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

• ClinicalTrials.gov Identifier: NCT04424511
• Recruitment Status: Recruiting
• First Posted: June 11, 2020
• Last Update Posted: October 6, 2022
• Sponsor: Tampere University
• Collaborators: Center for Vaccine Development CVD-Mali, Bamako, Mali; University College London Hospitals; Tro Da Ltd, UK; Duke-NUS Graduate Medical School; Bill and Melinda Gates Foundation (Funder); Pfizer Inc. (Provider of study drugs)
• Information provided by (Responsible Party): Per Ashorn, Tampere University

Tracking Information

• First Submitted Date: May 22, 2020
• First Posted Date: June 11, 2020
• Last Update Posted Date: October 6, 2022
• Actual Study Start Date: October 15, 2020
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 5, 2020)

Mortality [ Time Frame: 3-month time interval (total of 8 intervals per cluster) ]

Mortality rate (deaths per 1,000 years at risk) among children 1-11 months of age.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 4, 2022)

• Morbidity [ Time Frame: 3-month time interval (total of 8 intervals per cluster) ]
  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.
• Length-for-age Z-score [ Time Frame: 3-month time interval (total of 3 intervals per cluster) ]
  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.
• Weight-for age Z-score [ Time Frame: 3-month time interval (total of 3 intervals per cluster) ]
  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.
• Weight-for-length Z-score [ Time Frame: 3-month time interval (total of 3 intervals per cluster) ]
  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.
• Mid-upper arm circumference [ Time Frame: 3-month time interval (total of 3 intervals per cluster) ]
  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.
• Percentage of moderate or severe stunting [ Time Frame: 3-month time interval (total of 3 intervals per cluster) ]
  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.
• Percentage of moderate or severe wasting [ Time Frame: 3-month time interval (total of 3 intervals per cluster) ]
  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.
• Prevalence of phenotypic and genotypic macrolide resistance [ Time Frame: 12-month time interval (total of 3 intervals per cluster) ]
  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).
• Prevalence of phenotypic and genotypic macrolide resistance [ Time Frame: 12-month time interval (total of 3 intervals per cluster) ]
  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).
• Prevalence of phenotypic and genotypic AMR resistance to other "ACCESS" group antibiotics [ Time Frame: 12-month time interval (total of 3 intervals per cluster) ]
  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).
• Blood C-reactive protein concentration [ Time Frame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment. ]
  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).
• Blood malaria parasitemia and hemoglobin concentration [ Time Frame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment. ]
  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).
• Fecal neopterin, myeloperoxidase, and alpha-1-antitrypsin concentrations [ Time Frame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment. ]
  Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on intestinal inflammation (secondary outcome sample).
• Incidence of Adverse events [ Time Frame: 3-month time interval ]
  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).
• Incidence of Serious Adverse events [ Time Frame: within 14 days after MDA round. ]
  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.
• Mortality in children aged 12-59 month [ Time Frame: 3-month time interval (total of 8 intervals per cluster) ]
  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.
• Percentage of guardians and health care workers reporting MDA acceptable [ Time Frame: 24 months after enrollment ]
  Data collected through interviews of guardians and health care workers to assess acceptability of MDA.
• Percentage of the study population reached with MDA [ Time Frame: 24 months after enrollment ]
  Data collected on MDA distribution and through interviews of guardians and health care workers to assess equity of MDA.
• Cost and Cost-effectiveness of the intervention [ Time Frame: 24 months after enrollment ]
  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).

Original Secondary Outcome Measures (submitted: June 5, 2020)

