gates Foundation
First posted: 2018-09-19
Enrollment: 77664
Sex: ALL
Minimum age (years): 1
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

Brief summary: 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:

1. Determine the efficacy of biannual mass azithromycin distribution versus placebo in children aged 1-59 months for reduction in all-cause mortality.
2. 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.
3. 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: 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:

1. Determine the efficacy of biannual mass azithromycin distribution versus placebo in children aged 1-59 months for reduction in all-cause mortality.
2. 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.
3. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: All-cause Mortality Rate in Children Aged 1-59 Months
timeFrame: 36 months
measure: All-cause Mortality Rate in Individually Randomized Children at 4-12 Weeks of Age
timeFrame: 6 months
Secondary outcomes:
measure: Malaria Parasitemia in Children 1-59 Months at 36 Months
timeFrame: 36 months
measure: Weight-for-height Z-score in Individually Randomized Children at Healthy Child Visits
timeFrame: 6 months
measure: Height-for-age Z-score in Individually Randomized Children at Healthy Child Visits
timeFrame: 6 months
measure: Mid-upper Arm Circumference in Individually Randomized Children at Healthy Child Visits
timeFrame: 6 months
measure: Linear Growth in Individually Randomized Children
timeFrame: 6 months
measure: Weight Gain in Individually Randomized Children
timeFrame: 6 months
Other outcomes:
Locations:
city: Nouna
country: Burkina Faso
facility: Centre de Recherche en Sante de Nouna
Study officials:
affiliation: University of California, San Francisco
name: Catherine E Oldenburg, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Tom M Lietman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre de Recherche en Sante de Nouna, Burkina Faso
name: Ali Sie, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sie A, Ouattara M, Bountogo M, Bagagnan C, Coulibaly B, Boudo V, Lebas E, Brogdon JM, Lin Y, Barnighausen T, Porco TC, Doan T, Lietman TM, Oldenburg CE; Etude CHAT Study Group. A double-masked placebo-controlled trial of azithromycin to prevent child mortality in Burkina Faso, West Africa: Community Health with Azithromycin Trial (CHAT) study protocol. Trials. 2019 Dec 4;20(1):675. doi: 10.1186/s13063-019-3855-9.