xml: <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/NCT06010719</url>
    </required_header>
    <id_info>
      <org_study_id>23-39411</org_study_id>
      <nct_id>NCT06010719</nct_id>
    </id_info>
    <brief_title>Azithromycin as Adjunctive Treatment for Uncomplicated Severe Acute Malnutrition</brief_title>
    <acronym>AMOUR</acronym>
    <official_title>Azithromycin as Adjunctive Treatment for Uncomplicated Severe Acute Malnutrition: the AMOUR Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of California, San Francisco</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Centre de Recherche en Sante de Nouna, Burkina Faso</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University of California, San Francisco</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>Yes</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        Amoxicillin is recommended by the World Health Organization (WHO) as adjunctive therapy for&#xD;
        the treatment of uncomplicated severe acute malnutrition (SAM). Because children with&#xD;
        uncomplicated SAM may have asymptomatic infection due to immune suppression, presumptive&#xD;
        treatment with a broad-spectrum antibiotic may be beneficial by clearing any existing&#xD;
        infection and improving outcomes. Two randomized placebo-controlled randomized trials have&#xD;
        evaluated amoxicillin for uncomplicated SAM and have found conflicting results. These results&#xD;
        may indicate either that antibiotics are not helpful for the management of uncomplicated SAM,&#xD;
        or that a better antibiotic is needed. Recently, we demonstrated that biannual mass&#xD;
        azithromycin distribution as a single oral dose reduces all-cause child mortality in&#xD;
        sub-Saharan Africa. Children with uncomplicated SAM, who have an elevated risk of mortality&#xD;
        relative to their well-nourished peers, may particularly benefit from presumptive&#xD;
        azithromycin treatment. Our pilot data demonstrated feasibility in rapid enrollment of&#xD;
        children with uncomplicated SAM in our study area, and showed no significant difference&#xD;
        between azithromycin and amoxicillin, demonstrating equipoise for a full-scale trial. Here,&#xD;
        we propose an individually randomized trial in which children will be randomized to a)&#xD;
        azithromycin, b) amoxicillin, or c) placebo, and evaluated for differences in weight gain,&#xD;
        nutritional recovery, and the gut microbiome. The results of this study will strengthen the&#xD;
        evidence base for policy related to the use of antibiotics as part of the management of&#xD;
        uncomplicated SAM, including additional evidence of amoxicillin versus placebo as well as&#xD;
        evaluation of an antibiotic class that has not been considered for uncomplicated SAM, which&#xD;
        may lead to changes in guidelines for treatment.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        General study design. We propose a 1:1:1 individually randomized placebo-controlled trial in&#xD;
        which children aged 6-59 months with SAM (based on weight-for-height Z-scores (WHZ) and/or&#xD;
        mid-upper arm circumference (MUAC), defined in Eligibility) are randomized to one of three&#xD;
        study arms: 1) a single oral 20 mg/kg dose of azithromycin followed by 13 doses of placebo;&#xD;
        2) a 7-day twice-daily course of oral amoxicillin (14 total doses); or 3) 7 days of&#xD;
        twice-daily placebo (14 total doses). Children will be followed weekly until nutritional&#xD;
        recovery, and then at 8 weeks (primary outcome), and 3, 6, 9, and 12 months to assess relapse&#xD;
        and vital status. The primary outcome will be weight gain in g/kg/day at 8 weeks from&#xD;
        enrollment. Children in all groups will receive ready-to-use therapeutic food per standard of&#xD;
        care guidelines (described below).&#xD;
  &#xD;
        Study area and study team. This study will be conducted in Boromo District, Burkina Faso in&#xD;
        West Africa. Boromo is in central Burkina Faso and experiences a large burden of SAM&#xD;
        annually. As in much of the Sahel, food insecurity and malnutrition are highly seasonal, with&#xD;
        the malnutrition season aligning with the rainy season from approximately July through&#xD;
        October, prior to the annual harvest in November to December.37-39 The central Sahel, which&#xD;
        includes Burkina Faso, is a particularly vulnerable region for childhood malnutrition due to&#xD;
        seasonal food insecurity, ongoing political instability, and climate change which may alter&#xD;
        or shorten growing seasons.37,40 The COVID-19 pandemic has increased risk of poor nutritional&#xD;
        outcomes among children, particularly in already vulnerable settings.2 The Sahel, and Burkina&#xD;
        Faso in particular, is a critical region for nutritional interventions due to the continued&#xD;
        high prevalence of underweight and high mortality rates, and lack of progress in reducing&#xD;
