Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Mali

Phase 3

Completed

• Conditions: Mortality
• Interventions: Drug: Placebo; Drug: Azithromycin

• Registration Number: NCT04424511
• Lead Sponsor: Tampere University

Brief Summary

The LAKANA trial will assess the impact on mortality and other health outcomes of quarterly and biannual azithromycin mass drug administration (MDA) when delivered to 1-11-month (29-364 days) old infants in a high-mortality setting where malaria is holoendemic but there is also a functioning seasonal malaria chemoprevention (SMC) program in place. The long-term goal is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood mortality, and to determine the most effective treatment regimen. The main study hypotheses in terms of mortality effect are: i) Biannual azithromycin MDA to 1-11 month old infants reduces their mortality, ii) Quarterly azithromycin MDA to 1-11 month old infants reduces their mortality, iii) Quarterly azithromycin MDA has a bigger mortality effect than biannual MDA.

Detailed Description

Mass drug administration (MDA) of azithromycin has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. Because of the observed heterogeneity and possible effect modification by SMC or other co-interventions, further trials in new settings are needed in order to make evidence-based public health recommendations about the use of this treatment. The objectives of the LAKANA trial are:

* To evaluate the impact of two azithromycin MDA regimens on infant mortality and other health outcomes, when provided in a rural West-African high-mortality context with an ongoing seasonal malaria chemoprevention program.

* To evaluate the effect of alternative MDA frequencies on antimicrobial resistance (AMR) and host microbiota composition.

* To test hypotheses that azithromycin MDA eliminates malaria parasitaemia and reduces systemic and intestinal inflammation in asymptomatic children and to collect and store biological samples for assessing other possible mechanisms of azithromycin effect.

* To investigate the feasibility of alternative azithromycin MDA strategies, including economic analysis.

The LAKANA trial will be conducted in 1151 villages from 7-10 health districts in the Kayes, Kita and Koulikoro regions of Mali. LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design. Participating villages will be randomly allocated to three different intervention groups in a ratio of 3 : 2 : 4 (control : azithromycin quarterly : azithromycin biannually). Within each participating village, consenting households will be visited quarterly (at 3-month intervals), nine times. At the first eight of these visits, 1-11-month-old eligible infants (age 29-364 days), for whom there is a consent for study drug provision, will be given a single dose of study drug (azithromycin mixture or respective placebo mixture).

Mortality and serious adverse events (SAEs) data will be collected, and mortality-related questions answered using data from all the included 1151 villages. Mixed-effect Poisson regression model will be used to estimate the intervention effects on mortality, with random intercepts for the clusters. The investigators will explore effect modification by testing for interaction between the MDA intervention and the following variables:

* Age at the time of the MDA

* Sex of the child

* Weight-for-age

* Seasonality: rainy season vs non-rainy season at the time of the MDA

* SMC given to the child within 3 months before an MDA

* Order of MDA in the village

* District of residence

* Distance from the nearest health facility (in km)

* Household asset index

* Water, Sanitation, and Hygiene (WASH) index

* National outreach strategy category (standard/advanced)

The investigators will address the other study questions using a smaller separate secondary sample of 59 villages located around four selected health centers close to the city of Kita and a similar number of villages closer to Bamako, i.e. in Koulikoro or Kati (tertiary sample).

Study Timeline

• Study First Submitted: 2020-05-22
• Study First Submitted QC: 2020-06-05
• Study First Posted: 2020-06-11
• Study Start: 2020-10-15
• Primary Completion: 2024-12-31
• Study Completion: 2024-12-31
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-20
• Last Update Posted: 2025-05-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 149201

Inclusion Criteria

On a cluster (village) level:

1. Location within Kayes, Kita, or Koulikoro region of Mali
2. Considered accessible and safe by the local health authorities and research team
3. Considered non-urban by the local health authorities and research team
4. Permission from community leadership

On a household level (for trial enrollment):

1. Location within a cluster that is included in the study
2. Verbal consent from a head of household or an adult authorized by her / him

On a child level (for receiving study medication):

1. Residence in a household enrolled in the trial
2. Age between 29 and 364 days
3. Verbal consent from at least one caregiver

Exclusion Criteria

On child level (for not receiving study medication):

1. Weight below 3.0 kg
2. Known allergy to macrolides, as judged by a caregiver report of the infant experiencing an adverse reaction after oral ingestion of medication, which was deemed likely to be a macrolide by the interviewing data collector.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Placebo	Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age: 1. Single-dose of 0.5 ml / kg child weight 2. Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of placebo mixture.
Azithromycin-biannually (Azi-biannual)	Placebo	Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age: 1. Single-dose of 0.5 ml / kg child weight 2. Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of study drug. 3. Azithromycin will be given at quarterly visits between January and June, and Placebo mixture will be given at quarterly visits between July and December. Azithromycin dose will be 20 mg / kg.
Azithromycin-quarterly	Azithromycin	Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age: 1. Single-dose of 0.5 ml (20 mg) / kg child weight. 2. Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of azithromycin.
Azithromycin-biannually (Azi-biannual)	Azithromycin	Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age: 1. Single-dose of 0.5 ml / kg child weight 2. Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of study drug. 3. Azithromycin will be given at quarterly visits between January and June, and Placebo mixture will be given at quarterly visits between July and December. Azithromycin dose will be 20 mg / kg.

