<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/NCT01699633</url>
  </required_header>
  <id_info>
    <org_study_id>PK-TBHIV02</org_study_id>
    <secondary_id>R01HD071779</secondary_id>
    <nct_id>NCT01699633</nct_id>
  </id_info>
  <brief_title>Rifampin and Nevirapine Interactions in Young Children</brief_title>
  <official_title>Effect of Rifampin-containing Anti-TB Therapy on Nevirapine Plasma Pharmacokinetics in HIV/TB Co-infected Children &lt; 3 Years Old</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Miriam Hospital</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>The Miriam Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Nevirapine is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) for&#xD;
      treatment of HIV in children younger than 3 years old who have tuberculosis (TB) coinfection.&#xD;
      However, there is very limited data on the drug-drug interactions between rifampin and&#xD;
      nevirapine in children of this age group. The purpose of this study is to determine the&#xD;
      effect of rifampin-containing anti-TB treatment on the blood levels of nevirapine in young&#xD;
      children with HIV and TB coinfection. Also, the study will find out whether checking the&#xD;
      genetic makeup of a child could help to determine the appropriate dose of nevirapine in the&#xD;
      setting of concomitant anti-TB treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      HIV and TB coinfection is a common and a major cause of death in children globally. Treatment&#xD;
      of the two infections together at the same time saves lives but some of the TB medications&#xD;
      have significant drug-drug interactions with commonly used antiretroviral drugs (ARVs).&#xD;
      Rifampin induces the activity of cytochorme P450 (CYP) enzymes and may reduce the blood&#xD;
      levels of important ARVs such as nevirapine or efavirenz when coadministered. The CYP enzymes&#xD;
      activity can vary from person to person depending on genetic makeup, further complicating&#xD;
      drug-drug interactions. Nevirapine undergoes extensive metabolism by hepatic CYP3A and CYP2B6&#xD;
      enzymes. The induction of CYP3A4 and 2B6 by rifampin causes a 10 - 68% reduction in&#xD;
      nevirapine exposure upon concomitant dosing in adults. Pharmacokinetic studies suggest that&#xD;
      nevirapine trough concentrations in HIV-infected children tend to be lower or sub-therapeutic&#xD;
      in children younger than 3 years old. To our knowledge, the only study that evaluated the&#xD;
      influence of rifampin on nevirapine plasma concentrations in younger children reported&#xD;
      substantial reductions in nevirapine concentrations with rifampin co-administration. It is&#xD;
      currently unclear whether using the recommended nevirapine dose (200 mg/m2 twice daily)&#xD;
      without the two-week lead-in of 200 mg/m2 once daily will overcome the risk of&#xD;
      sub-therapeutic concentrations in the setting of concomitant anti-TB treatment. This study&#xD;
      will investigate the effect of rifampin-containing anti-TB therapy on nevirapine plasma&#xD;
      concentration in children younger than 3 years old, as well as find out whether CYP2B6 and&#xD;
      CYP3A4 enzymes genetic polymorphisms influence the magnitude of the drug-drug interactions.&#xD;
&#xD;
      Specific hypotheses to be tested are:&#xD;
&#xD;
        1. Rifampin-containing anti-TB therapy substantially reduces nevirapine Cmin and estimated&#xD;
           AUC0-12h in young HIV-infected children (by at least 40%).&#xD;
&#xD;
        2. CYP2B6 extensive metabolizers have substantially lower plasma nevirapine Cmin and&#xD;
           estimated AUC0-12h in the presence than in the absence of rifampin-containing TB&#xD;
           therapy, but no significant difference in intermediate and slow metabolizers.&#xD;
&#xD;
      A two-arm parallel assignment pharmacokinetic study in TB/HIV co-infected children will be&#xD;
      performed at the KATH. Children aged 3 - 35 months with HIV infection with or without TB&#xD;
      coinfection, antiretroviral therapy (ART)-naïve, not previously exposed to nevirapine will be&#xD;
      enrolled. The ART regimen will consist of nevirapine 200 mg/m2 plus zidovudine (ZDV) 180 -&#xD;
      240 mg/m2 and lamivudine (3TC) 4 mg/kg twice daily in accordance with WHO guidelines. There&#xD;
      will be no lead-in dosing of nevirapine in the co-infected patients on rifampin. The dose of&#xD;
      nevirapine in the HIV mono-infected group will be 200 mg/m2 daily x 2 weeks and then twice&#xD;
      daily afterwards. Standard anti-TB therapy will be prescribed to the HIV/TB co-infected&#xD;
      patients. Anti-TB treatment will start immediately upon diagnosis. Antiretroviral therapy&#xD;
      will be started as soon as anti-TB therapy is tolerated (typically within 2 to 8 weeks).&#xD;
&#xD;
      A complete medical history, physical examination, and staging of HIV disease will be&#xD;