        underweight in children.41 Previous evidence has suggested that the etiology of SAM varies&#xD;
        across sub-Saharan Africa, and that SAM in the Sahel may be more likely due to calorie&#xD;
        insufficiency (marasmus) compared to other regions that have a higher prevalence of protein&#xD;
        malnutrition (kwashiorkor). Amoxicillin has been hypothesized to have greater efficacy in&#xD;
        children with kwashiorkor vs marasmus, which may partially explain discrepant results in&#xD;
        amoxicillin trials from Malawi and Niger.7-9 Given the large burden of malnutrition in the&#xD;
        Sahel, evidence tailored specifically to this setting is critical to inform policy. The trial&#xD;
        will be conducted jointly by the University of California, San Francisco (PI: Dr. Catherine&#xD;
        Oldenburg) and the Centre de Recherche en Santé de Nouna (PI: Dr. Ali Sié). Our team has&#xD;
        collaborated on multiple randomized controlled trials for child health since 2016.42-45 In&#xD;
        addition to expertise in design, conduct, and analysis of antibiotic trials, our team has&#xD;
        extensive expertise in pediatric microbiome and resistome outcomes in antibiotic trials (led&#xD;
        by Dr. Thuy Doan).18,19,45,46 Enrollment facilities. Our pilot study was conducted in 6&#xD;
        health facilities in Boromo over a single malnutrition season. For the full trial, we propose&#xD;
        to expand to 18 primary healthcare facilities and enroll over a 3-year period (covering 3&#xD;
        malnutrition seasons). These facilities represent the first tier of the country's&#xD;
        government-run healthcare system and provide basic preventative and curative care and are&#xD;
        often nurse-led.&#xD;
  &#xD;
        Healthcare for children under 5 years of age attending public facilities is free of charge.&#xD;
        Primary care facilities typically provide outpatient treatment of common childhood illnesses,&#xD;
        vaccination clinics, and antenatal and maternity care. Each facility hosts a nutrition clinic&#xD;
        1-2 days/week during which children are screened and receive care for uncomplicated SAM on an&#xD;
        outpatient basis. Children with a clinical complication requiring inpatient treatment will be&#xD;
        referred to the local district hospital for treatment and will not be enrolled in the trial.&#xD;
        Children in the outpatient nutritional program receive weekly follow-up care, although rates&#xD;
        of default outside of trial settings are high. These facilities are typically under-resourced&#xD;
        and experience frequent stock-outs of key components of the outpatient SAM treatment package&#xD;
        (e.g., RUTF). All enrolled children will receive all components of outpatient SAM package&#xD;
        through the trial.&#xD;
  &#xD;
        We propose a 1:1:1 randomized double masked placebo-controlled trial to determine whether a&#xD;
        single oral dose of azithromycin is superior to 1) amoxicillin or 2) placebo for weight gain&#xD;
        in children with SAM. Children aged 6-59 months with SAM per Burkinabé national guidelines&#xD;
        will be randomized to one of three study arms and followed for 12 months, with the primary&#xD;
        outcome being weight gain (g/kg/day) at 8 weeks after enrollment in the study. Children will&#xD;
        be followed weekly until recovery, at 8 weeks, and then every 3 months to assess for relapse&#xD;
        and mortality.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">January 2024</start_date>
    <completion_date type="Anticipated">July 2028</completion_date>
    <primary_completion_date type="Anticipated">September 2027</primary_completion_date>
    <phase>Phase 4</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>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Change in Weight Gain</measure>
      <time_frame>8 weeks</time_frame>
      <description>This will be measured as weight gain in g/kg/day at 8 weeks from enrollment.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in α-diversity Microbiome</measure>
      <time_frame>8 weeks</time_frame>
      <description>The primary outcome will be α-diversity using inverse Simpson's diversity index at the 8-week study visit.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Time for Nutritional recovery</measure>
      <time_frame>12 weeks</time_frame>
      <description>Nutritional recovery will be defined as per Burkinabé national guidelines: weight-for-height z score (WHZ) ≥ -2 on two consecutive visits and no acute complication or edema for the past 7 days OR mid-upper arm circumfrence(MUAC)≥ 125mm on two consecutive visits and no acute complication or edema for the past 7 days. The criterion chosen to define recovery is the same as the one used to admit the child to the program.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number of Transfer to inpatient care</measure>
      <time_frame>12 weeks</time_frame>
