<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04424511</url>
  </required_header>
  <id_info>
    <org_study_id>LAKANA trial</org_study_id>
    <secondary_id>INV-003354</secondary_id>
    <nct_id>NCT04424511</nct_id>
  </id_info>
  <brief_title>Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Mali</brief_title>
  <acronym>LAKANA</acronym>
  <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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tampere University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Center for Vaccine Development CVD-Mali, Bamako, Mali</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University College London Hospitals</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tro Da Ltd, UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Duke-NUS Graduate Medical School</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bill and Melinda Gates Foundation (Funder)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer Inc. (Provider of study drugs)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Tampere University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The LAKANA trial will assess the impact on mortality and other health outcomes of quarterly&#xD;
      and biannual azithromycin mass drug administration (MDA) when delivered to 1-11-month (29-364&#xD;
      days) old infants in a high-mortality setting where malaria is holoendemic but there is also&#xD;
      a functioning seasonal malaria chemoprevention (SMC) program in place. The long-term goal is&#xD;
      to more precisely define the role of mass azithromycin treatments as an intervention for&#xD;
      reducing childhood mortality, and to determine the most effective treatment regimen. The main&#xD;
      study hypotheses in terms of mortality effect are: i) Biannual azithromycin MDA to 1-11 month&#xD;
      old infants reduces their mortality, ii) Quarterly azithromycin MDA to 1-11 month old infants&#xD;
      reduces their mortality, iii) Quarterly azithromycin MDA has a bigger mortality effect than&#xD;
      biannual MDA.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Mass drug administration (MDA) of azithromycin has been shown to reduce under-5 mortality in&#xD;
      some but not all sub-Saharan African settings. Because of the observed heterogeneity and&#xD;
      possible effect modification by SMC or other co-interventions, further trials in new settings&#xD;
      are needed in order to make evidence-based public health recommendations about the use of&#xD;
      this treatment. The objectives of the LAKANA trial are:&#xD;
&#xD;
        -  To evaluate the impact of two azithromycin MDA regimens on infant mortality and other&#xD;
           health outcomes, when provided in a rural West-African high-mortality context with an&#xD;
           ongoing seasonal malaria chemoprevention program.&#xD;
&#xD;
        -  To evaluate the effect of alternative MDA frequencies on antimicrobial resistance (AMR)&#xD;
           and host microbiota composition.&#xD;
&#xD;
        -  To test hypotheses that azithromycin MDA eliminates malaria parasitaemia and reduces&#xD;
           systemic and intestinal inflammation in asymptomatic children and to collect and store&#xD;
           biological samples for assessing other possible mechanisms of azithromycin effect.&#xD;
&#xD;
        -  To investigate the feasibility of alternative azithromycin MDA strategies, including&#xD;
           economic analysis.&#xD;
&#xD;
      The LAKANA trial will be conducted in 1150 villages from 7-10 health districts in the Kayes,&#xD;
      Kita and Koulikoro regions of Mali. LAKANA is a cluster-randomized, placebo-controlled,&#xD;
      double-blinded, parallel-group, three-arm clinical trial, with adaptive design. Participating&#xD;
      villages will be randomly allocated to three different intervention groups in a ratio of 3 :&#xD;
      2 : 4 (control : azithromycin quarterly : azithromycin biannually). Within each participating&#xD;
      village, consenting households will be visited quarterly (at 3-month intervals), nine times.&#xD;
      At the first eight of these visits, 1-11-month-old eligible infants (age 29-364 days), for&#xD;
      whom there is a consent for study drug provision, will be given a single dose of study drug&#xD;
      (azithromycin mixture or respective placebo mixture).&#xD;
&#xD;
      Mortality and serious adverse events (SAEs) data will be collected, and mortality-related&#xD;
      questions answered using data from all the included 1150 villages. Mixed-effect Poisson&#xD;
      regression model will be used to estimate the intervention effects on mortality, with random&#xD;
      intercepts for the clusters. The investigators will explore effect modification by testing&#xD;
      for interaction between the MDA intervention and the following variables:&#xD;
&#xD;
        -  Infant age at the time of MDA (1-5 months vs 6-11 months)&#xD;
&#xD;
        -  Infant weight-for-age at the time of MDA&#xD;
&#xD;
        -  Infant sex&#xD;
&#xD;
        -  Season of MDA dosing and time since the last SMC&#xD;
&#xD;
        -  Cluster level coverage of SMC&#xD;
&#xD;
        -  Cluster level baseline mortality (established at first census)&#xD;
&#xD;
        -  Cluster and individual level coverage and number of administered azithromycin MDA doses&#xD;
&#xD;
        -  District of residence&#xD;
&#xD;
        -  Distance from the nearest health facility&#xD;
&#xD;
        -  Household asset or income index&#xD;
&#xD;
        -  Household WASH index&#xD;
&#xD;
      The investigators will address the other study questions using a smaller separate secondary&#xD;
      sample of 59 villages located around four selected health centers close to the city of Kita&#xD;