      performed before initiation of ART and at subsequent study visits. Relevant data will be&#xD;
      collected using standardized forms. Baseline measurements prior to initiation of ART will&#xD;
      include complete blood count (CBC), blood urea nitrogen, creatinine, liver function tests&#xD;
      (LFTs), CD4 cell count determination and plasma HIV-1 RNA level. Measurements of CD4 cell&#xD;
      count and plasma HIV-1 RNA will be repeated at weeks 12 and 24 after starting ART. All study&#xD;
      participants will follow-up at 2 and 4 weeks, as well as monthly for assessment of treatment&#xD;
      side effects. Additional tests will be done when clinically indicated to evaluate for drug&#xD;
      toxicity.&#xD;
&#xD;
      Pharmacokinetic testing will be performed at week 4 of ART in both arms and at 4 weeks after&#xD;
      anti-TB treatment is stopped while the child is receiving ART only in the HIV/TB co-infected&#xD;
      group. All patients will be admitted to the hospital the night prior to complete PK sampling.&#xD;
      Study drugs will be administered after at least a 2-hour fast in non-breastfed children.&#xD;
      Younger children on exclusive breast-feeding will be allowed to breast feed as needed&#xD;
      throughout the study. At each sampling time, 2 mL of blood will be collected into an EDTA&#xD;
      tube at times 0, 2, 6 and 12 hours post-dose for determination of nevirapine concentrations.&#xD;
      Actual times of sampling will be recorded. The blood samples will be centrifuged at 3000g for&#xD;
      10 minutes and plasma stored at - 70oC until measurement of plasma drug concentrations.&#xD;
      Nevirapine concentrations in plasma will be measured using validated gas chromatography with&#xD;
      mass spectrometry and nonlinear mixed-effects modeling (using NONMEM, version VI) will be&#xD;
      used to estimate pharmacokinetic parameters (CL/F, AUC, Cmin, Cmax), inter-individual error,&#xD;
      and residual error. DNA sample will stored for genotyping of drug metabolizing enzymes and&#xD;
      transporters.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>October 2012</start_date>
  <completion_date type="Anticipated">May 2017</completion_date>
  <primary_completion_date type="Anticipated">May 2017</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>Area under time curve (AUC) of nevirapine</measure>
    <time_frame>At week of 4 of HIV therapy</time_frame>
    <description>Compare nevirapine AUC0-12h between HIV-infected children without TB and those with TB, as well as in the absence of and presence of rifampin-containing anti-TB therapy in co-infected patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of children with grade 3 or 4 liver enzymes elevations compared to baseline, new onset of skin rash, nausea, vomiting or treatment modification due to drug side effects</measure>
    <time_frame>Up to week 24 of HIV therapy</time_frame>
    <description>Compare frequency of adverse events as a measure of safety and tolerability between HIV-infected children with and without TB coinfection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with nevirapine 12-hour post-dose concentration (C12h) &lt; 3000 ng/mL</measure>
    <time_frame>Week 4 of HIV therapy</time_frame>
    <description>Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6, CYP3A4 polymorphisms) and nevirapine C12h will be investigated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to HIV-1 RNA suppression below 50 copies/mL and change in CD4 cell count from baseline</measure>
    <time_frame>Up to week 24 of HIV therapy</time_frame>
    <description>Relationship between nevirapine pharmacokinetics (AUC0-12h, C12h) and time to virologic suppression as well as increase in CD4 cell count from baseline in the combined study population</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak concentration (Cmax) and concentration at 12-hours (C12h) post-dose of nevirapine</measure>
    <time_frame>At week 4 of therapy</time_frame>
    <description>Compare nevirapine Cmax and C12h between HIV-infected children without TB and those with TB, as well as in the absence of and presence of rifampin-containing anti-TB therapy in co-infected patients</description>
  </secondary_outcome>
  <enrollment type="Anticipated">58</enrollment>
  <condition>Tuberculosis</condition>
  <condition>HIV</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      EDTA Plasma Whole blood DNA&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Children aged 3 to 35 months with HIV infection with or without TB&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. HIV seropositive children with or without active TB&#xD;
&#xD;
          2. Aged 3 to 35 months old&#xD;
&#xD;
          3. Antiretroviral-naïve and meet criteria for initiation of antiretroviral therapy&#xD;
&#xD;
          4. Are available for follow-up until achievement of a study endpoint like completion of&#xD;
