<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/NCT03268902</url>
  </required_header>
  <id_info>
    <org_study_id>19465</org_study_id>
    <nct_id>NCT03268902</nct_id>
  </id_info>
  <brief_title>Early Life Interventions for Childhood Growth and Development In Tanzania</brief_title>
  <acronym>ELICIT</acronym>
  <official_title>Early Life Interventions for Childhood Growth and Development In Tanzania</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Haydom Lutheran Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Virginia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bill and Melinda Gates Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Haydom Lutheran Hospital</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>
      This study aims to assess growth and cognitive effects of treatment with azithromycin and&#xD;
      nitazoxanide and/or nicotinamide (vitamin B3) supplementation nicotinamide.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Children living in rural sub-Saharan Africa experience massive challenges to child thriving,&#xD;
      with poor linear growth and delays in child development. In a cohort of 211 children living&#xD;
      in the rural Haydom area of Tanzania (participating in the Interactions of Malnutrition &amp;&#xD;
      Enteric Infections: Consequences for Child Health and Development &quot;MAL-ED&quot; Study), 70.6% had&#xD;
      stunted growth at 18 months. This rate of moderate and severe stunting (length-for-age&#xD;
      z-score [HAZ] &lt;-2 standard deviations) was the highest of the 8 study sites in MAL-ED.&#xD;
&#xD;
      This enormous deficit is likely associated with high rates of enteric infections with&#xD;
      Campylobacter, E. coli pathotypes, Cryptosporidium, and Giardia, organisms susceptible to&#xD;
      azithromycin and/or nitazoxanide. Infections such as these occur frequently in developing&#xD;
      areas and are often associated with environmental enteropathy, including ongoing enteric&#xD;
      inflammation and loss of enterocyte integrity, leading to possible bacterial translocation&#xD;
      and poorer absorption of ingested nutrients. The consequences of these infections, enteric&#xD;
      dysfunction and poor nutrient absorption frequently include growth stunting, learning delays,&#xD;
      and an overall loss of human capital.&#xD;
&#xD;
      Emerging evidence suggests a potential role for the tryptophan-niacin pathway (including the&#xD;
      end-product nicotinamide, an isoform of vitamin B3) in decreasing mucosal inflammation and&#xD;
      affecting enteral microbiota. At the Tanzania site of MAL-ED, serum levels of tryptophan were&#xD;
      related to subsequent linear growth, further suggesting importance of the tryptophan-niacin&#xD;
      pathway. What is not clear is whether early childhood growth and development could be&#xD;
      improved by targeting enteric infection and the tryptophan-niacin pathway by 1) delivering&#xD;
      antibiotics against specific bacteria and/or 2) providing vitamin B3 as&#xD;
      nicotinamide/niacinamide.&#xD;
&#xD;
      The main analysis will be intention-to-treat but a secondary analysis will be per protocol.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 5, 2017</start_date>
  <completion_date type="Actual">March 26, 2020</completion_date>
  <primary_completion_date type="Actual">February 28, 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <intervention_model_description>Each intervention will be assigned independently. Intervention domains will be randomized separately on an individual basis. This will provide 4 different combinations of interventions: 1). Nicotinamide, azithromycin and nitazoxanide 2). Azithromycin and nitazoxanide 3). Nicotinamide only 4). No active treatment.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Both participants and investigators will be blinded to the treatments allocated to each participant. The members of the DSMB will also be blinded.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Height-for-age z-score (HAZ) at 18 months</measure>
    <time_frame>18 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Weight-for-age z-score (WAZ) at 18 months</measure>
    <time_frame>18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Head circumference-for-age z-score (HCAZ) at 18 months</measure>
    <time_frame>18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stunting</measure>
    <time_frame>18 months</time_frame>
    <description>HAZ &lt;-2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All cause mortality</measure>
    <time_frame>0-18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalization</measure>
    <time_frame>0-18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Childhood illness</measure>
    <time_frame>0-18 months</time_frame>