      <description>Children will be transferred to inpatient care if they develop medical complications, or their condition deteriorates.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mortality</measure>
      <time_frame>12 months</time_frame>
      <description>Vital status will be assessed at all scheduled follow-up time points, and the child's vital status (alive, died, defaulted, unknown) will be recorded in the study's mobile application. A serious adverse event form will be filled out for any child who dies during the course of the study, and the death will be reported to the medical monitor within 24 hours of the report. This report will include additional information related to the circumstances surrounding the child's death and any diagnostics and/or care sought for the child. 12 months mortality status will be compared by arm and reported</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Mid-upper arm circumference (MUAC)</measure>
      <time_frame>8 weeks</time_frame>
      <description>MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Mid-upper arm circumference (MUAC)</measure>
      <time_frame>3 months</time_frame>
      <description>MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Mid-upper arm circumference (MUAC)</measure>
      <time_frame>6 months</time_frame>
      <description>MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Mid-upper arm circumference (MUAC)</measure>
      <time_frame>12 months</time_frame>
      <description>MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-height z score (WHZ)</measure>
      <time_frame>8 weeks</time_frame>
      <description>Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-height z score (WHZ)</measure>
      <time_frame>3 months</time_frame>
      <description>Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-height z score (WHZ)</measure>
      <time_frame>6 months</time_frame>
      <description>Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-height z score (WHZ)</measure>
      <time_frame>12 months</time_frame>
      <description>Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-age Z-score (WAZ)</measure>
      <time_frame>8 weeks</time_frame>
      <description>Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-age Z-score (WAZ)</measure>
      <time_frame>3 months</time_frame>
      <description>Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-age Z-score (WAZ)</measure>
      <time_frame>6 months</time_frame>
      <description>Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Weight-for-age Z-score (WAZ)</measure>
      <time_frame>12 months</time_frame>
      <description>Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Height-for-age Z-score (HAZ)</measure>
      <time_frame>12 months</time_frame>
      <description>Height-for-age (HAZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number and type of clinic visits</measure>
      <time_frame>12 months</time_frame>
      <description>At each study visit, caregivers will report if they sought medical care for their child for any reason since their last study visit, and if so, how many times they sought care, if the child was hospitalized, and the reason for seeking care (e.g., malaria, pneumonia, etc). different in number and type of clinic visits will be compared by arm and reported at 12 months</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Malaria positivity</measure>
      <time_frame>8 weeks</time_frame>
      <description>Azithromycin has been shown to have some activity against Plasmodium falciparum in vitro by targeting the plasmodial apicoplast. Some studies of azithromycin for trachoma and child mortality have shown a benefit of mass azithromycin distribution on malaria parasitemia. At baseline and 8 weeks, we will measure malaria positivity via rapid diagnostic test, tympanic temperature, and hemoglobin.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Anemia</measure>
      <time_frame>baseline</time_frame>
      <description>Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin &lt;11.0 g/dL.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Anemia</measure>
      <time_frame>8 weeks</time_frame>
      <description>Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin &lt;11.0 g/dL.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Anemia</measure>
      <time_frame>3 months</time_frame>
      <description>Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin &lt;11.0 g/dL.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>change in Resistome</measure>
      <time_frame>12 months</time_frame>
      <description>Nonhosts read pairs will be aligned to the MEGARes reference antimicrobial database using Burrows-Wheeler alignment with default settings. To decrease false-positive ARD identification, only ARDs with a gene fraction of &gt;80% will be identified as present in the sample and included in analyses. We will classify each identified ARD at the class and gene level. We will evaluate the resistome at each time point by arm to evaluate the persistence of alterations to the resistome following oral antibiotics.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>number of Relapse after recovery</measure>
