|Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Mali
|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.
|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 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.
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, acceptability and equity of alternative MDA strategies.
The LAKANA trial will be conducted in 830 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 data will be collected, and mortality-related questions primarily answered using data from approximately 770 villages (clusters) (primary outcome sample). 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 60 villages located around four selected health centers close to the city of Kita and 20 villages around two health facilities in Koulikoro.
Intervention Model: Parallel Assignment
Intervention Model Description:
LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design.Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
The investigators will utilize a matching placebo to mask study arm allocation. All children aged 1-11 months in all study communities will be offered biannual or quarterly azithromycin or placebo distribution in an identical fashion. Placebo will be identical to azithromycin in appearance, taste, odor, and packaging. The interventions will be coded only with a letter code.Primary Purpose: Treatment
- Drug: 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.
- 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.
|Same as current|
|December 2022 (Final data collection date for primary outcome measure)
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
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.
|Sexes Eligible for Study:||All|
|up to 364 Days (Child)
INV-003354 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
|Studies a U.S. FDA-regulated Drug Product: ||No|
|Studies a U.S. FDA-regulated Device Product: ||No|
|Product Manufactured in and Exported from the U.S.: ||No|
|Plan to Share IPD:||Yes|
|Plan Description:||Individual participant data collected during the trial, after deidentification. (The details are to be determined).|
|Supporting Materials:||Study Protocol|
|Supporting Materials:||Statistical Analysis Plan (SAP)|
|Supporting Materials:||Informed Consent Form (ICF)|
|Supporting Materials:||Clinical Study Report (CSR)|
|Time Frame:||Starting 6 months after publication|
|Access Criteria:||(The details are to be determined)|
|Per Ashorn, Tampere University
- Center for Vaccine Development CVD-Mali, Bamako, Mali
- University College London, UK.
- Tro Da Ltd, UK
- Duke-NUS Graduate Medical School
- Bill and Melinda Gates Foundation (Funder)
- Pfizer Inc. (Provider of study drugs)
|Principal Investigator:||Per Ashorn, MD, PhD||Center for Child Health Research, Tampere University|
|Principal Investigator:||Ulla Ashorn, PhD||Center for Child Health Research, Tampere University|
|Principal Investigator:||Samba Sow, MD, MSc||Center for Vaccine Development CVD-Mali|
|Principal Investigator:||Nigel Klein, MBBS, PhD||University College London, UK.|
|Principal Investigator:||Camilla Ducker, MBBS, MSc||Tro Da Ltd, UK|
|Principal Investigator:||Yin Bun Cheung, PhD||Centre for Quantitative Medicine, Duke-NUS Medical School|