<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/NCT03800381</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201801820 - HRZ PK -N</org_study_id>
    <secondary_id>5R01HD071779-11</secondary_id>
    <nct_id>NCT03800381</nct_id>
  </id_info>
  <brief_title>Adequacy of the New Pediatric Isoniazid/Rifampin/Pyrazinamide (HRZ) Tablet</brief_title>
  <official_title>Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</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>
      Lack of quality-assured pediatric formulations of the first-line antituberculosis (anti-TB)&#xD;
      drugs is barrier to optimized tuberculosis (TB) treatment outcome in children. In 2010 and&#xD;
      subsequently modified in 2014, the World Health Organization (WHO) recommended increased&#xD;
      dosages of the first-line anti-TB drugs for children, but there were no child-friendly&#xD;
      fixed-dose combination (FDC) formulations based on the guidelines. A large proportion of&#xD;
      children treated with the new guidelines using old formulations did not achieve the desired&#xD;
      rifampin peak concentration (Cmax) &gt; 8 mg/L and pyrazinamide Cmax &gt; 35 mg/L. The TB Alliance&#xD;
      and the WHO led the development of a new child-appropriate isoniazid/rifampin/pyrazinamide&#xD;
      (HRZ) and isoniazid/rifampin (HR) FDC formulation in line with current WHO recommended dosing&#xD;
      guidelines. The new formulations dissolve quickly in liquid, have palatable fruit flavors,&#xD;
      and are expected to improved daily adherence but no studies have evaluated the&#xD;
      pharmacokinetics (PK) of the FDC formulation in children. The study team hypothesize that the&#xD;
      new dispersible HRZ FDC tablet, dosed according to current WHO weight-band dosing&#xD;
      recommendations will result in better PK parameters for each drug component than that&#xD;
      achieved by the old formulation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will evaluate the PK of the new pediatric HRZ FDC tablet in Ghanaian children with&#xD;
      TB with and without HIV coinfection. The new HRZ FDC dispersible tablet was designed to be&#xD;
      child-friendly and to achieve recommended dosages for each weight-band. The formulation has&#xD;
      been rolled out in Africa without PK studies in the target population to verify that the&#xD;
      tablets achieves adequate drug concentrations. The current study will evaluate the adequacy&#xD;
      of the formulation by examining the PK of the component drugs as well as the effect of HIV&#xD;
      coinfection. The direct PK data will be used in a population PK model and stimulations to&#xD;
      define optimal weight-band dosages and proportions of the components of the pediatric FDC&#xD;
      tablets.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 28, 2019</start_date>
  <completion_date type="Anticipated">August 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Peak concentration (Cmax) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Mean and median Cmax of rifampin, isoniazid and pyrazinamide in children with TB treated with the new HRZ FDC tablet.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the time-concentration curve from 0-8 hours (AUC0-8h) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Mean and median AUC0-8h of rifampin, isoniazid and pyrazinamide in children with TB treated with the new HRZ FDC tablet.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Geometric mean values of Cmax of rifampin, isoniazid and pyrazinamide in children with HIV/TB coinfection compared to those with TB alone.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-8h of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection.</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Geometric mean values of AUC0-8h of rifampin, isoniazid and pyrazinamide in children with HIV/TB coinfection compared to those with TB alone.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AUC0-8h of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Geometric mean values of AUC0-8h of rifampin, isoniazid, and pyrazinamide in children with TB treated with the new FDC tablet compared to those treated with the old formulation in our previous study (historical controls).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Geometric mean values of Cmax of rifampin, isoniazid, and pyrazinamide in children with TB treated with the new FDC tablet compared to those treated with the old formulation in our previous study (historical controls).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of children treated with new pediatric HRZ FDC tablet who develop with liver enzymes elevations.</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Frequency of liver enzymes elevations compared to baseline requiring treatment modification in children with TB with and without HIV coinfection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify optimal weight-band dosages of the new HRZ FDC tablet</measure>
    <time_frame>After at least 4 weeks of anti-TB therapy</time_frame>
    <description>Use a population PK model that incorporates demographic, clinical and genetic factors and stimulations to identify the optimal weight-band dosing of the new FDC formulation.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">92</enrollment>
  <condition>Tuberculosis</condition>
  <condition>Human Immunodeficiency Virus</condition>
  <condition>Coinfection</condition>
  <arm_group>
    <arm_group_label>Active TB only</arm_group_label>