      <time_frame>12 months</time_frame>
      <description>Long-term relapse outcomes will also be assessed at 12 months by study arm by classifying children as having SAM or recovered, regardless of whether they were considered recovered previously.</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">7000</enrollment>
    <condition>Malnutrition, Child</condition>
    <condition>Severe Acute Malnutrition</condition>
    <arm_group>
      <arm_group_label>Azithromycin</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the azithromycin arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, except that the standard amoxicillin treatment will be changed to azithromycin. Children will receive a directly observed dose of azithromycin (20 mg/kg, single directly observed dose, oral suspension), followed by a 7-day course of placebo (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Amoxicillin</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the amoxicillin arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, including a 7-day course of amoxicillin (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the placebo arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, except that the the standard amoxicillin treatment will be changed to placebo (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Azithromycin</intervention_name>
      <description>oral azithromycin (20 mg/kg, single directly observed dose, oral suspension),</description>
      <arm_group_label>Azithromycin</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Amoxicillin</intervention_name>
      <description>Standard of Care. A 7-day, twice-daily course of amoxicillin will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).</description>
      <arm_group_label>Amoxicillin</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>A 7-day, twice-daily course of placebo will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Children with uncomplicated SAM per Burkina Faso's national guidelines who present to an&#xD;
          eligible enrollment site during the study period and meet all of the eligibility criteria&#xD;
          below will be considered for enrollment:&#xD;
  &#xD;
          Inclusion criteria:&#xD;
  &#xD;
            -  Age 6-59 months&#xD;
  &#xD;
            -  WHZ&lt;-3 SD or MUAC&lt;115 mm&#xD;
  &#xD;
            -  Primary residence within a catchment area of an enrollment site&#xD;
  &#xD;
            -  Available for full 8-week study (primary endpoint)&#xD;
  &#xD;
            -  Not admitted to a nutritional program for SAM treatment in the previous 2 weeks&#xD;
  &#xD;
            -  No edema&#xD;
  &#xD;
            -  No antibiotic use in the past 7 days&#xD;
  &#xD;
            -  No clinical complications requiring antibiotic or inpatient treatment**&#xD;
  &#xD;
            -  No congenital abnormality or chronic debilitating illness that would lead to&#xD;
               predictable growth faltering or reduce likelihood of SAM treatment benefit (such as&#xD;
               cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc)&#xD;
  &#xD;
            -  No known allergies to macrolides/azalides or amoxicillin/penicillin&#xD;
  &#xD;
            -  Sufficient appetite according to a feeding test with RUTF&#xD;
  &#xD;
            -  Written informed consent from at least one parent or guardian&#xD;
  &#xD;
          Exclusion criteria:&#xD;
  &#xD;
            -  Age less than 6 month or more than 59 months&#xD;
  &#xD;
            -  WHZ&gt;-3 SD or MUAC&gt;115 mm&#xD;
  &#xD;
            -  Primary residence is not within a catchment area of an enrollment site&#xD;
  &#xD;
            -  Not Available for full 8-week study (primary endpoint)&#xD;
  &#xD;
            -  Admitted to a nutritional program for SAM treatment in the previous 2 weeks&#xD;
  &#xD;
            -  Edema&#xD;
  &#xD;
            -  Antibiotic use in the past 7 days&#xD;
  &#xD;
            -  Clinical complications requiring antibiotic or inpatient treatment**&#xD;
  &#xD;
            -  Congenital abnormality or chronic debilitating illness that would lead to predictable&#xD;
               growth faltering or reduce likelihood of SAM treatment benefit (such as cerebral&#xD;
               palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc)&#xD;
  &#xD;
            -  Known allergies to macrolides/azalides or amoxicillin/penicillin&#xD;
  &#xD;
            -  No Sufficient appetite according to a feeding test with RUTF&#xD;
  &#xD;
            -  No Written informed consent from at least one parent or guardian&#xD;
  &#xD;
                 -  Per Burkinabé guidelines, children any of the following conditions will not be&#xD;
                    eligible for the trial and will be referred to an inpatient facility: MUAC &lt;115&#xD;
                    mm with complications; MUAC &lt;115 mm plus edema; bipedal pitting edema; anorexia&#xD;
                    or no appetite for RUTF; diarrhea and dehydration; unable to ingest anything&#xD;