      and a similar number of villages closer to Bamako, i.e. in Koulikoro or Kati (tertiary&#xD;
      sample).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 15, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>3-month time interval (total of 8 intervals per cluster)</time_frame>
    <description>Mortality rate (deaths per 1,000 years at risk) among children 1-11 months of age.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Morbidity</measure>
    <time_frame>3-month time interval (total of 8 intervals per cluster)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length-for-age Z-score</measure>
    <time_frame>3-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weight-for age Z-score</measure>
    <time_frame>3-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weight-for-length Z-score</measure>
    <time_frame>3-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mid-upper arm circumference</measure>
    <time_frame>3-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of moderate or severe stunting</measure>
    <time_frame>3-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>Percentage of moderate or severe stunting (length-for-age Z-score &lt; -2 / -3) in 6-8 and 12-14 months old children from the secondary outcome sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of moderate or severe wasting</measure>
    <time_frame>3-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>Percentage of moderate or severe wasting (Weight-for-length Z-score &lt; -2 / -3) in 6-8 and 12-14 months old children from the secondary outcome sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of phenotypic and genotypic macrolide resistance</measure>
    <time_frame>12-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>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).&#xD;
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).&#xD;
(secondary outcome sample).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of phenotypic and genotypic macrolide resistance</measure>
    <time_frame>12-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of phenotypic and genotypic AMR resistance to other &quot;ACCESS&quot; group antibiotics</measure>
    <time_frame>12-month time interval (total of 3 intervals per cluster)</time_frame>
    <description>Prevalence of phenotypic and genotypic AMR against other antibiotics categorised by the World Health Organization (WHO) into &quot;ACCESS&quot; group, among azithromycin-resistant E. coli strains isolated from stool samples or azithromycin-resistant S. pneumoniae strains isolated from nasopharyngeal swabs (secondary outcome sample).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood C-reactive protein concentration</measure>
    <time_frame>Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment.</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood malaria parasitemia and hemoglobin concentration</measure>
    <time_frame>Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment.</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fecal neopterin, myeloperoxidase, and alpha-1-antitrypsin concentrations</measure>
    <time_frame>Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment.</time_frame>
    <description>Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on intestinal inflammation (secondary outcome sample).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse events</measure>
    <time_frame>3-month time interval</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Serious Adverse events</measure>
    <time_frame>within 14 days after MDA round.</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality in children aged 12-59 month</measure>
    <time_frame>3-month time interval (total of 8 intervals per cluster)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of guardians and health care workers reporting MDA acceptable</measure>
    <time_frame>24 months after enrollment</time_frame>
    <description>Data collected through interviews of guardians and health care workers to assess acceptability of MDA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of the study population reached with MDA</measure>
    <time_frame>24 months after enrollment</time_frame>
    <description>Data collected on MDA distribution and through interviews of guardians and health care workers to assess equity of MDA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost and Cost-effectiveness of the intervention</measure>
    <time_frame>24 months after enrollment</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">100000</enrollment>
  <condition>Mortality</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age:&#xD;
Single-dose of 0.5 ml / kg child weight&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Azithromycin-biannually (Azi-biannual)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age:&#xD;
Single-dose of 0.5 ml / kg child weight&#xD;
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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Azithromycin-quarterly</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age:&#xD;
Single-dose of 0.5 ml (20 mg) / kg child weight.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>Azithromycin-biannually (Azi-biannual)</arm_group_label>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azithromycin</intervention_name>
    <description>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.</description>
    <arm_group_label>Azithromycin-biannually (Azi-biannual)</arm_group_label>
    <arm_group_label>Azithromycin-quarterly</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        On a cluster (village) level:&#xD;
&#xD;
          1. Location within Kayes, Kita, or Koulikoro region of Mali&#xD;
&#xD;
          2. Considered accessible and safe by the local health authorities and research team&#xD;
