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

Tampere University

Status and phase: Active, not recruiting; Phase 3

Conditions: Mortality

Treatments: Drug: Azithromycin; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT04424511

LAKANA trial

INV-003354 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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 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:

1. Infant age at the time of MDA (1-5 months vs 6-11 months)
2. Infant weight-for-age, length-for-age, weight-for-length at the time of MDA
3. Infant sex
4. Season of MDA dosing (malaria versus non malaria season) and SMC implementation in village (SMC given versus SMC not given)
5. Cluster level coverage of SMC
6. Cluster level baseline mortality (established at first census)
7. Cluster and individual level coverage and number of administered azithromycin MDA doses
8. District of residence
9. Distance from the nearest health facility
10. Household asset or income index
11. Household WASH index
12. National outreach strategy category (standard/advanced)
13. Hard-to-reach village status assessed by the field workers

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).

Enrollment: 100,000 estimated patients

Sex: All

Ages: 29 to 364 days old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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100,000 participants in 3 patient groups, including a placebo group

Control

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Azithromycin-biannually (Azi-biannual)

Active Comparator group

Description:

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.

Treatment:

Drug: Azithromycin

Drug: Placebo

Azithromycin-quarterly

Active Comparator group

Description:

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.

Treatment:

Drug: Azithromycin