                    without vomiting; severe pneumonia; open cutaneous lesions; hypothermia (35*C);&#xD;
                    fever (38.5*C); paleness suggesting severe anemia; hypoglycemia; very weak,&#xD;
                    lethargic, or unconscious; convulsions; signs of vitamin A deficiency; or a&#xD;
                    condition requiring IV infusion or an NG tube.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>6 Months</minimum_age>
      <maximum_age>59 Months</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Catherine Oldenburg, ScD</last_name>
      <phone>4154761442</phone>
      <email>catherine.oldenburg@ucsf.edu</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Elodie Lebas, RN</last_name>
      <phone>4154761442</phone>
      <email>elodie.lebas@ucsf.edu</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Centre de recherche en Santé de nouna</name>
        <address>
          <city>Nouna</city>
          <state>Kossi</state>
          <country>Burkina Faso</country>
        </address>
      </facility>
      <contact>
        <last_name>Ali Sie, MD PDH</last_name>
        <phone>+22670252957</phone>
        <email>sieali@yahoo.fr</email>
      </contact>
      <contact_backup>
        <last_name>Bountogo Mamadou, MD</last_name>
        <phone>+22670398944</phone>
        <email>drbountogo@yahoo.fr</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Burkina Faso</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 18, 2023</study_first_submitted>
    <study_first_submitted_qc>August 18, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 25, 2023</study_first_posted>
    <last_update_submitted>August 18, 2023</last_update_submitted>
    <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 25, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Malnutrition</mesh_term>
      <mesh_term>Severe Acute Malnutrition</mesh_term>
      <mesh_term>Child Nutrition Disorders</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Amoxicillin</mesh_term>
      <mesh_term>Azithromycin</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>The informed consent documents will contain language permitting secondary use with broad data sharing under controlled access with general use restrictions in GitHub. Any data shared will be de-identified. Participants will not be contacted or re-consented for future sharing or accessing data through repositories. Privacy and confidentiality protections will be consistent with applicable local laws in Burkina Faso. Data will be de-identified by removing all 18 HIPAA identifiers prior to sharing. All data sharing plans will be reviewed and approved by the respective institutional review boards at all participating institutions and will be reviewed during the informed consent process with caregivers. Caregivers may opt out of data sharing, for study data overall or specifically for biospecimen and/or genomic data.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06010719
  org study id: 23-39411
  nct id: NCT06010719
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  Amoxicillin is recommended by the World Health Organization (WHO) as adjunctive therapy for
        the treatment of uncomplicated severe acute malnutrition (SAM). Because children with
        uncomplicated SAM may have asymptomatic infection due to immune suppression, presumptive
        treatment with a broad-spectrum antibiotic may be beneficial by clearing any existing
        infection and improving outcomes. Two randomized placebo-controlled randomized trials have
        evaluated amoxicillin for uncomplicated SAM and have found conflicting results. These results
        may indicate either that antibiotics are not helpful for the management of uncomplicated SAM,
        or that a better antibiotic is needed. Recently, we demonstrated that biannual mass
        azithromycin distribution as a single oral dose reduces all-cause child mortality in
        sub-Saharan Africa. Children with uncomplicated SAM, who have an elevated risk of mortality
        relative to their well-nourished peers, may particularly benefit from presumptive
        azithromycin treatment. Our pilot data demonstrated feasibility in rapid enrollment of
        children with uncomplicated SAM in our study area, and showed no significant difference
        between azithromycin and amoxicillin, demonstrating equipoise for a full-scale trial. Here,
        we propose an individually randomized trial in which children will be randomized to a)
        azithromycin, b) amoxicillin, or c) placebo, and evaluated for differences in weight gain,
        nutritional recovery, and the gut microbiome. The results of this study will strengthen the
        evidence base for policy related to the use of antibiotics as part of the management of
        uncomplicated SAM, including additional evidence of amoxicillin versus placebo as well as
        evaluation of an antibiotic class that has not been considered for uncomplicated SAM, which
        may lead to changes in guidelines for treatment.