• Morbidity [ Time Frame: 3-month time interval (total of 9 intervals per cluster) ]
  Morbidity (14-day period prevalence of fever with respiratory symptoms (ARI), fever without respiratory symptoms (malaria), and diarrhea) in children aged 1-59 months assessed in each participating cluster (village) from the secondary outcome sample.
• Length-for-age Z-score [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  Length-for-age Z-score in 6-8 and 12-14 months old children from the secondary outcome sample of 60 clusters. Length measures will be taken at 6, 9, 12, and 15 months after the enrollment of the village into the trial. Length-for-age Z-score will be calculated using the WHO Child Growth Standards.
• Weight-for age Z-score [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  Weight-for age Z-score in 6-8 and 12-14 months old children from the secondary outcome sample of 60 clusters. Weight measures will be taken at 6, 9, 12, and 15 months after the enrollment of the village into the trial. Weight-for-age Z-score will be calculated using the WHO Child Growth Standards.
• Weight-for-length Z-score [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  Weight-for-length Z-score in 6-8 and 12-14 months old children from the secondary outcome sample of 60 clusters. Length and weight measures will be taken at 6, 9, 12, and 15 months after the enrollment of the village into the trial. Weight-for-length Z score will be calculated using the WHO Child Growth Standards.
• Mid-upper arm circumference [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  Mid-upper arm circumference in 6-8 and 12-14 months old children from the secondary outcome sample of 60 clusters. Measures will be taken at 6, 9, 12, and 15 months after the enrollment of the village into the trial.
• Percentage of moderate or severe stunting [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  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 of 60 clusters.
• Percentage of moderate or severe wasting [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  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 of 60 clusters.
• Prevalence of phenotypic azithromycin resistance [ Time Frame: 12-month time interval (total of 3 intervals per cluster) ]
  Prevalence of phenotypic azithromycin resistance among E. coli strains isolated from stool samples or S. pneumoniae strains isolated from nasopharyngeal swabs among 4-14-month old infants and 49-59-month old children. Biological samples taken at enrollment, at 12 months, 24 months and 36 months after enrollment (secondary outcome sample).
• Prevalence of phenotypic AMR resistance to other "Access" group antibiotics [ Time Frame: 12-month time interval (total of 3 intervals per cluster) ]
  Prevalence of phenotypic 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 among 49-59 month old children. Biological samples taken at enrollment, at 12 months, 24 months and 36 months after enrollment (secondary outcome sample).
• Prevalence of genetic markers of azithromycin and other antibiotic resistance [ Time Frame: 12-month time interval (total of 3 intervals per cluster) ]
  Prevalence of genetic markers of azithromycin and other antibiotic resistance (resistome) of intestinal microbiota among 4-14 month old children. Biological samples taken at enrollment, at 12 months, 24 months and 36 months after enrollment (secondary outcome sample).
• Blood C-reactive protein concentration [ Time Frame: Biological samples taken before and 14 days after MDA round, 9 months after enrollment. ]
  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).
• Blood malaria parasitemia and hemoglobin concentration [ Time Frame: Biological samples taken before and 14 days after MDA round, 9 months after enrollment. ]
  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).
• Fecal calprotectin concentration [ Time Frame: Biological samples taken before and 14 days after MDA round, at 9 months after enrollment. ]
  Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on intestinal inflammation (secondary outcome sample).
• Incidence of Adverse events [ Time Frame: 3-month time interval (total of 4 intervals per cluster) ]
  Incidence of adverse events within 14 days of study drug administration. Data collected from 4-11 months old infants at 9 months after enrollment, and only for 6-8 months old infants at 6, 12, and 15 months after enrollment (secondary outcome sample).
• Incidence of Serious Adverse events [ Time Frame: within 14 days after MDA round. ]
  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.
• Mortality in children aged 12-59 month [ Time Frame: 3-month time interval (total of 8 intervals per cluster) ]
  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.
• Percentage of guardians and health care workers reporting MDA acceptable [ Time Frame: 24 months after enrollment ]
  Data collected through interviews of guardians and health care workers to assess acceptability of MDA.
• Percentage of the study population reached with MDA [ Time Frame: 24 months after enrollment ]
  Data collected on MDA distribution and through interviews of guardians and health care workers to assess equity of MDA.
• Cost of treatment delivered to the health system [ Time Frame: 24 months after enrollment ]
  Data collected on MDA distribution to assess the economic aspects of MDA.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.
• 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 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).

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
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)
Masking Description:

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

• Condition: Mortality

Intervention

• 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.

Study Arms

• Placebo Comparator: 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.
  Intervention: Drug: Placebo
• Active Comparator: 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.
  Interventions:

  • Drug: Placebo
  • Drug: Azithromycin
• Active Comparator: 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.
  Intervention: Drug: Azithromycin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 5, 2020): 100000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 29 Days to 364 Days (Child)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Per Ashorn, MD, PhD; 407280345 ext +358; per.ashorn@tuni.fi

Contact: Ulla Ashorn, PhD; 407080354 ext +358; ulla.ashorn@tuni.fi

• Listed Location Countries: Mali

Administrative Information

• NCT Number: NCT04424511
• Other Study ID Numbers: LAKANA trial; INV-003354 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• 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)

• Current Responsible Party: Per Ashorn, Tampere University
• Original Responsible Party: Same as current
• Current Study Sponsor: Tampere University
• Original Study Sponsor: Same as current

Collaborators

• Center for Vaccine Development CVD-Mali, Bamako, Mali
• University College London Hospitals
• Tro Da Ltd, UK
• Duke-NUS Graduate Medical School
• Bill and Melinda Gates Foundation (Funder)
• Pfizer Inc. (Provider of study drugs)

Investigators

• 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 Hospitals
• Principal Investigator: Camilla Ducker, MBBS, MSc; Tro Da Ltd, UK
• Principal Investigator: Yin Bun Cheung, PhD; Centre for Quantitative Medicine, Duke-NUS Medical School

• PRS Account: Tampere University
• Verification Date: October 2022