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

NCT ID: NCT04424511

Last Updated: 2025-05-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 149201 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-15
• Study Completion Date: 2024-12-31

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).

Conditions

Mortality

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Control

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Azithromycin-biannually (Azi-biannual)

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.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Azithromycin

Intervention Type: DRUG

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.

Azithromycin-quarterly

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.

Group Type: ACTIVE_COMPARATOR

Azithromycin

Intervention Type: DRUG

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.

Interventions

Placebo

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.

Intervention Type: DRUG

Azithromycin

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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 29 Days
• Maximum Eligible Age: 364 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Center for Vaccine Development CVD-Mali, Bamako, Mali

UNKNOWN

Sponsor Role: collaborator

University College London Hospitals

OTHER

Sponsor Role: collaborator

Tro Da Ltd, UK

UNKNOWN

Sponsor Role: collaborator

Duke-NUS Graduate Medical School

OTHER

Sponsor Role: collaborator

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

Pfizer Inc. (Provider of study drugs)

UNKNOWN

Sponsor Role: collaborator

Tampere University

OTHER

Sponsor Role: lead

Responsible Party

Per Ashorn

MD, PhD, Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Per Ashorn, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Center for Child Health Research, Tampere University

Ulla Ashorn, PhD

Role: PRINCIPAL_INVESTIGATOR

Center for Child Health Research, Tampere University

Samba Sow, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

Center for Vaccine Development CVD-Mali

Nigel Klein, MBBS, PhD

Role: PRINCIPAL_INVESTIGATOR

University College London Hospitals

Camilla Ducker, MBBS, MSc

Role: PRINCIPAL_INVESTIGATOR

Tro Da Ltd, UK

Yin Bun Cheung, PhD

Role: PRINCIPAL_INVESTIGATOR

Centre for Quantitative Medicine, Duke-NUS Medical School

Dagmar Alber, PhD

Role: PRINCIPAL_INVESTIGATOR

University College London Hospitals

Locations

Center for Vaccine Development CVD-Mali

Bamako, , Mali

Countries

Mali

References

Haidara FC, Adubra L, Abdou M, Alber D, Ashorn U, Cheung YB, Cloutman-Green E, Diallo M, Ducker C, Fan YM, Gruffudd G, Hallamaa L, Haapaniemi T, Ihamuotila R, Juma J, Klein N, Luoma J, Martell O, Murugesan A, Okello C, Samake O, Traore CAT, Vehmasto T, Ylikruuvi K, Sow S, Ashorn P. Mass Administration of Azithromycin to Infants in Mali to Reduce Mortality. N Engl J Med. 2025 Oct 16;393(15):1498-1508. doi: 10.1056/NEJMoa2504644.

Reference Type: DERIVED

PMID: 41092331 (View on PubMed)

Luoma J, Adubra L, Alber D, Ashorn P, Ashorn U, Cloutman-Green E, Diallo F, Ducker C, Elovainio R, Fan YM, Gates L, Gruffudd G, Haapaniemi T, Haidara F, Hallamaa L, Ihamuotila R, Klein N, Martell O, Sow S, Vehmasto T, Cheung YB. Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1-11-month-old infants in Mali. Trials. 2023 Nov 15;24(1):733. doi: 10.1186/s13063-023-07771-6.

Reference Type: DERIVED

PMID: 37968741 (View on PubMed)

Adubra L, Alber D, Ashorn P, Ashorn U, Cheung YB, Cloutman-Green E, Diallo F, Ducker C, Elovainio R, Fan YM, Gates L, Gruffudd G, Haapaniemi T, Haidara F, Hallamaa L, Ihamuotila R, Klein N, Luoma J, Martell O, Sow S, Vehmasto T; LAKANA Trial Team. Testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1-11-month-old infants in Mali (LAKANA): study protocol for a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial. Trials. 2023 Jan 3;24(1):5. doi: 10.1186/s13063-022-06966-7.

Reference Type: DERIVED

PMID: 36597115 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

https://lakana.org/

The study website providing access to essential study materials, including the study protocol, Statistical Analysis Plan (SAP), Standard Operating Procedures (SOPs), and Data Collection Forms (DCFs).

Other Identifiers

INV-003354

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

LAKANA trial

Identifier Type: -

Identifier Source: org_study_id