  General study design. We propose a 1:1:1 individually randomized placebo-controlled trial in
        which children aged 6-59 months with SAM (based on weight-for-height Z-scores (WHZ) and/or
        mid-upper arm circumference (MUAC), defined in Eligibility) are randomized to one of three
        study arms: 1) a single oral 20 mg/kg dose of azithromycin followed by 13 doses of placebo;
        2) a 7-day twice-daily course of oral amoxicillin (14 total doses); or 3) 7 days of
        twice-daily placebo (14 total doses). Children will be followed weekly until nutritional
        recovery, and then at 8 weeks (primary outcome), and 3, 6, 9, and 12 months to assess relapse
        and vital status. The primary outcome will be weight gain in g/kg/day at 8 weeks from
        enrollment. Children in all groups will receive ready-to-use therapeutic food per standard of
        care guidelines (described below).
  
        Study area and study team. This study will be conducted in Boromo District, Burkina Faso in
        West Africa. Boromo is in central Burkina Faso and experiences a large burden of SAM
        annually. As in much of the Sahel, food insecurity and malnutrition are highly seasonal, with
        the malnutrition season aligning with the rainy season from approximately July through
        October, prior to the annual harvest in November to December.37-39 The central Sahel, which
        includes Burkina Faso, is a particularly vulnerable region for childhood malnutrition due to
        seasonal food insecurity, ongoing political instability, and climate change which may alter
        or shorten growing seasons.37,40 The COVID-19 pandemic has increased risk of poor nutritional
        outcomes among children, particularly in already vulnerable settings.2 The Sahel, and Burkina
        Faso in particular, is a critical region for nutritional interventions due to the continued
        high prevalence of underweight and high mortality rates, and lack of progress in reducing
        underweight in children.41 Previous evidence has suggested that the etiology of SAM varies
        across sub-Saharan Africa, and that SAM in the Sahel may be more likely due to calorie
        insufficiency (marasmus) compared to other regions that have a higher prevalence of protein
        malnutrition (kwashiorkor). Amoxicillin has been hypothesized to have greater efficacy in
        children with kwashiorkor vs marasmus, which may partially explain discrepant results in
        amoxicillin trials from Malawi and Niger.7-9 Given the large burden of malnutrition in the
        Sahel, evidence tailored specifically to this setting is critical to inform policy. The trial
        will be conducted jointly by the University of California, San Francisco (PI: Dr. Catherine
        Oldenburg) and the Centre de Recherche en Santé de Nouna (PI: Dr. Ali Sié). Our team has
        collaborated on multiple randomized controlled trials for child health since 2016.42-45 In
        addition to expertise in design, conduct, and analysis of antibiotic trials, our team has
        extensive expertise in pediatric microbiome and resistome outcomes in antibiotic trials (led
        by Dr. Thuy Doan).18,19,45,46 Enrollment facilities. Our pilot study was conducted in 6
        health facilities in Boromo over a single malnutrition season. For the full trial, we propose
        to expand to 18 primary healthcare facilities and enroll over a 3-year period (covering 3
        malnutrition seasons). These facilities represent the first tier of the country's
        government-run healthcare system and provide basic preventative and curative care and are
        often nurse-led.
  
        Healthcare for children under 5 years of age attending public facilities is free of charge.
