<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/NCT03827811</url>
  </required_header>
  <id_info>
    <org_study_id>PandrTB</org_study_id>
    <nct_id>NCT03827811</nct_id>
  </id_info>
  <brief_title>Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis-PandrTB Tuberculosis</brief_title>
  <acronym>PandrTB</acronym>
  <official_title>Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cape Town</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Partners in Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Epicentre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medecins Sans Frontieres, Netherlands</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute of Tropical Medicine, Belgium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Interactive Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cape Town</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>
      PandrTB is a study of the pharmacokinetics(PK) and pharmacodynamics(PD) of bedaquiline,&#xD;
      delamanid, clofazimine, linezolid, moxifloxacin, levofloxacin and pyrazinamide used in novel&#xD;
      combinations to treat multidrug-resistant tuberculosis(MDR-TB).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PandrTB is an observational study nested in the endTB (a randomized study that will evaluate&#xD;
      five 9-month, injectable-sparing regimens) and endTB-Q (and RCT evaluating a 4 drug oral&#xD;
      regimen given for 6 or 9 months) trials. These trials are providing evidence to support the&#xD;
      transformation of MDR-TB treatment. As part of PandrTB: the plasma concentrations of the&#xD;
      experimental arm drugs (the new and repurposed drugs bedaquiline, delamanid, clofazimine and&#xD;
      linezolid, as well as levofloxacin, moxifloxacin and pyrazinamide) will be measured; MICs&#xD;
      will be determined in baseline isolates; and MGIT cultures, additional to those in the endTB&#xD;
      study, will be performed at weeks 6 and 10. Nonlinear mixed-effects models will describe the&#xD;
      population PK of the drugs and a pharmacodynamic (PD) model of treatment response of&#xD;
      Mycobacterium tuberculosis(Mtb) load over time. Recursive partitioning methods will evaluate&#xD;
      baseline MICs and PK measures as drivers of treatment response (as described by the&#xD;
      parameters of the PD model of initial treatment response of Mtb load over time, and the endTB&#xD;
      trial endpoints: time to culture conversion, longer-term outcomes, and acquisition of&#xD;
      phenotypic resistance). Thus the key drugs and plasma drug exposure thresholds for activity&#xD;
      will be defined, and exposure-dependent synergy or antagonism identified. The risks of&#xD;
      toxicities (as assessed in the endTB study) will be estimated, by plasma drug exposure and&#xD;
      important comorbidity (including HIV infection). In this way, the PK-efficacy and PK-toxicity&#xD;
      analyses will allow definition of target plasma drug exposures. Simulations will predict&#xD;
      optimal doses. To advance the understanding of drug penetration, we will develop approaches&#xD;
      to measure free drug plasma concentrations. Drug-drug interactions will be described. Thus&#xD;
      PandrTB will inform how best to use these new and repurposed drugs in combination, to create&#xD;
      the most effective and least toxic regimens while minimizing the development of further drug&#xD;
      resistance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 30, 2020</start_date>
  <completion_date type="Anticipated">April 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">April 30, 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>Drug exposure (AUC)</measure>
    <time_frame>5 years</time_frame>
    <description>drug exposures derived using population PK models</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of decline of viable M.tubercolosis in sputum</measure>
    <time_frame>5 years</time_frame>
    <description>A pharmacodynamic biomarker model of response to treatment will be used to derive the rate of decline of Mtb in MIGT cultures. The effect of PK on this measure will be evaluated.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Collecting adverse events as a measure of safety</measure>
    <time_frame>5 years</time_frame>
    <description>The effect of pharmacokinetics on drug and regimen saftey will be evaluated using recursive partitioning methods.</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">625</enrollment>
  <condition>Multi-drug Resistant Tuberculosis</condition>
  <arm_group>
    <arm_group_label>PandrTB cohort</arm_group_label>
    <description>endTB and endTB-Q study participants on experimental regimen</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood will be stored for evaluation of genetic variants associated with drug&#xD;
      concentrations and effects.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Adults and adolescents (≥15 years) will be enrolled. There is increasing recognition that&#xD;
        adolescents have been neglected in the development of treatments for diseases like HIV and&#xD;
        TB, given that they comprise and important population. Minors are included in the endTB&#xD;
        clinical trial and it would be wrong to exclude them from a PK study designed to optimize&#xD;
        doses.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All patients enrolled to the experimental arms of the endTB study and provide their written&#xD;
        informed consent to participate in the PandrTB study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Helen McIlleron, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cape Town</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Helen McIlleron, PhD</last_name>
    <phone>27214066779</phone>
    <email>helen.mcilleron@uct.ac.za</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Marilyn Solomons</last_name>
    <phone>0244066779</phone>
    <email>marilyn.solomons@uct.ac.za</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Scientific Center of Phthisiopulmonology</name>
      <address>
        <city>Almaty</city>
        <country>Kazakhstan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anel Belgozhanova</last_name>
      <email>abelgozhanova@pih.org</email>
    </contact>
    <investigator>
      <last_name>Sagit Bektasov</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Partners in Health Lesotho House 233 Corner Lancers and Caldwell Roads</name>
      <address>
        <city>Maseru</city>
        <zip>100</zip>
        <country>Lesotho</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Indus Hospital</name>
      <address>
        <city>Karachi</city>
        <country>Pakistan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Annum Aftab</last_name>