Primary Outcome Measures

Name	Time	Method
Mortality	3-month time interval (total of 8 intervals per cluster)	Mortality rate (deaths per 1,000 years at risk) among children 1-11 months of age.

Secondary Outcome Measures

Name	Time	Method
Morbidity	3-month time interval (total of 8 intervals per cluster)	Morbidity (14-day period prevalence of fever with respiratory symptoms (ARI), fever without respiratory symptoms (malaria), and diarrhea) in children aged 4-14 months assessed in each participating cluster (village) from the secondary outcome sample.
Length-for-age Z-score	3-month time interval (total of 3 intervals per cluster)	Length-for-age Z-score in 6-8 and 12-14 months old children from the secondary outcome sample. Length measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial. Length-for-age Z-score will be calculated using the WHO Child Growth Standards.
Length	3-month time interval (total of 3 intervals per cluster)	Attained length in cm in 6-8 and 12-14 months old children from the secondary outcome sample. Length measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial.
Weight	3-month time interval (total of 3 intervals per cluster)	Attained weight in grams in 6-8 and 12-14 months old children from the secondary outcome sample. Weight measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial.
Weight-for age Z-score	3-month time interval (total of 3 intervals per cluster)	Weight-for age Z-score in 6-8 and 12-14 months old children from the secondary outcome sample. Weight measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial. Weight-for-age Z-score will be calculated using the WHO Child Growth Standards.
Weight-for-length Z-score	3-month time interval (total of 3 intervals per cluster)	Weight-for-length Z-score in 6-8 and 12-14 months old children from the secondary outcome sample. Length and weight measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial. Weight-for-length Z score will be calculated using the WHO Child Growth Standards.
Mid-upper arm circumference	3-month time interval (total of 3 intervals per cluster)	Mid-upper arm circumference in 6-8 and 12-14 months old children from the secondary outcome sample. Measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial.
Percentage of moderate or severe stunting	3-month time interval (total of 3 intervals per cluster)	Percentage of moderate or severe stunting (length-for-age Z-score \< -2 / -3) in 6-8 and 12-14 months old children from the secondary outcome sample.
Percentage of moderate or severe wasting	3-month time interval (total of 3 intervals per cluster)	Percentage of moderate or severe wasting (Weight-for-length Z-score \< -2 / -3) in 6-8 and 12-14 months old children from the secondary outcome sample.
Percentage of moderate or severe Underweight	3-month time interval (total of 3 intervals per cluster)	Percentage of moderate or severe Underweight (Weight-for-age Z-score \< -2 / -3) in 6-8 and 12-14 months old children from the secondary outcome sample.
Prevalence of phenotypic and genotypic macrolide resistance	12-month time interval (total of 3 intervals per cluster)	prevalence of phenotypic azithromycin resistance among S. pneumoniae or E. coli strains isolated from 24-35-month-old children, who have received 1-4 rounds of azithromycin MDA 1 year before and who live in a village that continued azithromycin MDA
Prevalence of phenotypic and genotypic AMR resistance to other "ACCESS" group antibiotics	12-month time interval (total of 3 intervals per cluster)	Prevalence of phenotypic and genotypic AMR against other antibiotics categorised by the World Health Organization (WHO) into "ACCESS" group, among azithromycin-resistant E. coli strains isolated from stool samples or azithromycin-resistant S. pneumoniae strains isolated from nasopharyngeal swabs (secondary outcome sample).
Blood C-reactive protein concentration	Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.	Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on systemic inflammation (blood C-reactive protein concentration) (secondary outcome sample).
Blood malaria parasitemia and hemoglobin concentration	Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.	Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on malaria prevalence and blood hemoglobin concentration (secondary outcome sample).
Fecal neopterin, myeloperoxidase, and alpha-1-antitrypsin concentrations	Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.	Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on intestinal inflammation and function (secondary outcome sample).
Incidence of Adverse events	3-month time interval	Incidence of adverse events within 14 days of study drug administration. Data collected from 4-11 months old infants at 9 months after enrollment (secondary outcome sample).
Incidence of Serious Adverse events	within 14 days after MDA round.	Incidence of serious adverse events (Death, life-threatening event, hospitalization, and other serious events as judged by a study physician) within 14 days of study drug administration, among 1-11 months old infants.
Mortality in children aged 12-59 month	3-month time interval (total of 8 intervals per cluster)	Mortality rate (deaths per 1000 years at risk) among children who were 12-59 month old when the latest azithromycin MDA took place in their village of residence.
Percentage of guardians and health care workers reporting MDA acceptable	24 months after enrollment	Data collected through interviews of guardians and health care workers to assess acceptability of MDA.
Percentage of the study population reached with MDA	24 months after enrollment	Data collected on MDA distribution and through interviews of guardians and health care workers to assess equity of MDA.
Cost and Cost-effectiveness of the intervention	24 months after enrollment	Data collected on MDA distribution to assess the economic aspects of MDA.The effectiveness will be determined by the trial outcome - both the primary outcome of mortality and the secondary outcomes of morbidity and possible AMR effects. The effectiveness will be expressed in different units such as deaths averted, or disability adjusted life years (DALYs).

Trial Locations

Locations (1)

Center for Vaccine Development CVD-Mali; 🇲🇱 Bamako, Mali