             study or discontinuation of HAART, and/or PK sampling&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unable to obtain informed signed consent parent(s) or legal guardian&#xD;
&#xD;
          2. 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;
          3. Hemoglobin &lt; 6 g/dl, white blood cells &lt; 2500/mm3, serum creatinine &gt; 1.5 mg/dl, AST&#xD;
             and ALT &gt; 2X upper limit of normal.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>35 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Awewura Kwara, MD, MPH&amp;TM</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Miriam Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Awewura Kwara, MD, MPH&amp;TM</last_name>
    <phone>4017932463</phone>
    <email>akwara@lifespan.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sampson Antwi, MBChB</last_name>
    <phone>+233265812061</phone>
    <email>antwisampson@yahoo.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Komfo Anokye Teaching Hospital</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>antwisampson10@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>September 2012</verification_date>
  <study_first_submitted>September 14, 2012</study_first_submitted>
  <study_first_submitted_qc>October 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>October 11, 2012</last_update_submitted>
  <last_update_submitted_qc>October 11, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 12, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug-drug interactions</keyword>
  <keyword>Drug-gene interactions</keyword>
  <keyword>Nevirapine</keyword>
  <keyword>Rifampicin</keyword>
  <keyword>children</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <!-- 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/NCT01699633
org study id: PK-TBHIV02
secondary id: R01HD071779
nct id: NCT01699633
lead sponsor: 
collaborator: 
has dmc: Yes
Nevirapine is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) for
      treatment of HIV in children younger than 3 years old who have tuberculosis (TB) coinfection.
      However, there is very limited data on the drug-drug interactions between rifampin and
      nevirapine in children of this age group. The purpose of this study is to determine the
      effect of rifampin-containing anti-TB treatment on the blood levels of nevirapine in young
      children with HIV and TB coinfection. Also, the study will find out whether checking the
      genetic makeup of a child could help to determine the appropriate dose of nevirapine in the
      setting of concomitant anti-TB treatment.
HIV and TB coinfection is a common and a major cause of death in children globally. Treatment
      of the two infections together at the same time saves lives but some of the TB medications
      have significant drug-drug interactions with commonly used antiretroviral drugs (ARVs).
      Rifampin induces the activity of cytochorme P450 (CYP) enzymes and may reduce the blood
      levels of important ARVs such as nevirapine or efavirenz when coadministered. The CYP enzymes
      activity can vary from person to person depending on genetic makeup, further complicating
      drug-drug interactions. Nevirapine undergoes extensive metabolism by hepatic CYP3A and CYP2B6
      enzymes. The induction of CYP3A4 and 2B6 by rifampin causes a 10 - 68% reduction in
      nevirapine exposure upon concomitant dosing in adults. Pharmacokinetic studies suggest that
      nevirapine trough concentrations in HIV-infected children tend to be lower or sub-therapeutic
      in children younger than 3 years old. To our knowledge, the only study that evaluated the
      influence of rifampin on nevirapine plasma concentrations in younger children reported
      substantial reductions in nevirapine concentrations with rifampin co-administration. It is
      currently unclear whether using the recommended nevirapine dose (200 mg/m2 twice daily)
      without the two-week lead-in of 200 mg/m2 once daily will overcome the risk of
      sub-therapeutic concentrations in the setting of concomitant anti-TB treatment. This study
      will investigate the effect of rifampin-containing anti-TB therapy on nevirapine plasma
      concentration in children younger than 3 years old, as well as find out whether CYP2B6 and
      CYP3A4 enzymes genetic polymorphisms influence the magnitude of the drug-drug interactions.

      Specific hypotheses to be tested are:

        1. Rifampin-containing anti-TB therapy substantially reduces nevirapine Cmin and estimated
           AUC0-12h in young HIV-infected children (by at least 40%).

        2. CYP2B6 extensive metabolizers have substantially lower plasma nevirapine Cmin and
           estimated AUC0-12h in the presence than in the absence of rifampin-containing TB
           therapy, but no significant difference in intermediate and slow metabolizers.