    <description>Incidence of diarrhea, lower respiratory infection and febrile illness</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anemia</measure>
    <time_frame>12 and 18 months</time_frame>
    <description>Moderate to severe anemia by WHO definition for age and altitude</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Enteropathogen burden</measure>
    <time_frame>6, 6.5, 12, 12.5, 18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microbiota composition</measure>
    <time_frame>6, 6.5, 12, 18 months</time_frame>
    <description>Composition of intestinal microbiome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stool myeloperoxidase concentration</measure>
    <time_frame>6, 12, 18 months</time_frame>
    <description>Stool myeloperoxidase ELISA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-reactive protein concentration in serum</measure>
    <time_frame>12 and 18 months</time_frame>
    <description>High-sensitivity CRP concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin-like growth factor 1 concentration in serum</measure>
    <time_frame>12 and 18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Collagen X concentration in serum</measure>
    <time_frame>12 and 18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tryptophan-kynurenine ratio</measure>
    <time_frame>12 and 18 months</time_frame>
    <description>Ratio of tryptophan concentration to kynurenine concentration in metabolomic testing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Niacin and nicotinamide metabolite concentration</measure>
    <time_frame>6, 12, 18 months</time_frame>
    <description>Concentration of downstream metabolites of niacin and nicotinamide as tested by metabolomic analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Small intestinal bacterial overgrowth</measure>
    <time_frame>6, 12 and 18 months</time_frame>
    <description>Prevalence of SIBO as tested via exhaled hydrogen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malawi Developmental Assessment Tool score</measure>
    <time_frame>18 months</time_frame>
    <description>The MDAT is a measure of child cognitive development</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">1188</enrollment>
  <condition>Malnutrition</condition>
  <condition>Stunting</condition>
  <condition>Cognitive Development</condition>
  <condition>Enteric Pathogens</condition>
  <arm_group>
    <arm_group_label>Nicotinamide and Antimicrobials</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nicotinamide Azithromycin Oral Liquid Product Nitazoxanide Oral Suspension</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Antimicrobials only</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo Azithromycin Oral Liquid Product Nitazoxanide Oral Suspension</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nicotinamide only</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nicotinamide Placebo Placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No active treatment</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo Placebo Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azithromycin Oral Liquid Product</intervention_name>
    <description>Azithromycin 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months</description>
    <arm_group_label>Antimicrobials only</arm_group_label>
    <arm_group_label>Nicotinamide and Antimicrobials</arm_group_label>
    <other_name>Throza DPS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitazoxanide Oral Suspension</intervention_name>
    <description>Nitazoxanide 100 mg given twice daily for 3 days at 12 and 15 months</description>
    <arm_group_label>Antimicrobials only</arm_group_label>
    <arm_group_label>Nicotinamide and Antimicrobials</arm_group_label>
    <other_name>Alinia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Nicotinamide</intervention_name>
    <description>Mothers in the nicotinamide arm will be given nicotinamide 250 mg daily from delivery through 6 months post-partum in capsule form.&#xD;
Children in the nicotinamide arm will be given 100 mg/d in powder form between 6 and 18 months of age</description>
    <arm_group_label>Nicotinamide and Antimicrobials</arm_group_label>
    <arm_group_label>Nicotinamide only</arm_group_label>
    <other_name>Vitamin B3</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Contain inert excipients only. Azithromycin placebo 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months. Nitazoxanide placebo 100 mg given twice daily for 3 days at 12 and 15 months.&#xD;
Mothers in the nicotinamide placebo arm will be given placebo 250 mg daily from delivery through 6 months post-partum in capsule form.&#xD;
Children in the nicotinamide placebo arm will be given 100 mg/d of placebo in powder form between 6 and 18 months of age</description>
    <arm_group_label>Antimicrobials only</arm_group_label>