        Primary care facilities typically provide outpatient treatment of common childhood illnesses,
        vaccination clinics, and antenatal and maternity care. Each facility hosts a nutrition clinic
        1-2 days/week during which children are screened and receive care for uncomplicated SAM on an
        outpatient basis. Children with a clinical complication requiring inpatient treatment will be
        referred to the local district hospital for treatment and will not be enrolled in the trial.
        Children in the outpatient nutritional program receive weekly follow-up care, although rates
        of default outside of trial settings are high. These facilities are typically under-resourced
        and experience frequent stock-outs of key components of the outpatient SAM treatment package
        (e.g., RUTF). All enrolled children will receive all components of outpatient SAM package
        through the trial.
  
        We propose a 1:1:1 randomized double masked placebo-controlled trial to determine whether a
        single oral dose of azithromycin is superior to 1) amoxicillin or 2) placebo for weight gain
        in children with SAM. Children aged 6-59 months with SAM per Burkinabé national guidelines
        will be randomized to one of three study arms and followed for 12 months, with the primary
        outcome being weight gain (g/kg/day) at 8 weeks after enrollment in the study. Children will
        be followed weekly until recovery, at 8 weeks, and then every 3 months to assess for relapse
        and mortality.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Change in Weight Gain
  time frame: 8 weeks
  description: This will be measured as weight gain in g/kg/day at 8 weeks from enrollment.
  measure: Change in α-diversity Microbiome
  time frame: 8 weeks
  description: The primary outcome will be α-diversity using inverse Simpson's diversity index at the 8-week study visit.
  measure: Time for Nutritional recovery
  time frame: 12 weeks
  description: Nutritional recovery will be defined as per Burkinabé national guidelines: weight-for-height z score (WHZ) ≥ -2 on two consecutive visits and no acute complication or edema for the past 7 days OR mid-upper arm circumfrence(MUAC)≥ 125mm on two consecutive visits and no acute complication or edema for the past 7 days. The criterion chosen to define recovery is the same as the one used to admit the child to the program.
  measure: Number of Transfer to inpatient care
  time frame: 12 weeks
  description: Children will be transferred to inpatient care if they develop medical complications, or their condition deteriorates.
  measure: Mortality
  time frame: 12 months
  description: Vital status will be assessed at all scheduled follow-up time points, and the child's vital status (alive, died, defaulted, unknown) will be recorded in the study's mobile application. A serious adverse event form will be filled out for any child who dies during the course of the study, and the death will be reported to the medical monitor within 24 hours of the report. This report will include additional information related to the circumstances surrounding the child's death and any diagnostics and/or care sought for the child. 12 months mortality status will be compared by arm and reported
  measure: Change in Mid-upper arm circumference (MUAC)
  time frame: 8 weeks
  description: MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.
  measure: Change in Mid-upper arm circumference (MUAC)
  time frame: 3 months
  description: MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.
  measure: Change in Mid-upper arm circumference (MUAC)
  time frame: 6 months
  description: MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.
  measure: Change in Mid-upper arm circumference (MUAC)
  time frame: 12 months
  description: MUAC will be measured at all study visits. We will assess the change in MUAC over time across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.
  measure: Change in Weight-for-height z score (WHZ)
  time frame: 8 weeks
  description: Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
  measure: Change in Weight-for-height z score (WHZ)
  time frame: 3 months
  description: Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
  measure: Change in Weight-for-height z score (WHZ)
  time frame: 6 months
  description: Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
  measure: Change in Weight-for-height z score (WHZ)
  time frame: 12 months
  description: Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
  measure: Change in Weight-for-age Z-score (WAZ)
  time frame: 8 weeks
  description: Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.
  measure: Change in Weight-for-age Z-score (WAZ)
  time frame: 3 months
  description: Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.
  measure: Change in Weight-for-age Z-score (WAZ)
  time frame: 6 months
  description: Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.
  measure: Change in Weight-for-age Z-score (WAZ)
  time frame: 12 months
  description: Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.