    <description>Children with clinical diagnosis or acid-fast bacilli (AFB) smear positive TB disease</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Active TB with HIV Co-infection</arm_group_label>
    <description>Children with clinical diagnosis or AFB smear positive TB disease who test positive for HIV infection</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Observational PK study</intervention_name>
    <description>The study team will examine the PK and tolerability of the new HRZ 50/75/150 mg dispersible tablet in children with TB with and without HIV coinfection. Intensive PK testing will be performed after at least 4 weeks of treatment in children on first-line anti-TB therapy using the new pediatric HRZ FDC tablet.</description>
    <arm_group_label>Active TB only</arm_group_label>
    <arm_group_label>Active TB with HIV Co-infection</arm_group_label>
    <other_name>New pediatric isoniazid/rifampin/pyrazinamide (HRZ) FDC tablet</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Ethylenediaminetetraacetic acid (EDTA) plasma and whole blood deoxyribonucleic acid (DNA)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Children aged 3 months to14 years with active TB with or without HIV co-infection&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children with active TB with or without HIV coinfection. Active TB diagnosis defined&#xD;
             by clinical criteria consistent with active TB and/or a positive AFB smear.&#xD;
&#xD;
          -  Available for follow-up until completion of TB treatment and/or achievement of a study&#xD;
             endpoint like discontinuation of therapy, and/or pharmacokinetic sampling.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Children with concurrent conditions other than HIV, have acute hepatitis within 30&#xD;
             days of study entry, persistent vomiting, and diarrhea will be excluded from the&#xD;
             study.&#xD;
&#xD;
          -  Unable to obtain informed signed consent from parent(s) or legal guardian.&#xD;
&#xD;
          -  Have AIDS-related opportunistic infections other than TB, history of or proven acute&#xD;
             hepatitis within 30 days of study entry, persistent vomiting, or diarrhea.&#xD;
&#xD;
          -  Hemoglobin &lt; 6 g/dl, white blood cells &lt; 2500/mm3, serum creatinine &gt; 1.5 mg/dl,&#xD;
             aspartate transaminase (AST) and alanine transaminase (ALT) &gt; 2 times upper limit of&#xD;
             normal.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>14 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Awewura Kwara, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Awewura Kwara, MD</last_name>
    <phone>3522739501</phone>
    <email>awewura.kwara@medicine.ufl.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Oluwayemisi Ojewale, MBChB, MPH</last_name>
    <phone>3522739446</phone>
    <email>Oluwayemisi.Ojewale@medicine.ufl.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Kwame Nkrumah University of Science and Technology</name>
      <address>
        <city>Kumasi</city>
        <country>Ghana</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sampson Antwi, MBChB</last_name>
      <phone>+233265812061</phone>
      <email>antwisampson@yahoo.com</email>
    </contact>
    <contact_backup>
      <last_name>Anthony Enimil, MBchB</last_name>
      <phone>+233208164433</phone>
      <email>tenimil@live.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Ghana</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 3, 2019</study_first_submitted>
  <study_first_submitted_qc>January 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>December 21, 2022</last_update_submitted>
  <last_update_submitted_qc>December 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pharmacokinetic</keyword>
  <keyword>Pharmacogenomic</keyword>
  <keyword>Antituberculosis drugs</keyword>
  <keyword>Children</keyword>
  <keyword>Tuberculosis</keyword>
  <keyword>TB/HIV coinfection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Coinfection</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Isoniazid</mesh_term>
    <mesh_term>Pyrazinamide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03800381
org study id: IRB201801820 - HRZ PK -N
secondary id: 5R01HD071779-11
nct id: NCT03800381
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
Lack of quality-assured pediatric formulations of the first-line antituberculosis (anti-TB)
      drugs is barrier to optimized tuberculosis (TB) treatment outcome in children. In 2010 and
      subsequently modified in 2014, the World Health Organization (WHO) recommended increased
      dosages of the first-line anti-TB drugs for children, but there were no child-friendly
      fixed-dose combination (FDC) formulations based on the guidelines. A large proportion of
      children treated with the new guidelines using old formulations did not achieve the desired
      rifampin peak concentration (Cmax) > 8 mg/L and pyrazinamide Cmax > 35 mg/L. The TB Alliance
      and the WHO led the development of a new child-appropriate isoniazid/rifampin/pyrazinamide
      (HRZ) and isoniazid/rifampin (HR) FDC formulation in line with current WHO recommended dosing
      guidelines. The new formulations dissolve quickly in liquid, have palatable fruit flavors,
      and are expected to improved daily adherence but no studies have evaluated the
      pharmacokinetics (PK) of the FDC formulation in children. The study team hypothesize that the
      new dispersible HRZ FDC tablet, dosed according to current WHO weight-band dosing
      recommendations will result in better PK parameters for each drug component than that
      achieved by the old formulation.
This study will evaluate the PK of the new pediatric HRZ FDC tablet in Ghanaian children with
      TB with and without HIV coinfection. The new HRZ FDC dispersible tablet was designed to be
      child-friendly and to achieve recommended dosages for each weight-band. The formulation has
      been rolled out in Africa without PK studies in the target population to verify that the
      tablets achieves adequate drug concentrations. The current study will evaluate the adequacy
      of the formulation by examining the PK of the component drugs as well as the effect of HIV
      coinfection. The direct PK data will be used in a population PK model and stimulations to
      define optimal weight-band dosages and proportions of the components of the pediatric FDC
      tablets.
observational model: Cohort
time perspective: Prospective
measure: Peak concentration (Cmax) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.
time frame: After at least 4 weeks of anti-TB therapy
description: Mean and median Cmax of rifampin, isoniazid and pyrazinamide in children with TB treated with the new HRZ FDC tablet.
measure: Area under the time-concentration curve from 0-8 hours (AUC0-8h) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.
time frame: After at least 4 weeks of anti-TB therapy
description: Mean and median AUC0-8h of rifampin, isoniazid and pyrazinamide in children with TB treated with the new HRZ FDC tablet.
measure: Cmax of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection
time frame: After at least 4 weeks of anti-TB therapy
description: Geometric mean values of Cmax of rifampin, isoniazid and pyrazinamide in children with HIV/TB coinfection compared to those with TB alone.
measure: AUC0-8h of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection.
time frame: After at least 4 weeks of anti-TB therapy
description: Geometric mean values of AUC0-8h of rifampin, isoniazid and pyrazinamide in children with HIV/TB coinfection compared to those with TB alone.
measure: AUC0-8h of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.
time frame: After at least 4 weeks of anti-TB therapy
description: Geometric mean values of AUC0-8h of rifampin, isoniazid, and pyrazinamide in children with TB treated with the new FDC tablet compared to those treated with the old formulation in our previous study (historical controls).
measure: Cmax of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.
time frame: After at least 4 weeks of anti-TB therapy
description: Geometric mean values of Cmax of rifampin, isoniazid, and pyrazinamide in children with TB treated with the new FDC tablet compared to those treated with the old formulation in our previous study (historical controls).
measure: Proportion of children treated with new pediatric HRZ FDC tablet who develop with liver enzymes elevations.
time frame: After at least 4 weeks of anti-TB therapy
description: Frequency of liver enzymes elevations compared to baseline requiring treatment modification in children with TB with and without HIV coinfection.
measure: Identify optimal weight-band dosages of the new HRZ FDC tablet
time frame: After at least 4 weeks of anti-TB therapy
description: Use a population PK model that incorporates demographic, clinical and genetic factors and stimulations to identify the optimal weight-band dosing of the new FDC formulation.
arm group label: Active TB only
description: Children with clinical diagnosis or acid-fast bacilli (AFB) smear positive TB disease
arm group label: Active TB with HIV Co-infection
description: Children with clinical diagnosis or AFB smear positive TB disease who test positive for HIV infection
intervention type: Other
intervention name: Observational PK study
description: The study team will examine the PK and tolerability of the new HRZ 50/75/150 mg dispersible tablet in children with TB with and without HIV coinfection. Intensive PK testing will be performed after at least 4 weeks of treatment in children on first-line anti-TB therapy using the new pediatric HRZ FDC tablet.
arm group label: Active TB only
arm group label: Active TB with HIV Co-infection
other name: New pediatric isoniazid/rifampin/pyrazinamide (HRZ) FDC tablet
Ethylenediaminetetraacetic acid (EDTA) plasma and whole blood deoxyribonucleic acid (DNA)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 3 Months
maximum age: 14 Years
healthy volunteers: No
last name: Awewura Kwara, MD
role: Principal Investigator
affiliation: University of Florida
last name: Awewura Kwara, MD
phone: 3522739501
email: awewura.kwara@medicine.ufl.edu
last name: Oluwayemisi Ojewale, MBChB, MPH
phone: 3522739446
email: Oluwayemisi.Ojewale@medicine.ufl.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: Ghana
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Coinfection
mesh term: Rifampin
mesh term: Isoniazid
mesh term: Pyrazinamide
sharing ipd: Undecided