    <arm_group_label>Nicotinamide only</arm_group_label>
    <arm_group_label>No active treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Maternal age ≥18&#xD;
&#xD;
          2. Infant ≤ 14 days&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Maternal inability to adhere to protocol&#xD;
&#xD;
          2. Multiple gestation&#xD;
&#xD;
          3. Severe illness (significant birth defect, hospitalization, severe neonatal illness)&#xD;
&#xD;
          4. Birth weight &lt;1500 g&#xD;
&#xD;
          5. Lack of breastfeeding at enrollment (and lack of intention to continue breastfeeding&#xD;
             at time of enrollment).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>0 Days</minimum_age>
    <maximum_age>14 Days</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Estomih Mduma</last_name>
    <role>Principal Investigator</role>
    <affiliation>Haydom Lutheran Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Haydom Lutheran Hospital</name>
      <address>
        <city>Haydom</city>
        <state>Manyara</state>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Tanzania</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>August 29, 2017</study_first_submitted>
  <study_first_submitted_qc>August 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <last_update_submitted>May 5, 2021</last_update_submitted>
  <last_update_submitted_qc>May 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2021</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Niacinamide</mesh_term>
    <mesh_term>Niacin</mesh_term>
    <mesh_term>Nicotinic Acids</mesh_term>
    <mesh_term>Azithromycin</mesh_term>
    <mesh_term>Nitazoxanide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 5, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/02/NCT03268902/SAP_002.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/NCT03268902
org study id: 19465
nct id: NCT03268902
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This study aims to assess growth and cognitive effects of treatment with azithromycin and
      nitazoxanide and/or nicotinamide (vitamin B3) supplementation nicotinamide.
Children living in rural sub-Saharan Africa experience massive challenges to child thriving,
      with poor linear growth and delays in child development. In a cohort of 211 children living
      in the rural Haydom area of Tanzania (participating in the Interactions of Malnutrition &
      Enteric Infections: Consequences for Child Health and Development "MAL-ED" Study), 70.6% had
      stunted growth at 18 months. This rate of moderate and severe stunting (length-for-age
      z-score [HAZ] <-2 standard deviations) was the highest of the 8 study sites in MAL-ED.

      This enormous deficit is likely associated with high rates of enteric infections with
      Campylobacter, E. coli pathotypes, Cryptosporidium, and Giardia, organisms susceptible to
      azithromycin and/or nitazoxanide. Infections such as these occur frequently in developing
      areas and are often associated with environmental enteropathy, including ongoing enteric
      inflammation and loss of enterocyte integrity, leading to possible bacterial translocation
      and poorer absorption of ingested nutrients. The consequences of these infections, enteric
      dysfunction and poor nutrient absorption frequently include growth stunting, learning delays,
      and an overall loss of human capital.

      Emerging evidence suggests a potential role for the tryptophan-niacin pathway (including the
      end-product nicotinamide, an isoform of vitamin B3) in decreasing mucosal inflammation and
      affecting enteral microbiota. At the Tanzania site of MAL-ED, serum levels of tryptophan were
      related to subsequent linear growth, further suggesting importance of the tryptophan-niacin
      pathway. What is not clear is whether early childhood growth and development could be
      improved by targeting enteric infection and the tryptophan-niacin pathway by 1) delivering
      antibiotics against specific bacteria and/or 2) providing vitamin B3 as
      nicotinamide/niacinamide.

      The main analysis will be intention-to-treat but a secondary analysis will be per protocol.
allocation: Randomized
intervention model: Factorial Assignment
intervention model description: Each intervention will be assigned independently. Intervention domains will be randomized separately on an individual basis. This will provide 4 different combinations of interventions: 1). Nicotinamide, azithromycin and nitazoxanide 2). Azithromycin and nitazoxanide 3). Nicotinamide only 4). No active treatment.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Both participants and investigators will be blinded to the treatments allocated to each participant. The members of the DSMB will also be blinded.
