<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/NCT01704144</url>
  </required_header>
  <id_info>
    <org_study_id>PK-PTBHIV03</org_study_id>
    <secondary_id>R01HD071779</secondary_id>
    <nct_id>NCT01704144</nct_id>
  </id_info>
  <brief_title>Rifampin and Efavirenz Interactions in Older Children</brief_title>
  <official_title>Effect of Rifampin-containing Anti-TB Treatment on Efavirenz Pharmacokinetics in HIV/TB Co-infected Children Aged 3 - 14 Years</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>
      Efavirenz is an essential component of HIV treatment in children aged 3 years or older on&#xD;
      anti-tuberculosis (anti-TB) treatment. However, the appropriate efavirenz dose during anti-TB&#xD;
      treatment remains unclear. Rifampin (an anti-TB drug) increases the activity of the drug&#xD;
      metabolizing enzymes that breakdown efavirenz, which may lead to low blood levels of&#xD;
      efavirenz and treatment failure during cotreatment. The drug-to-drug interactions between the&#xD;
      HIV and anti-TB drugs also vary between individuals based on genetic factors. This study will&#xD;
      investigate the effects of anti-TB treatment, as well as drug-gene interactions on the blood&#xD;
      concentrations of efavirenz in children with HIV and TB infections. Such data could enhance&#xD;
      optimization of efavirenz dosage or selection of alternate regimens in some children.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Efavirenz-based antiretroviral therapy (ART) is the preferred regimen in children older than&#xD;
      3 years on rifampin-containing anti-TB therapy. Efavirenz trough plasma concentrations below&#xD;
      1000 ng/mL have been associated with increased risk of virologic failure among HIV-infected&#xD;
      adults, while concentrations above 4000 ng/mL have been associated with risk of central&#xD;
      nervous system side effects. Efavirenz is primarily metabolized by hepatic CYP2B6, with&#xD;
      secondary contributions from CYP2A6. On average, rifampin co-administration causes a 26%&#xD;
      reduction in efavirenz plasma exposure but some individuals have paradoxically elevated&#xD;
      efavirenz concentrations with co-administration in adult pharmacokinetic studies. The&#xD;
      inter-individual variability in the drug-to-drug interactions suggest that efavirenz dose&#xD;
      adjustment with concomitant anti-TB therapy may not be necessary in some patients. In&#xD;
      children, there is very limited data on the pharmacokinetic interactions between&#xD;
      rifampin-containing TB treatment and efavirenz. To our knowledge, there is only one published&#xD;
      study in children to date. Among 15 TB/HIV co-infected children treated with standard&#xD;
      efavirenz-based active antiretroviral therapy and rifampin-containing TB treatment, a wide&#xD;
      inter-patient variability in efavirenz concentration as well as a bimodal distribution of&#xD;
      efavirenz trough concentrations were observed. Overall, rifampin-containing anti-TB treatment&#xD;
      had no significant influence on the mean change in efavirenz concentration in the study&#xD;
      population as a whole, but 60% and 53% of children had efavirenz trough concentration &lt; 1000&#xD;
      ng/mL during and after anti-TB, respectively. This data suggest that current dosing of&#xD;
      efavirenz may be suboptimal in a large proportion of children irrespective of anti-TB&#xD;
      therapy. To overcome the risk of under-dosing of efavirenz especially with concurrent anti-TB&#xD;
      treatment, the WHO recommended prescribing the maximum dose for each weight-band when&#xD;
      efavirenz is coadministered with anti-TB treatment. This study seeks to evaluate whether the&#xD;
      current dosing of efavirenz provides adequate efavirenz concentrations in children, as well&#xD;
      as explore how genetic factors influence efavirenz pharmacokinetics with concomitant anti-TB&#xD;
      treatment. The specific hypotheses to be tested are:&#xD;
&#xD;
        1. At the population level, efavirenz plasma concentrations in TB/HIV co-infected children&#xD;
           who are treated with the maximized weight-based efavirenz dosage during&#xD;
           rifampin-containing anti-TB therapy will be comparable to concentrations in HIV-infected&#xD;
           children receiving ART without anti-TB treatment.&#xD;
&#xD;
        2. Co-treatment with rifampin- and efavirenz-containing therapies will lead to&#xD;
           substantially decreased (by at least 40%) efavirenz concentration in the children with&#xD;
           CYP2B6 extensive but not in those with intermediate or slow metabolizer genotypes.&#xD;
&#xD;
      A two-arm, as well as a two-period pharmacokinetic study in HIV-infected children with and&#xD;
      without TB will be performed at the Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana.&#xD;
      Eligible participants will include children aged 3 - 14 years with HIV with or without TB&#xD;
      coinfection, ART-naïve and eligible to initiate ART. The ART regimen will consist of the WHO&#xD;
      recommended weight-band dosing of efavirenz (10-13.9kg - 200 mg; 14-24.9kg - 300mg; 25-39.9kg&#xD;
      - 400 mg and &gt; 40Kg - 600 mg), plus ZDV 180 - 240 mg/m2 and 3TC 4 mg/kg twice daily.&#xD;
      Tenofovir may be used in place of ZDV. Standard anti-TB therapy will be prescribed to the&#xD;
      co-infected patients and will start immediately upon TB diagnosis.&#xD;
&#xD;
      A complete medical history, physical examination, and staging of HIV disease will be&#xD;
      performed before initiation of ART. Baseline measurements prior to initiation of ART will&#xD;
      include CBC, blood urea nitrogen, creatinine, LFTs, CD4 cell count determination and plasma&#xD;
      HIV-1 RNA level. Weeks 12 and 24 CD4 cell count and plasma HIV-1 RNA will obtained at&#xD;
      scheduled follow-up. Pharmacokinetic sampling will be performed at week 4 of ART in both arms&#xD;
      and at 4 weeks after anti-TB treatment in the co-infected group. At each sampling time, 3 mL&#xD;
      of blood will be collected into an EDTA tube. Blood samples will be collected at times 0 2,&#xD;
      8, 12 and 24 hours post-dose for determination of efavirenz concentrations. Efavirenz&#xD;
      concentrations in plasma will be measured using a HPLC-MS. After sample analysis, a data set&#xD;
      will be constructed. Anticipated covariates included in this data set to be explored will&#xD;
      include age, sex, weight, relevant drug-metabolizing enzyme genotype, TB therapy status&#xD;
      (on/off), and CD4 cell count. Nonlinear mixed-effects modeling (using NONMEM, version VI)&#xD;
      will be used to estimate pharmacokinetic parameters (CL/F, V/F, AUC, Cmin, Cmax, elimination&#xD;
      rate constant), inter-individual error, and residual error. Results of this population&#xD;
      analysis may be used to simulate alternative efavirenz dosing strategies in this TB/HIV&#xD;
      co-infected population, or in relevant sub-populations with variant PK/pharmacogenetics.&#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 from time 0-24 hours(AUC0-24h) of efavirenz</measure>
    <time_frame>At week of 4 of HIV therapy</time_frame>
    <description>Compare efavirenz AUC0-24h between HIV-infected children without TB and those with TB on 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 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 efavirenz 24-hour post-dose concentration (C24h) &lt; 1000 ng/mL</measure>
    <time_frame>At week 4 of therapy</time_frame>
    <description>Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6 516G&gt;T, as well as CYP3A4, ABCB1, CAR and PXR polymorphisms) and efavirenz AUC0-24h and efavirenz C24h will be investigated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children who discontinue efavirenz therapy due to drug side effects</measure>
    <time_frame>Up to week 24 of HIV therapy</time_frame>
    <description>Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6 polymorphisms) and treatment modification due to drug side effects in the combined study population</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough concentration (C24h) of efavirenz</measure>
    <time_frame>At week 4 of therapy</time_frame>
    <description>Compare efavirenz C24h 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>
  <secondary_outcome>
    <measure>AUC, Cmax and clearance of efavirenz on and off rifampin-containing anti-Tb therapy in HIV/TB co-infected patients</measure>
    <time_frame>at week 24 of therapy</time_frame>
  </secondary_outcome>
  <enrollment type="Anticipated">160</enrollment>
  <condition>HIV</condition>
  <condition>Tuberculosis</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      EDTA plasma Whole blood DNA&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HIV-infected children with and with TB aged 3 to 14 years old&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Children with active TB with or without HIV co-infection. Active TB diagnosis defined&#xD;
             by clinical criteria consistent with active TB and/or a positive AFB smear or&#xD;
             mycobacterial culture.&#xD;
&#xD;
          2. Aged 3 months to 14 years old&#xD;
&#xD;
          3. Are available for follow-up until completion of TB treatment and/or achievement of a&#xD;
             study endpoint like discontinuation of therapy, and/or pharmacokinetic 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 Years</minimum_age>
    <maximum_age>14 Years</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>antwisampson10@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>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 11, 2012</study_first_posted>
  <last_update_submitted>October 16, 2012</last_update_submitted>
  <last_update_submitted_qc>October 16, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 17, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Efavirenz</keyword>
  <keyword>rifampin</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Drug-drug interactions</keyword>
  <keyword>Drug-gene interactions</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/NCT01704144
org study id: PK-PTBHIV03
secondary id: R01HD071779
nct id: NCT01704144
lead sponsor: 
collaborator: 
has dmc: Yes
Efavirenz is an essential component of HIV treatment in children aged 3 years or older on
      anti-tuberculosis (anti-TB) treatment. However, the appropriate efavirenz dose during anti-TB
      treatment remains unclear. Rifampin (an anti-TB drug) increases the activity of the drug
      metabolizing enzymes that breakdown efavirenz, which may lead to low blood levels of
      efavirenz and treatment failure during cotreatment. The drug-to-drug interactions between the
      HIV and anti-TB drugs also vary between individuals based on genetic factors. This study will
      investigate the effects of anti-TB treatment, as well as drug-gene interactions on the blood
      concentrations of efavirenz in children with HIV and TB infections. Such data could enhance
      optimization of efavirenz dosage or selection of alternate regimens in some children.
Efavirenz-based antiretroviral therapy (ART) is the preferred regimen in children older than
      3 years on rifampin-containing anti-TB therapy. Efavirenz trough plasma concentrations below
      1000 ng/mL have been associated with increased risk of virologic failure among HIV-infected
      adults, while concentrations above 4000 ng/mL have been associated with risk of central
      nervous system side effects. Efavirenz is primarily metabolized by hepatic CYP2B6, with
      secondary contributions from CYP2A6. On average, rifampin co-administration causes a 26%
      reduction in efavirenz plasma exposure but some individuals have paradoxically elevated
      efavirenz concentrations with co-administration in adult pharmacokinetic studies. The
      inter-individual variability in the drug-to-drug interactions suggest that efavirenz dose
      adjustment with concomitant anti-TB therapy may not be necessary in some patients. In
      children, there is very limited data on the pharmacokinetic interactions between
      rifampin-containing TB treatment and efavirenz. To our knowledge, there is only one published
      study in children to date. Among 15 TB/HIV co-infected children treated with standard
      efavirenz-based active antiretroviral therapy and rifampin-containing TB treatment, a wide
      inter-patient variability in efavirenz concentration as well as a bimodal distribution of
      efavirenz trough concentrations were observed. Overall, rifampin-containing anti-TB treatment
      had no significant influence on the mean change in efavirenz concentration in the study
      population as a whole, but 60% and 53% of children had efavirenz trough concentration < 1000
      ng/mL during and after anti-TB, respectively. This data suggest that current dosing of
      efavirenz may be suboptimal in a large proportion of children irrespective of anti-TB
      therapy. To overcome the risk of under-dosing of efavirenz especially with concurrent anti-TB
      treatment, the WHO recommended prescribing the maximum dose for each weight-band when
      efavirenz is coadministered with anti-TB treatment. This study seeks to evaluate whether the
      current dosing of efavirenz provides adequate efavirenz concentrations in children, as well
      as explore how genetic factors influence efavirenz pharmacokinetics with concomitant anti-TB
      treatment. The specific hypotheses to be tested are:

        1. At the population level, efavirenz plasma concentrations in TB/HIV co-infected children
           who are treated with the maximized weight-based efavirenz dosage during
           rifampin-containing anti-TB therapy will be comparable to concentrations in HIV-infected
           children receiving ART without anti-TB treatment.

        2. Co-treatment with rifampin- and efavirenz-containing therapies will lead to
           substantially decreased (by at least 40%) efavirenz concentration in the children with
           CYP2B6 extensive but not in those with intermediate or slow metabolizer genotypes.

      A two-arm, as well as a two-period pharmacokinetic study in HIV-infected children with and
      without TB will be performed at the Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana.
      Eligible participants will include children aged 3 - 14 years with HIV with or without TB
      coinfection, ART-naïve and eligible to initiate ART. The ART regimen will consist of the WHO
      recommended weight-band dosing of efavirenz (10-13.9kg - 200 mg; 14-24.9kg - 300mg; 25-39.9kg
      - 400 mg and > 40Kg - 600 mg), plus ZDV 180 - 240 mg/m2 and 3TC 4 mg/kg twice daily.
      Tenofovir may be used in place of ZDV. Standard anti-TB therapy will be prescribed to the
      co-infected patients and will start immediately upon TB diagnosis.

      A complete medical history, physical examination, and staging of HIV disease will be
      performed before initiation of ART. Baseline measurements prior to initiation of ART will
      include CBC, blood urea nitrogen, creatinine, LFTs, CD4 cell count determination and plasma
      HIV-1 RNA level. Weeks 12 and 24 CD4 cell count and plasma HIV-1 RNA will obtained at
      scheduled follow-up. Pharmacokinetic sampling will be performed at week 4 of ART in both arms
      and at 4 weeks after anti-TB treatment in the co-infected group. At each sampling time, 3 mL
      of blood will be collected into an EDTA tube. Blood samples will be collected at times 0 2,
      8, 12 and 24 hours post-dose for determination of efavirenz concentrations. Efavirenz
      concentrations in plasma will be measured using a HPLC-MS. After sample analysis, a data set
      will be constructed. Anticipated covariates included in this data set to be explored will
      include age, sex, weight, relevant drug-metabolizing enzyme genotype, TB therapy status
      (on/off), and CD4 cell count. Nonlinear mixed-effects modeling (using NONMEM, version VI)
      will be used to estimate pharmacokinetic parameters (CL/F, V/F, AUC, Cmin, Cmax, elimination
      rate constant), inter-individual error, and residual error. Results of this population
      analysis may be used to simulate alternative efavirenz dosing strategies in this TB/HIV
      co-infected population, or in relevant sub-populations with variant PK/pharmacogenetics.
observational model: Cohort
time perspective: Prospective
measure: Area under time curve from time 0-24 hours(AUC0-24h) of efavirenz
time frame: At week of 4 of HIV therapy
description: Compare efavirenz AUC0-24h between HIV-infected children without TB and those with TB on 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 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 efavirenz 24-hour post-dose concentration (C24h) < 1000 ng/mL
time frame: At week 4 of therapy
description: Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6 516G>T, as well as CYP3A4, ABCB1, CAR and PXR polymorphisms) and efavirenz AUC0-24h and efavirenz C24h will be investigated
measure: Number of children who discontinue efavirenz therapy due to drug side effects
time frame: Up to week 24 of HIV therapy
description: Relationship between clinical factors (weight, gender, nutritional status) as well as genetic factors (CYP2B6 polymorphisms) and treatment modification due to drug side effects in the combined study population
measure: Trough concentration (C24h) of efavirenz
time frame: At week 4 of therapy
description: Compare efavirenz C24h 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: AUC, Cmax and clearance of efavirenz on and off rifampin-containing anti-Tb therapy in HIV/TB co-infected patients
time frame: at week 24 of therapy
EDTA plasma Whole blood DNA
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 3 Years
maximum age: 14 Years
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: antwisampson10@yahoo.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Ghana
responsible party type: Sponsor
mesh term: Tuberculosis