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

Study Overview
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Brief Summary
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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
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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 1150 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 1150 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: Infant age at the time of MDA (1-5 months vs 6-11 months) Infant weight-for-age at the time of MDA Infant sex Season of MDA dosing and time since the last SMC Cluster level coverage of SMC Cluster level baseline mortality (established at first census) Cluster and individual level coverage and number of administered azithromycin MDA doses District of residence Distance from the nearest health facility Household asset or income index Household WASH index 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).

Official Title
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LAKANA , a Cluster-randomized, Double-blinded, Parallel Group, Controlled Trial, Testing the Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Rural Mali.

Conditions
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Mortality

Intervention / Treatment
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* Drug: Placebo
* Drug: Azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: On a cluster (village) level: Location within Kayes, Kita, or Koulikoro region of Mali Considered accessible and safe by the local health authorities and research team Considered non-urban by the local health authorities and research team Permission from community leadership On a household level (for trial enrollment): Location within a cluster that is included in the study Verbal consent from a head of household or an adult authorized by her / him On a child level (for receiving study medication): Residence in a household enrolled in the trial Age between 29 and 364 days Verbal consent from at least one caregiver Exclusion Criteria: On child level (for not receiving study medication): Weight below 3.0 kg 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.

Ages Eligible for Study
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Minimum Age: 29 Days
Maximum Age: 364 Days

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age: Single-dose of 0.5 ml / kg child weight 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. | Drug: Placebo<br>* Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age. Weight-based dosing will be used: single-dose of 0.5 ml / kg child weight.<br>|
| Active Comparator: Azithromycin-biannually (Azi-biannual)<br>Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age: Single-dose of 0.5 ml / kg child weight 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. 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. | Drug: Placebo<br>* Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age. Weight-based dosing will be used: single-dose of 0.5 ml / kg child weight.<br>Drug: Azithromycin<br>* Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age. Weight-based dosing will be used: single-dose of 0.5 ml (20 mg) / kg child weight.<br>|
| Active Comparator: Azithromycin-quarterly<br>Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age: Single-dose of 0.5 ml (20 mg) / kg child weight. 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. | Drug: Azithromycin<br>* Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age. Weight-based dosing will be used: single-dose of 0.5 ml (20 mg) / kg child weight.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morbidity | 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. | 3-month time interval (total of 8 intervals per cluster) | 
| Length-for-age Z-score | 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, and 21 months after the enrollment of the village into the trial. Length-for-age Z-score will be calculated using the WHO Child Growth Standards. | 3-month time interval (total of 3 intervals per cluster) | 
| Weight-for age Z-score | 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, and 21 months after the enrollment of the village into the trial. Weight-for-age Z-score will be calculated using the WHO Child Growth Standards. | 3-month time interval (total of 3 intervals per cluster) | 
| Weight-for-length Z-score | 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, and 21 months after the enrollment of the village into the trial. Weight-for-length Z score will be calculated using the WHO Child Growth Standards. | 3-month time interval (total of 3 intervals per cluster) | 
| Mid-upper arm circumference | 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, and 21 months after the enrollment of the village into the trial. | 3-month time interval (total of 3 intervals per cluster) | 
| Percentage of moderate or severe stunting | 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. | 3-month time interval (total of 3 intervals per cluster) | 
| Percentage of moderate or severe wasting | 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. | 3-month time interval (total of 3 intervals per cluster) | 
| Prevalence of phenotypic and genotypic macrolide resistance | Prevalence of phenotypic and genotypic macrolide resistance among E. coli strains isolated from stool samples or S. pneumoniae strains isolated from nasopharyngeal swabs among among 4-14-month-old children, at one year after the MDA intervention has stopped (i.e., 36 months after MDA 1, the baseline). Genetic markers of azithromycin and other antibiotic resistance (resistome) of intestinal microbiota among 4-14-month-old children, at one year after the MDA intervention has stopped (i.e., 36 months after MDA 1, the baseline). (secondary outcome sample). | 12-month time interval (total of 3 intervals per cluster) | 
| Prevalence of phenotypic and genotypic macrolide resistance | Prevalence of phenotypic and genotypic macrolide resistance among E. coli strains isolated from stool samples or S. pneumoniae strains isolated from nasopharyngeal swabs among 49-59-month-old children, at 24 months after village enrolment to the trial, i.e., after 8 rounds of MDA. (secondary outcome sample). | 12-month time interval (total of 3 intervals per cluster) | 
| Prevalence of phenotypic and genotypic AMR resistance to other ACCESS group antibiotics | 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). | 12-month time interval (total of 3 intervals per cluster) | 
| Blood C-reactive protein concentration | 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). | Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment. | 
| Blood malaria parasitemia and hemoglobin concentration | 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). | Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment. | 
| Fecal neopterin, myeloperoxidase, and alpha-1-antitrypsin concentrations | Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on intestinal inflammation (secondary outcome sample). | Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment. | 
| Incidence of Adverse events | 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). | 3-month time interval | 
| Incidence of Serious Adverse events | 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. | within 14 days after MDA round. | 
| Mortality in children aged 12-59 month | 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. | 3-month time interval (total of 8 intervals per cluster) | 
| Percentage of guardians and health care workers reporting MDA acceptable | Data collected through interviews of guardians and health care workers to assess acceptability of MDA. | 24 months after enrollment | 
| Percentage of the study population reached with MDA | Data collected on MDA distribution and through interviews of guardians and health care workers to assess equity of MDA. | 24 months after enrollment | 
| Cost and Cost-effectiveness of the intervention | 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). | 24 months after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mass Drug Administration, Azithromycin, Infant and Child Mortality, Infant and Child health, Infant and Child growth, Infant and Child morbidity, Antimicrobial Resistance, Feasibility, Acceptability, Safety, Cost, Inflammation, Infection