measure: Height-for-age z-score (HAZ) at 18 months
time frame: 18 months
measure: Weight-for-age z-score (WAZ) at 18 months
time frame: 18 months
measure: Head circumference-for-age z-score (HCAZ) at 18 months
time frame: 18 months
measure: Stunting
time frame: 18 months
description: HAZ <-2
measure: All cause mortality
time frame: 0-18 months
measure: Hospitalization
time frame: 0-18 months
measure: Childhood illness
time frame: 0-18 months
description: Incidence of diarrhea, lower respiratory infection and febrile illness
measure: Anemia
time frame: 12 and 18 months
description: Moderate to severe anemia by WHO definition for age and altitude
measure: Enteropathogen burden
time frame: 6, 6.5, 12, 12.5, 18 months
measure: Microbiota composition
time frame: 6, 6.5, 12, 18 months
description: Composition of intestinal microbiome
measure: Stool myeloperoxidase concentration
time frame: 6, 12, 18 months
description: Stool myeloperoxidase ELISA
measure: C-reactive protein concentration in serum
time frame: 12 and 18 months
description: High-sensitivity CRP concentration
measure: Insulin-like growth factor 1 concentration in serum
time frame: 12 and 18 months
measure: Collagen X concentration in serum
time frame: 12 and 18 months
measure: Tryptophan-kynurenine ratio
time frame: 12 and 18 months
description: Ratio of tryptophan concentration to kynurenine concentration in metabolomic testing
measure: Niacin and nicotinamide metabolite concentration
time frame: 6, 12, 18 months
description: Concentration of downstream metabolites of niacin and nicotinamide as tested by metabolomic analysis
measure: Small intestinal bacterial overgrowth
time frame: 6, 12 and 18 months
description: Prevalence of SIBO as tested via exhaled hydrogen
measure: Malawi Developmental Assessment Tool score
time frame: 18 months
description: The MDAT is a measure of child cognitive development
arm group label: Nicotinamide and Antimicrobials
arm group type: Experimental
description: Nicotinamide Azithromycin Oral Liquid Product Nitazoxanide Oral Suspension
arm group label: Antimicrobials only
arm group type: Experimental
description: Placebo Azithromycin Oral Liquid Product Nitazoxanide Oral Suspension
arm group label: Nicotinamide only
arm group type: Experimental
description: Nicotinamide Placebo Placebo
arm group label: No active treatment
arm group type: Placebo Comparator
description: Placebo Placebo Placebo
intervention type: Drug
intervention name: Azithromycin Oral Liquid Product
description: Azithromycin 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months
arm group label: Antimicrobials only
arm group label: Nicotinamide and Antimicrobials
other name: Throza DPS
intervention type: Drug
intervention name: Nitazoxanide Oral Suspension
description: Nitazoxanide 100 mg given twice daily for 3 days at 12 and 15 months
arm group label: Antimicrobials only
arm group label: Nicotinamide and Antimicrobials
other name: Alinia
intervention type: Dietary Supplement
intervention name: Nicotinamide
description: Mothers in the nicotinamide arm will be given nicotinamide 250 mg daily from delivery through 6 months post-partum in capsule form.
Children in the nicotinamide arm will be given 100 mg/d in powder form between 6 and 18 months of age
arm group label: Nicotinamide and Antimicrobials
arm group label: Nicotinamide only
other name: Vitamin B3
intervention type: Drug
intervention name: Placebos
description: Contain inert excipients only. Azithromycin placebo 20 mg/kg administered by study personnel at 6, 9, 12 and 15 months. Nitazoxanide placebo 100 mg given twice daily for 3 days at 12 and 15 months.
Mothers in the nicotinamide placebo arm will be given placebo 250 mg daily from delivery through 6 months post-partum in capsule form.
Children in the nicotinamide placebo arm will be given 100 mg/d of placebo in powder form between 6 and 18 months of age
arm group label: Antimicrobials only
arm group label: Nicotinamide only
arm group label: No active treatment
criteria: 
gender: All
minimum age: 0 Days
maximum age: 14 Days
healthy volunteers: No
last name: Estomih Mduma
role: Principal Investigator
affiliation: Haydom Lutheran Hospital
facility: 
country: Tanzania
responsible party type: Sponsor
mesh term: Malnutrition
mesh term: Niacinamide
mesh term: Niacin
mesh term: Nicotinic Acids
mesh term: Azithromycin
mesh term: Nitazoxanide
sharing ipd: No
provided document: 