&#xD;
          3. Considered non-urban by the local health authorities and research team&#xD;
&#xD;
          4. Permission from community leadership&#xD;
&#xD;
        On a household level (for trial enrollment):&#xD;
&#xD;
          1. Location within a cluster that is included in the study&#xD;
&#xD;
          2. Verbal consent from a head of household or an adult authorized by her / him&#xD;
&#xD;
        On a child level (for receiving study medication):&#xD;
&#xD;
          1. Residence in a household enrolled in the trial&#xD;
&#xD;
          2. Age between 29 and 364 days&#xD;
&#xD;
          3. Verbal consent from at least one caregiver&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        On child level (for not receiving study medication):&#xD;
&#xD;
          1. Weight below 3.0 kg&#xD;
&#xD;
          2. Known allergy to macrolides, as judged by a caregiver report of the infant&#xD;
             experiencing an adverse reaction after oral ingestion of medication, which was deemed&#xD;
             likely to be a macrolide by the interviewing data collector.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>29 Days</minimum_age>
    <maximum_age>364 Days</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Per Ashorn, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Child Health Research, Tampere University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ulla Ashorn, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Child Health Research, Tampere University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Samba Sow, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Vaccine Development CVD-Mali</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nigel Klein, MBBS, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University College London Hospitals</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Camilla Ducker, MBBS, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tro Da Ltd, UK</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Yin Bun Cheung, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre for Quantitative Medicine, Duke-NUS Medical School</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Per Ashorn, MD, PhD</last_name>
    <phone>407280345</phone>
    <phone_ext>+358</phone_ext>
    <email>per.ashorn@tuni.fi</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ulla Ashorn, PhD</last_name>
    <phone>407080354</phone>
    <phone_ext>+358</phone_ext>
    <email>ulla.ashorn@tuni.fi</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Center for Vaccine Development CVD-Mali</name>
      <address>
        <city>Bamako</city>
        <zip>BP 251</zip>
        <country>Mali</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Samba Sow, MD, MSc</last_name>
      <phone>76348947</phone>
      <phone_ext>+223</phone_ext>
      <email>ssow@som.umaryland.edu</email>
    </contact>
    <contact_backup>
      <last_name>Camilla Ducker, MBBS, MSc</last_name>
      <email>camilla@troda.org</email>
    </contact_backup>
    <investigator>
      <last_name>Samba Sow, MD, MSc</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Mali</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>May 22, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>October 4, 2022</last_update_submitted>
  <last_update_submitted_qc>October 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tampere University</investigator_affiliation>
    <investigator_full_name>Per Ashorn</investigator_full_name>
    <investigator_title>MD, PhD, Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>Mass Drug Administration</keyword>
  <keyword>Azithromycin</keyword>
  <keyword>Infant and Child Mortality</keyword>
  <keyword>Infant and Child health</keyword>
  <keyword>Infant and Child growth</keyword>
  <keyword>Infant and Child morbidity</keyword>
  <keyword>Antimicrobial Resistance</keyword>
  <keyword>Feasibility</keyword>
  <keyword>Acceptability</keyword>
  <keyword>Safety</keyword>
  <keyword>Cost</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Infection</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azithromycin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data collected during the trial, after deidentification. (The details are to be determined).</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Starting 6 months after publication</ipd_time_frame>
    <ipd_access_criteria>(The details are to be determined)</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 27, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/11/NCT04424511/Prot_SAP_ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04424511
org study id: LAKANA trial
secondary id: INV-003354
nct id: NCT04424511
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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).
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.
primary purpose: Treatment
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.
measure: Mortality
time frame: 3-month time interval (total of 8 intervals per cluster)
description: Mortality rate (deaths per 1,000 years at risk) among children 1-11 months of age.
measure: Morbidity
time frame: 3-month time interval (total of 8 intervals per cluster)
description: 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.
measure: Length-for-age Z-score
time frame: 3-month time interval (total of 3 intervals per cluster)
description: 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.
measure: Weight-for age Z-score
time frame: 3-month time interval (total of 3 intervals per cluster)
description: 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.
measure: Weight-for-length Z-score
time frame: 3-month time interval (total of 3 intervals per cluster)
description: 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.