  measure: Height-for-age Z-score (HAZ)
  time frame: 12 months
  description: Height-for-age (HAZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
  measure: Number and type of clinic visits
  time frame: 12 months
  description: At each study visit, caregivers will report if they sought medical care for their child for any reason since their last study visit, and if so, how many times they sought care, if the child was hospitalized, and the reason for seeking care (e.g., malaria, pneumonia, etc). different in number and type of clinic visits will be compared by arm and reported at 12 months
  measure: Malaria positivity
  time frame: 8 weeks
  description: Azithromycin has been shown to have some activity against Plasmodium falciparum in vitro by targeting the plasmodial apicoplast. Some studies of azithromycin for trachoma and child mortality have shown a benefit of mass azithromycin distribution on malaria parasitemia. At baseline and 8 weeks, we will measure malaria positivity via rapid diagnostic test, tympanic temperature, and hemoglobin.
  measure: Anemia
  time frame: baseline
  description: Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin <11.0 g/dL.
  measure: Anemia
  time frame: 8 weeks
  description: Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin <11.0 g/dL.
  measure: Anemia
  time frame: 3 months
  description: Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin <11.0 g/dL.
  measure: change in Resistome
  time frame: 12 months
  description: Nonhosts read pairs will be aligned to the MEGARes reference antimicrobial database using Burrows-Wheeler alignment with default settings. To decrease false-positive ARD identification, only ARDs with a gene fraction of >80% will be identified as present in the sample and included in analyses. We will classify each identified ARD at the class and gene level. We will evaluate the resistome at each time point by arm to evaluate the persistence of alterations to the resistome following oral antibiotics.
  measure: number of Relapse after recovery
  time frame: 12 months
  description: Long-term relapse outcomes will also be assessed at 12 months by study arm by classifying children as having SAM or recovered, regardless of whether they were considered recovered previously.
  arm group label: Azithromycin
  arm group type: Experimental
  description: Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the azithromycin arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, except that the standard amoxicillin treatment will be changed to azithromycin. Children will receive a directly observed dose of azithromycin (20 mg/kg, single directly observed dose, oral suspension), followed by a 7-day course of placebo (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).
  arm group label: Amoxicillin
  arm group type: Active Comparator
  description: Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the amoxicillin arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, including a 7-day course of amoxicillin (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the placebo arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, except that the the standard amoxicillin treatment will be changed to placebo (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).
  intervention type: Drug
  intervention name: Azithromycin
  description: oral azithromycin (20 mg/kg, single directly observed dose, oral suspension),
  arm group label: Azithromycin
  intervention type: Drug
  intervention name: Amoxicillin
  description: Standard of Care. A 7-day, twice-daily course of amoxicillin will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).
  arm group label: Amoxicillin
  intervention type: Other
  intervention name: Placebo
  description: A 7-day, twice-daily course of placebo will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 6 Months
  maximum age: 59 Months
  healthy volunteers: No
  last name: Catherine Oldenburg, ScD
  phone: 4154761442
  email: catherine.oldenburg@ucsf.edu
  last name: Elodie Lebas, RN
  phone: 4154761442
  email: elodie.lebas@ucsf.edu
  facility: 
  contact: 
  contact backup: 
  country: Burkina Faso
  responsible party type: Sponsor
  mesh term: Malnutrition
  mesh term: Severe Acute Malnutrition
  mesh term: Child Nutrition Disorders
  mesh term: Amoxicillin
  mesh term: Azithromycin
  sharing ipd: No
  ipd description: The informed consent documents will contain language permitting secondary use with broad data sharing under controlled access with general use restrictions in GitHub. Any data shared will be de-identified. Participants will not be contacted or re-consented for future sharing or accessing data through repositories. Privacy and confidentiality protections will be consistent with applicable local laws in Burkina Faso. Data will be de-identified by removing all 18 HIPAA identifiers prior to sharing. All data sharing plans will be reviewed and approved by the respective institutional review boards at all participating institutions and will be reviewed during the informed consent process with caregivers. Caregivers may opt out of data sharing, for study data overall or specifically for biospecimen and/or genomic data.