      A two-arm parallel assignment pharmacokinetic study in TB/HIV co-infected children will be
      performed at the KATH. Children aged 3 - 35 months with HIV infection with or without TB
      coinfection, antiretroviral therapy (ART)-naïve, not previously exposed to nevirapine will be
      enrolled. The ART regimen will consist of nevirapine 200 mg/m2 plus zidovudine (ZDV) 180 -
      240 mg/m2 and lamivudine (3TC) 4 mg/kg twice daily in accordance with WHO guidelines. There
      will be no lead-in dosing of nevirapine in the co-infected patients on rifampin. The dose of
      nevirapine in the HIV mono-infected group will be 200 mg/m2 daily x 2 weeks and then twice
      daily afterwards. Standard anti-TB therapy will be prescribed to the HIV/TB co-infected
      patients. Anti-TB treatment will start immediately upon diagnosis. Antiretroviral therapy
      will be started as soon as anti-TB therapy is tolerated (typically within 2 to 8 weeks).

      A complete medical history, physical examination, and staging of HIV disease will be
      performed before initiation of ART and at subsequent study visits. Relevant data will be
      collected using standardized forms. Baseline measurements prior to initiation of ART will
      include complete blood count (CBC), blood urea nitrogen, creatinine, liver function tests
      (LFTs), CD4 cell count determination and plasma HIV-1 RNA level. Measurements of CD4 cell
      count and plasma HIV-1 RNA will be repeated at weeks 12 and 24 after starting ART. All study
      participants will follow-up at 2 and 4 weeks, as well as monthly for assessment of treatment
      side effects. Additional tests will be done when clinically indicated to evaluate for drug
      toxicity.

      Pharmacokinetic testing will be performed at week 4 of ART in both arms and at 4 weeks after
      anti-TB treatment is stopped while the child is receiving ART only in the HIV/TB co-infected
      group. All patients will be admitted to the hospital the night prior to complete PK sampling.
      Study drugs will be administered after at least a 2-hour fast in non-breastfed children.
      Younger children on exclusive breast-feeding will be allowed to breast feed as needed
      throughout the study. At each sampling time, 2 mL of blood will be collected into an EDTA
      tube at times 0, 2, 6 and 12 hours post-dose for determination of nevirapine concentrations.
      Actual times of sampling will be recorded. The blood samples will be centrifuged at 3000g for
      10 minutes and plasma stored at - 70oC until measurement of plasma drug concentrations.
      Nevirapine concentrations in plasma will be measured using validated gas chromatography with
      mass spectrometry and nonlinear mixed-effects modeling (using NONMEM, version VI) will be
      used to estimate pharmacokinetic parameters (CL/F, AUC, Cmin, Cmax), inter-individual error,
      and residual error. DNA sample will stored for genotyping of drug metabolizing enzymes and
      transporters.
observational model: Cohort
time perspective: Prospective
measure: Area under time curve (AUC) of nevirapine
time frame: At week of 4 of HIV therapy
description: Compare nevirapine AUC0-12h between HIV-infected children without TB and those with TB, as well as in the absence of and presence of rifampin-containing anti-TB therapy in co-infected patients
measure: Number of children with grade 3 or 4 liver enzymes elevations compared to baseline, new onset of skin rash, nausea, vomiting or treatment modification due to drug side effects
time frame: Up to week 24 of HIV therapy
description: Compare frequency of adverse events as a measure of safety and tolerability between HIV-infected children with and without TB coinfection
measure: Number of children with nevirapine 12-hour post-dose concentration (C12h) < 3000 ng/mL
time frame: Week 4 of HIV therapy
description: Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6, CYP3A4 polymorphisms) and nevirapine C12h will be investigated
measure: Time to HIV-1 RNA suppression below 50 copies/mL and change in CD4 cell count from baseline
time frame: Up to week 24 of HIV therapy
description: Relationship between nevirapine pharmacokinetics (AUC0-12h, C12h) and time to virologic suppression as well as increase in CD4 cell count from baseline in the combined study population
measure: Peak concentration (Cmax) and concentration at 12-hours (C12h) post-dose of nevirapine
time frame: At week 4 of therapy
description: Compare nevirapine Cmax and C12h between HIV-infected children without TB and those with TB, as well as in the absence of and presence of rifampin-containing anti-TB therapy in co-infected patients
EDTA Plasma Whole blood DNA
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 3 Months
maximum age: 35 Months
healthy volunteers: No
last name: Awewura Kwara, MD, MPH&TM
role: Principal Investigator
affiliation: The Miriam Hospital
last name: Awewura Kwara, MD, MPH&TM
phone: 4017932463
email: akwara@lifespan.org
last name: Sampson Antwi, MBChB
phone: +233265812061
email: antwisampson@yahoo.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Ghana
responsible party type: Sponsor
mesh term: Tuberculosis