Clinical trial NCT04424511: Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Mali
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Mortality
Keywords: 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
Lead sponsor: Tampere University
Sponsor class: OTHER
Collaborators: name: Center for Vaccine Development CVD-Mali, Bamako, Mali
name: University College London Hospitals
name: Tro Da Ltd, UK
name: Duke-NUS Graduate Medical School
name: Bill and Melinda Gates Foundation (Funder)
name: Pfizer Inc. (Provider of study drugs)
First posted: 2020-06-11
Enrollment: 149201
Sex: ALL
Minimum age (years): 29
Maximum age (years): 364
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design.
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Mortality
timeFrame: 3-month time interval (total of 8 intervals per cluster)
Secondary outcomes:
measure: Morbidity
timeFrame: 3-month time interval (total of 8 intervals per cluster)
measure: Length-for-age Z-score
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Length
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Weight
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Weight-for age Z-score
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Weight-for-length Z-score
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Mid-upper arm circumference
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Percentage of moderate or severe stunting
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Percentage of moderate or severe wasting
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Percentage of moderate or severe Underweight
timeFrame: 3-month time interval (total of 3 intervals per cluster)
measure: Prevalence of phenotypic and genotypic macrolide resistance
timeFrame: 12-month time interval (total of 3 intervals per cluster)
measure: Prevalence of phenotypic and genotypic macrolide resistance
timeFrame: 12-month time interval (total of 3 intervals per cluster)
measure: Prevalence of phenotypic and genotypic macrolide resistance
timeFrame: 12-month time interval (total of 3 intervals per cluster)
measure: Prevalence of phenotypic and genotypic macrolide resistance
timeFrame: 12-month time interval (total of 3 intervals per cluster)
measure: Prevalence of phenotypic and genotypic AMR resistance to other "ACCESS" group antibiotics
timeFrame: 12-month time interval (total of 3 intervals per cluster)
measure: Blood C-reactive protein concentration
timeFrame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.
measure: Blood malaria parasitemia and hemoglobin concentration
timeFrame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.
measure: Fecal neopterin, myeloperoxidase, and alpha-1-antitrypsin concentrations
timeFrame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.
measure: Incidence of Adverse events
timeFrame: 3-month time interval
measure: Incidence of Serious Adverse events
timeFrame: within 14 days after MDA round.
measure: Mortality in children aged 12-59 month
timeFrame: 3-month time interval (total of 8 intervals per cluster)
measure: Percentage of guardians and health care workers reporting MDA acceptable
timeFrame: 24 months after enrollment
measure: Percentage of the study population reached with MDA
timeFrame: 24 months after enrollment
measure: Cost and Cost-effectiveness of the intervention
timeFrame: 24 months after enrollment
Other outcomes:
Locations:
city: Bamako
country: Mali
facility: Center for Vaccine Development CVD-Mali
Study officials:
affiliation: Center for Child Health Research, Tampere University
name: Per Ashorn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for Child Health Research, Tampere University
name: Ulla Ashorn, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for Vaccine Development CVD-Mali
name: Samba Sow, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University College London Hospitals
name: Nigel Klein, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tro Da Ltd, UK
name: Camilla Ducker, MBBS, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre for Quantitative Medicine, Duke-NUS Medical School
name: Yin Bun Cheung, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University College London Hospitals
name: Dagmar Alber, PhD
role: PRINCIPAL_INVESTIGATOR
References: