<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/NCT04487145</url>
  </required_header>
  <id_info>
    <org_study_id>18-26978</org_study_id>
    <secondary_id>2R01HD068174-06A1</secondary_id>
    <nct_id>NCT04487145</nct_id>
  </id_info>
  <brief_title>Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy</brief_title>
  <acronym>DPART</acronym>
  <official_title>DPART Study: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Makerere University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <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 California, San Francisco</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Open-label prospective intensive pharmacokinetic study of dihydroartemisinin-piperaquine (DP)&#xD;
      in HIV-infected children on efavirenz (EFV)-, lopinavir/ritonavir (LPV/r)-, or dolutegravir&#xD;
      (DTG)-based antiretroviral therapy (ART) and HIV-uninfected children not on ART. All children&#xD;
      will be malaria-uninfected at the time of enrollment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary goal of the study is to assess the pharmacokinetics (PK) and safety of DP in the&#xD;
      setting of co-administration with first-line ART regimens (EFV-, LPV/r- or DTG-based ART) in&#xD;
      children without malaria. Up to 190 children will be enrolled in one of the 5 groups: 1,&#xD;
      HIV-infected children age 3 - 10 years on LPV/r-based ART (n=20 for signal dose DP, 30&#xD;
      standard 3-dose DP). 2, HIV-infected children age 3 - 10 years on EFV-based ART (n=30), 3,&#xD;
      HIV-infected children age 11 - 17 years on DTG-based ART (n=30), 4, HIV-uninfected children&#xD;
      age 3-10 years (standard 3-dose DP, n=20 for PK sampling after the 1st dose DP, n=30 for&#xD;
      sampling after the 3rd dose DP), 5, HIV-uninfected children age 11-17 years (n=30 children&#xD;
      receiving 3-dose DP).&#xD;
&#xD;
      HIV-infected participants will be enrolled from the Baylor Uganda Center of Excellence on the&#xD;
      Mulago Hospital Complex, Kampala, Uganda. HIV-uninfected participants will be enrolled from&#xD;
      Masafu General Hospital (MGH) complex in Busia, and other clinics in the surrounding area. DP&#xD;
      weight-based dosing will follow World Health Organization (WHO) Treatment Guidelines for&#xD;
      uncomplicated malaria (April 2015). All HIV-infected participants must be stabilized (i.e. no&#xD;
      change in regimen for at least 10 days) on EFV, LPV/r, or DTG + 2 nucleoside reverse&#xD;
      transcriptase inhibitors (NRTI). HIV-infected children on LPV/r will be enrolled in two&#xD;
      Phases: Phase I participants (Group L1) will receive a single dose of DP to determine the&#xD;
      magnitude (PK and safety) of the interaction before 3 doses are evaluated, Phase II&#xD;
      participants (Group L3) will receive a 3-dose DP regimen (which consists of 3 days of a once&#xD;
      daily DP dose). Phase I results will inform Phase II dosing, as a lower dose of DP over 3&#xD;
      days may be warranted. Phase II will not begin until PK and safety results from Phase I are&#xD;
      evaluated. Participants in L1 and L3 will be encouraged to participate sequentially in Phase&#xD;
      I and Phase II separated by a minimum 42-day washout period; however different children may&#xD;
      be enrolled for the 2 phases. Weight-based dose of dihydroartemisinin-piperaquine (DP): 5-&#xD;
      &lt;8kg, 20+160mg; 8- &lt;11kg, 30+240mg; 11- &lt;17kg, 40+320mg; 17- &lt;25kg, 60+480mg; 25- &lt;36kg,&#xD;
      80+640mg; 36- &lt;60kg, 120+960mg; 60-&lt;80kg, 160+1280mg; &gt;80kg, 200+1600mg.&#xD;
&#xD;
      Subjects will undergo an intensive PK study sampling design, which entails multiple venous&#xD;
      blood collections in a smaller sample of individuals to accurately estimate drug exposure&#xD;
      over time. These studies will be conducted in both HIV-infected and HIV-uninfected&#xD;
      participants and will allow the researchers to investigate dihydroartemisinin (DHA) and&#xD;
      piperaquine (PQ) PK exposure in the context of EFV-, LPV/r- and DTG-based ART in&#xD;
      HIV-uninfected children. Comparisons will be based on an intensive PK design for DP area&#xD;
      under the concentration-time curve (AUC) estimations. A sample size of 20&#xD;
      children/adolescents will be needed in groups L1 and C1. A sample size of 30 will be needed&#xD;
      for each of the other arms (D3, E3, L3, C3a, and C3b). Sampling will occur up to day 42 in&#xD;
      the 3-dose groups given the long half-life of PQ and for 14 or 28 days in the single dose&#xD;
      groups. The generation of an AUC will permit robust comparisons so that results will inform&#xD;
      treatment guidelines and policy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 23, 2020</start_date>
  <completion_date type="Actual">April 11, 2022</completion_date>
  <primary_completion_date type="Actual">April 11, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is an open-label prospective pharmacokinetic and safety study of DP and 3 different ART regimens (EFV-, LPV/r- and DTG-based ART) in non-malaria-infected 1) HIV-infected children and 2) HIV uninfected children not on ART (controls).</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the plasma concentration versus time curve for all drug analytes</measure>
    <time_frame>42 days</time_frame>
    <description>AUC 0-8hr or AUC 0-24hr for dihydroartemisinin and AUC 0-infinity for piperaquine</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of single dose DP in HIV-infected children on LPV/r-based ART determined via assessment of mean change in QT intervals from baseline</measure>
    <time_frame>28 days</time_frame>
    <description>Cardiotoxicity associated with PQ is QT interval prolongation. Electrocardiogram (ECG) will be performed to provide data on QT intervals in msec.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of 3-dose DP regimens determined via-assessment of mean change in QT intervals from baseline</measure>
    <time_frame>42 days</time_frame>
    <description>Safety determined via assessment of mean change in QT intervals from baseline in HIV-infected children on LPV/r- EFV-, and DTG-based ART and HIV-uninfected controls</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The effects of DP on EFV pharmacokinetics as measured by mid-level of EFV</measure>
    <time_frame>4 days</time_frame>
    <description>Pre-ART sample to quantify mid-level of EFV, sampled collected via venipuncture on Day 0, 2, &amp; 3 to allow for comparisons of EFV level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The association of anthropomorphic indicators of malnutrition measured as weight-for age (WFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children</measure>
    <time_frame>42 days</time_frame>
    <description>Children will be characterized as a) &quot;stunted&quot; but not underweight [i.e. weight for age (WFA) z-score&gt;-2); b) underweight, but not stunted (WFA z-score ≤-2); or c) of normal nutritional status (WFA z-scores &gt;-1).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess auto-induction of DHA from single dose to 3-doses</measure>
    <time_frame>4 days</time_frame>
    <description>DHA AUC after 1st dose will be compared to AUC after 3rd dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CYP2B6 pharmacogenetics and its impact on EFV PK.</measure>
    <time_frame>4 days</time_frame>
    <description>To assess prevalence of CYP2B6 pharmacogenetic variants and their impact on EFV PK</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The association of anthropomorphic indicators of malnutrition measured as height-for-age (HFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children</measure>
    <time_frame>42 days</time_frame>
    <description>Children will be characterized as a) &quot;stunted&quot; but not underweight [i.e. height for age (HFA) z-score ≤-2); b) underweight, but not stunted (HFA z-score&gt;-2); or c) of normal nutritional status (HFA z-scores &gt;-1).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effects of DP on DTG pharmacokinetics as measured by trough-level (Cmin) of DTG</measure>
    <time_frame>4 days</time_frame>
    <description>Pre-ART sample to quantify trough of DTG, sampled collected via venipuncture on Day 0, 2, &amp; 3 to allow for comparisons of DTG level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effects of DP on LPV/r pharmacokinetics as measured by trough-level (Cmin) of LPV/r</measure>
    <time_frame>4 days</time_frame>
    <description>Pre-ART sample to quantify trough of LPV/r, sampled collected via venipuncture on Day 0, 2, &amp; 3 to allow for comparisons of LPV/r level.</description>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Actual">190</enrollment>
  <condition>Drug-Drug Interaction</condition>
  <condition>HIV Infection</condition>
  <arm_group>
    <arm_group_label>HIV-infected children on EFV-based ART (E3)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 HIV-infected children age 3 - 10 years on EFV-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-infected children on DTG-based ART (D3)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 HIV-infected children age 11 - 17 years on DTG-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-infected children on LPV/r-based ART (L1)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>20 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take one oral dose DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-infected children on LPV/r-based ART (L3)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-uninfected children (C1)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>20 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 1st dose. Control group for L1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-uninfected children (C3a)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>30 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 3rd dose. Control group for E3 and L3.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-uninfected children (C3b)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>30 HIV-uninfected children age 11-17 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. Control group for D3.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dihydroartemisinin-piperaquine</intervention_name>
    <description>It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.</description>
    <arm_group_label>HIV-infected children on DTG-based ART (D3)</arm_group_label>
    <arm_group_label>HIV-infected children on EFV-based ART (E3)</arm_group_label>
    <arm_group_label>HIV-infected children on LPV/r-based ART (L1)</arm_group_label>
    <arm_group_label>HIV-infected children on LPV/r-based ART (L3)</arm_group_label>
    <arm_group_label>HIV-uninfected children (C1)</arm_group_label>
    <arm_group_label>HIV-uninfected children (C3a)</arm_group_label>
    <arm_group_label>HIV-uninfected children (C3b)</arm_group_label>
    <other_name>DP</other_name>
    <other_name>Duocotexin</other_name>
    <other_name>Eurartesim</other_name>
    <other_name>DHA-PQ</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All participants:&#xD;
&#xD;
          -  Agreement to come to clinic for all follow-up PK and safety evaluations&#xD;
&#xD;
          -  Provision of informed consent.&#xD;
&#xD;
        HIV-infected participants:&#xD;
&#xD;
          -  Residency within 30km of Mulago Hospital.&#xD;
&#xD;
          -  Confirmed HIV infection (confirmed positive rapid HIV test or HIV RNA as per&#xD;
&#xD;
          -  Ugandan guidelines).&#xD;
&#xD;
          -  On stable EFV-, LPV/r- or DTG-based ART for at least 10 days prior to enrollment.&#xD;
&#xD;
          -  Age 3 - 10 years if on EFV-based ART or LPV/r-based ART.&#xD;
&#xD;
          -  Age 11 - 17 years if on DTG-based ART.&#xD;
&#xD;
        HIV-uninfected participants:&#xD;
&#xD;
          -  Residency within 30km of Masafu General Hospital&#xD;
&#xD;
          -  Confirmed HIV negative test (confirmed positive rapid HIV test or HIV RNA as&#xD;
&#xD;
          -  per Ugandan guidelines)&#xD;
&#xD;
          -  Age 3 - 17 years.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of significant comorbidities such as malignancy, active tuberculosis or&#xD;
&#xD;
          -  other active WHO stage 4 disease&#xD;
&#xD;
          -  Receipt of any medications known to affect CYP450 metabolism (except ART)&#xD;
&#xD;
          -  within 14 days of study enrolment (see 4.2.1)&#xD;
&#xD;
          -  Hemoglobin &lt; 7.0 g/dL&#xD;
&#xD;
          -  Current malaria infection or recent treatment with antimalarials within 28 days of&#xD;
&#xD;
          -  enrolment.&#xD;
&#xD;
          -  Asymptomatic parasitemia detected by microscopy or rapid diagnostic test (RDT)&#xD;
&#xD;
          -  History of side effects with DP&#xD;
&#xD;
          -  Prior history of cardiac disease (personal or family), baseline corrected QT intervals&#xD;
             (QTc) &gt;450msec, or&#xD;
&#xD;
          -  receipt of any cardiotoxic drugs or those known to prolong QT intervals History of&#xD;
&#xD;
          -  significant comorbidities such as malignancy, active tuberculosis or other WHO&#xD;
&#xD;
          -  stage 4 disease&#xD;
&#xD;
          -  Weight &lt; 6kg&#xD;
&#xD;
          -  HIV-infected females on DTG-based ART and age 13-17 years who are pregnant&#xD;
&#xD;
          -  or of childbearing potential and do not agree to consistent and reliable&#xD;
&#xD;
          -  contraception.&#xD;
&#xD;
        The following medications are disallowed within 3 weeks prior to receiving study drug:&#xD;
&#xD;
          -  Carbamazepine&#xD;
&#xD;
          -  Clarithromycin&#xD;
&#xD;
          -  Erythromycin (oral)&#xD;
&#xD;
          -  Ketoconazole&#xD;
&#xD;
          -  Phenobarbital&#xD;
&#xD;
          -  Phenytoin&#xD;
&#xD;
          -  Rifabutin&#xD;
&#xD;
          -  Rifampicin&#xD;
&#xD;
          -  Halofantrine&#xD;
&#xD;
          -  Any other medication known to significantly affect CYP450 metabolism.&#xD;
&#xD;
          -  Grapefruit juice should be avoided during the study due to its potential effects on&#xD;
             CYP3A4.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Francesca Aweeka</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sunil Parikh</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Norah Mwebaza</last_name>
    <role>Principal Investigator</role>
    <affiliation>Makerere University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Adeodata Kekitiinwa</last_name>
    <role>Study Chair</role>
    <affiliation>Baylor College of Medicine Children's foundation Uganda</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Masafu General Hospital (MGH) at Busia District, Eastern Uganda</name>
      <address>
        <city>Masafu</city>
        <state>Busia</state>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor-Uganda Center of Excellence on Mulago Hospital Complex and Masafu General Hospital</name>
      <address>
        <city>Kampala</city>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Uganda</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>July 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>May 18, 2022</last_update_submitted>
  <last_update_submitted_qc>May 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug drug interaction</keyword>
  <keyword>HIV</keyword>
  <keyword>malaria</keyword>
  <keyword>dihydroartemisinin</keyword>
  <keyword>piperaquine</keyword>
  <keyword>lopinavir</keyword>
  <keyword>ritonavir</keyword>
  <keyword>efavirenz</keyword>
  <keyword>dolutegravir</keyword>
  <keyword>Children</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Piperaquine</mesh_term>
    <mesh_term>Artenimol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04487145
org study id: 18-26978
secondary id: 2R01HD068174-06A1
nct id: NCT04487145
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Open-label prospective intensive pharmacokinetic study of dihydroartemisinin-piperaquine (DP)
      in HIV-infected children on efavirenz (EFV)-, lopinavir/ritonavir (LPV/r)-, or dolutegravir
      (DTG)-based antiretroviral therapy (ART) and HIV-uninfected children not on ART. All children
      will be malaria-uninfected at the time of enrollment.
The primary goal of the study is to assess the pharmacokinetics (PK) and safety of DP in the
      setting of co-administration with first-line ART regimens (EFV-, LPV/r- or DTG-based ART) in
      children without malaria. Up to 190 children will be enrolled in one of the 5 groups: 1,
      HIV-infected children age 3 - 10 years on LPV/r-based ART (n=20 for signal dose DP, 30
      standard 3-dose DP). 2, HIV-infected children age 3 - 10 years on EFV-based ART (n=30), 3,
      HIV-infected children age 11 - 17 years on DTG-based ART (n=30), 4, HIV-uninfected children
      age 3-10 years (standard 3-dose DP, n=20 for PK sampling after the 1st dose DP, n=30 for
      sampling after the 3rd dose DP), 5, HIV-uninfected children age 11-17 years (n=30 children
      receiving 3-dose DP).

      HIV-infected participants will be enrolled from the Baylor Uganda Center of Excellence on the
      Mulago Hospital Complex, Kampala, Uganda. HIV-uninfected participants will be enrolled from
      Masafu General Hospital (MGH) complex in Busia, and other clinics in the surrounding area. DP
      weight-based dosing will follow World Health Organization (WHO) Treatment Guidelines for
      uncomplicated malaria (April 2015). All HIV-infected participants must be stabilized (i.e. no
      change in regimen for at least 10 days) on EFV, LPV/r, or DTG + 2 nucleoside reverse
      transcriptase inhibitors (NRTI). HIV-infected children on LPV/r will be enrolled in two
      Phases: Phase I participants (Group L1) will receive a single dose of DP to determine the
      magnitude (PK and safety) of the interaction before 3 doses are evaluated, Phase II
      participants (Group L3) will receive a 3-dose DP regimen (which consists of 3 days of a once
      daily DP dose). Phase I results will inform Phase II dosing, as a lower dose of DP over 3
      days may be warranted. Phase II will not begin until PK and safety results from Phase I are
      evaluated. Participants in L1 and L3 will be encouraged to participate sequentially in Phase
      I and Phase II separated by a minimum 42-day washout period; however different children may
      be enrolled for the 2 phases. Weight-based dose of dihydroartemisinin-piperaquine (DP): 5-
      <8kg, 20+160mg; 8- <11kg, 30+240mg; 11- <17kg, 40+320mg; 17- <25kg, 60+480mg; 25- <36kg,
      80+640mg; 36- <60kg, 120+960mg; 60-<80kg, 160+1280mg; >80kg, 200+1600mg.

      Subjects will undergo an intensive PK study sampling design, which entails multiple venous
      blood collections in a smaller sample of individuals to accurately estimate drug exposure
      over time. These studies will be conducted in both HIV-infected and HIV-uninfected
      participants and will allow the researchers to investigate dihydroartemisinin (DHA) and
      piperaquine (PQ) PK exposure in the context of EFV-, LPV/r- and DTG-based ART in
      HIV-uninfected children. Comparisons will be based on an intensive PK design for DP area
      under the concentration-time curve (AUC) estimations. A sample size of 20
      children/adolescents will be needed in groups L1 and C1. A sample size of 30 will be needed
      for each of the other arms (D3, E3, L3, C3a, and C3b). Sampling will occur up to day 42 in
      the 3-dose groups given the long half-life of PQ and for 14 or 28 days in the single dose
      groups. The generation of an AUC will permit robust comparisons so that results will inform
      treatment guidelines and policy.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: This is an open-label prospective pharmacokinetic and safety study of DP and 3 different ART regimens (EFV-, LPV/r- and DTG-based ART) in non-malaria-infected 1) HIV-infected children and 2) HIV uninfected children not on ART (controls).
primary purpose: Prevention
masking: None (Open Label)
measure: Area under the plasma concentration versus time curve for all drug analytes
time frame: 42 days
description: AUC 0-8hr or AUC 0-24hr for dihydroartemisinin and AUC 0-infinity for piperaquine
measure: Safety of single dose DP in HIV-infected children on LPV/r-based ART determined via assessment of mean change in QT intervals from baseline
time frame: 28 days
description: Cardiotoxicity associated with PQ is QT interval prolongation. Electrocardiogram (ECG) will be performed to provide data on QT intervals in msec.
measure: Safety of 3-dose DP regimens determined via-assessment of mean change in QT intervals from baseline
time frame: 42 days
description: Safety determined via assessment of mean change in QT intervals from baseline in HIV-infected children on LPV/r- EFV-, and DTG-based ART and HIV-uninfected controls
measure: The effects of DP on EFV pharmacokinetics as measured by mid-level of EFV
time frame: 4 days
description: Pre-ART sample to quantify mid-level of EFV, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of EFV level.
measure: The association of anthropomorphic indicators of malnutrition measured as weight-for age (WFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children
time frame: 42 days
description: Children will be characterized as a) "stunted" but not underweight [i.e. weight for age (WFA) z-score>-2); b) underweight, but not stunted (WFA z-score ≤-2); or c) of normal nutritional status (WFA z-scores >-1).
measure: Assess auto-induction of DHA from single dose to 3-doses
time frame: 4 days
description: DHA AUC after 1st dose will be compared to AUC after 3rd dose.
measure: CYP2B6 pharmacogenetics and its impact on EFV PK.
time frame: 4 days
description: To assess prevalence of CYP2B6 pharmacogenetic variants and their impact on EFV PK
measure: The association of anthropomorphic indicators of malnutrition measured as height-for-age (HFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children
time frame: 42 days
description: Children will be characterized as a) "stunted" but not underweight [i.e. height for age (HFA) z-score ≤-2); b) underweight, but not stunted (HFA z-score>-2); or c) of normal nutritional status (HFA z-scores >-1).
measure: The effects of DP on DTG pharmacokinetics as measured by trough-level (Cmin) of DTG
time frame: 4 days
description: Pre-ART sample to quantify trough of DTG, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of DTG level.
measure: The effects of DP on LPV/r pharmacokinetics as measured by trough-level (Cmin) of LPV/r
time frame: 4 days
description: Pre-ART sample to quantify trough of LPV/r, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of LPV/r level.
arm group label: HIV-infected children on EFV-based ART (E3)
arm group type: Experimental
description: 30 HIV-infected children age 3 - 10 years on EFV-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.
arm group label: HIV-infected children on DTG-based ART (D3)
arm group type: Experimental
description: 30 HIV-infected children age 11 - 17 years on DTG-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.
arm group label: HIV-infected children on LPV/r-based ART (L1)
arm group type: Experimental
description: 20 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take one oral dose DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.
arm group label: HIV-infected children on LPV/r-based ART (L3)
arm group type: Experimental
description: 30 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.
arm group label: HIV-uninfected children (C1)
arm group type: Active Comparator
description: 20 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 1st dose. Control group for L1.
arm group label: HIV-uninfected children (C3a)
arm group type: Active Comparator
description: 30 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 3rd dose. Control group for E3 and L3.
arm group label: HIV-uninfected children (C3b)
arm group type: Active Comparator
description: 30 HIV-uninfected children age 11-17 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. Control group for D3.
intervention type: Drug
intervention name: Dihydroartemisinin-piperaquine
description: It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.
arm group label: HIV-infected children on DTG-based ART (D3)
arm group label: HIV-infected children on EFV-based ART (E3)
arm group label: HIV-infected children on LPV/r-based ART (L1)
arm group label: HIV-infected children on LPV/r-based ART (L3)
arm group label: HIV-uninfected children (C1)
arm group label: HIV-uninfected children (C3a)
arm group label: HIV-uninfected children (C3b)
other name: DP
other name: Duocotexin
other name: Eurartesim
other name: DHA-PQ
criteria: 
gender: All
minimum age: 3 Years
maximum age: 17 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Francesca Aweeka
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Sunil Parikh
role: Principal Investigator
affiliation: Yale University
last name: Norah Mwebaza
role: Principal Investigator
affiliation: Makerere University
last name: Adeodata Kekitiinwa
role: Study Chair
affiliation: Baylor College of Medicine Children's foundation Uganda
facility: 
facility: 
country: Uganda
responsible party type: Sponsor
mesh term: HIV Infections
mesh term: Piperaquine
mesh term: Artenimol
sharing ipd: No