measure: Mid-upper arm circumference
time frame: 3-month time interval (total of 3 intervals per cluster)
description: 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.
measure: Percentage of moderate or severe stunting
time frame: 3-month time interval (total of 3 intervals per cluster)
description: 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.
measure: Percentage of moderate or severe wasting
time frame: 3-month time interval (total of 3 intervals per cluster)
description: 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.
measure: Prevalence of phenotypic and genotypic macrolide resistance
time frame: 12-month time interval (total of 3 intervals per cluster)
description: 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).
measure: Prevalence of phenotypic and genotypic macrolide resistance
time frame: 12-month time interval (total of 3 intervals per cluster)
description: 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).
measure: Prevalence of phenotypic and genotypic AMR resistance to other "ACCESS" group antibiotics
time frame: 12-month time interval (total of 3 intervals per cluster)
description: 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).
measure: Blood C-reactive protein concentration
time frame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment.
description: 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).
measure: Blood malaria parasitemia and hemoglobin concentration
time frame: Biological samples taken before and 14 days after the fourth MDA round, 9 months after enrollment.
description: 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).
measure: 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.
description: Biological samples taken from 4-11 months old infants to assess effect of azithromycin MDA on intestinal inflammation (secondary outcome sample).
measure: Incidence of Adverse events
time frame: 3-month time interval
description: 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).
measure: Incidence of Serious Adverse events
time frame: within 14 days after MDA round.
description: 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.
measure: Mortality in children aged 12-59 month
time frame: 3-month time interval (total of 8 intervals per cluster)
description: 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.
measure: Percentage of guardians and health care workers reporting MDA acceptable
time frame: 24 months after enrollment
description: Data collected through interviews of guardians and health care workers to assess acceptability of MDA.
measure: Percentage of the study population reached with MDA
time frame: 24 months after enrollment
description: Data collected on MDA distribution and through interviews of guardians and health care workers to assess equity of MDA.
measure: Cost and Cost-effectiveness of the intervention
time frame: 24 months after enrollment
description: 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).
arm group label: Control
arm group type: Placebo Comparator
description: Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age:
Single-dose of 0.5 ml / kg child weight
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.
arm group label: Azithromycin-biannually (Azi-biannual)
arm group type: Active Comparator
description: Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age:
Single-dose of 0.5 ml / kg child weight
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.
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.
arm group label: Azithromycin-quarterly
arm group type: Active Comparator
description: Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age:
Single-dose of 0.5 ml (20 mg) / kg child weight.
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 type: Drug
intervention name: Placebo
description: 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.
arm group label: Azithromycin-biannually (Azi-biannual)
arm group label: Control
intervention type: Drug
intervention name: Azithromycin
description: 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.
arm group label: Azithromycin-biannually (Azi-biannual)
arm group label: Azithromycin-quarterly
criteria: 
gender: All
minimum age: 29 Days
maximum age: 364 Days
healthy volunteers: Accepts Healthy Volunteers
last name: Per Ashorn, MD, PhD
role: Principal Investigator
affiliation: Center for Child Health Research, Tampere University
last name: Ulla Ashorn, PhD
role: Principal Investigator
affiliation: Center for Child Health Research, Tampere University
last name: Samba Sow, MD, MSc
role: Principal Investigator
affiliation: Center for Vaccine Development CVD-Mali
last name: Nigel Klein, MBBS, PhD
role: Principal Investigator
affiliation: University College London Hospitals
last name: Camilla Ducker, MBBS, MSc
role: Principal Investigator
affiliation: Tro Da Ltd, UK
last name: Yin Bun Cheung, PhD
role: Principal Investigator
affiliation: Centre for Quantitative Medicine, Duke-NUS Medical School
last name: Per Ashorn, MD, PhD
phone: 407280345
phone ext: +358
email: per.ashorn@tuni.fi
last name: Ulla Ashorn, PhD
phone: 407080354
phone ext: +358
email: ulla.ashorn@tuni.fi
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Mali
responsible party type: Principal Investigator
investigator affiliation: Tampere University
investigator full name: Per Ashorn
investigator title: MD, PhD, Professor of Pediatrics
mesh term: Azithromycin
sharing ipd: Yes
ipd description: Individual participant data collected during the trial, after deidentification. (The details are to be determined).
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Starting 6 months after publication
ipd access criteria: (The details are to be determined)
provided document: 