      <email>annum.aftab@ird.global</email>
    </contact>
    <investigator>
      <last_name>Uzma Khan</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Peru-1</name>
      <address>
        <city>Lima</city>
        <country>Peru</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sara Perea</last_name>
      <email>sperea_ses@pih.org</email>
    </contact>
    <investigator>
      <last_name>Jimmy Garlarza</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Peru_2</name>
      <address>
        <city>Lima</city>
        <country>Peru</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sara Perea</last_name>
      <email>sperea_ses@pih.org</email>
    </contact>
    <investigator>
      <last_name>Jimmy Galarza</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Khayelitsha Town 2 Clinic</name>
      <address>
        <city>Cape Town</city>
        <state>Western Cape</state>
        <zip>7764</zip>
        <country>South Africa</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Hanoi Lung Hospital</name>
      <address>
        <city>Hanoi</city>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hanh Nguyen</last_name>
      <email>hanh202000@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Ha Phan</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Kazakhstan</country>
    <country>Lesotho</country>
    <country>Pakistan</country>
    <country>Peru</country>
    <country>South Africa</country>
    <country>Vietnam</country>
  </location_countries>
  <link>
    <url>http://www.who.int/tb/publications/global_report/en/</url>
    <description>World Health Organization. Global tuberculosis report 2016. Geneva: WHO; 2016</description>
  </link>
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    <citation>Savic RM, Ruslami R, Hibma JE, Hesseling A, Ramachandran G, Ganiem AR, Swaminathan S, McIlleron H, Gupta A, Thakur K, van Crevel R, Aarnoutse R, Dooley KE. Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children. Clin Pharmacol Ther. 2015 Dec;98(6):622-9. doi: 10.1002/cpt.202. Epub 2015 Oct 22.</citation>
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  <verification_date>November 2022</verification_date>
  <study_first_submitted>August 7, 2018</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>November 1, 2022</last_update_submitted>
  <last_update_submitted_qc>November 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cape Town</investigator_affiliation>
    <investigator_full_name>Helen Margaret McIlleron</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>MDR</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Multidrug-Resistant</mesh_term>
  </condition_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/NCT03827811
org study id: PandrTB
nct id: NCT03827811
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
PandrTB is a study of the pharmacokinetics(PK) and pharmacodynamics(PD) of bedaquiline,
      delamanid, clofazimine, linezolid, moxifloxacin, levofloxacin and pyrazinamide used in novel
      combinations to treat multidrug-resistant tuberculosis(MDR-TB).
PandrTB is an observational study nested in the endTB (a randomized study that will evaluate
      five 9-month, injectable-sparing regimens) and endTB-Q (and RCT evaluating a 4 drug oral
      regimen given for 6 or 9 months) trials. These trials are providing evidence to support the
      transformation of MDR-TB treatment. As part of PandrTB: the plasma concentrations of the
      experimental arm drugs (the new and repurposed drugs bedaquiline, delamanid, clofazimine and
      linezolid, as well as levofloxacin, moxifloxacin and pyrazinamide) will be measured; MICs
      will be determined in baseline isolates; and MGIT cultures, additional to those in the endTB
      study, will be performed at weeks 6 and 10. Nonlinear mixed-effects models will describe the
      population PK of the drugs and a pharmacodynamic (PD) model of treatment response of
      Mycobacterium tuberculosis(Mtb) load over time. Recursive partitioning methods will evaluate
      baseline MICs and PK measures as drivers of treatment response (as described by the
      parameters of the PD model of initial treatment response of Mtb load over time, and the endTB
      trial endpoints: time to culture conversion, longer-term outcomes, and acquisition of
      phenotypic resistance). Thus the key drugs and plasma drug exposure thresholds for activity
      will be defined, and exposure-dependent synergy or antagonism identified. The risks of
      toxicities (as assessed in the endTB study) will be estimated, by plasma drug exposure and
      important comorbidity (including HIV infection). In this way, the PK-efficacy and PK-toxicity
      analyses will allow definition of target plasma drug exposures. Simulations will predict
      optimal doses. To advance the understanding of drug penetration, we will develop approaches
      to measure free drug plasma concentrations. Drug-drug interactions will be described. Thus
      PandrTB will inform how best to use these new and repurposed drugs in combination, to create
      the most effective and least toxic regimens while minimizing the development of further drug
      resistance.
observational model: Cohort
time perspective: Prospective
measure: Drug exposure (AUC)
time frame: 5 years
description: drug exposures derived using population PK models
measure: Rate of decline of viable M.tubercolosis in sputum
time frame: 5 years
description: A pharmacodynamic biomarker model of response to treatment will be used to derive the rate of decline of Mtb in MIGT cultures. The effect of PK on this measure will be evaluated.
measure: Collecting adverse events as a measure of safety
time frame: 5 years
description: The effect of pharmacokinetics on drug and regimen saftey will be evaluated using recursive partitioning methods.
arm group label: PandrTB cohort
description: endTB and endTB-Q study participants on experimental regimen
Whole blood will be stored for evaluation of genetic variants associated with drug
      concentrations and effects.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 15 Years
maximum age: 99 Years
healthy volunteers: No
last name: Helen McIlleron, PhD
role: Principal Investigator
affiliation: University of Cape Town
last name: Helen McIlleron, PhD
phone: 27214066779
email: helen.mcilleron@uct.ac.za
last name: Marilyn Solomons
phone: 0244066779
email: marilyn.solomons@uct.ac.za
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Completed
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
investigator: 
country: Kazakhstan
country: Lesotho
country: Pakistan
country: Peru
country: South Africa
country: Vietnam
url: http://www.who.int/tb/publications/global_report/en/
description: World Health Organization. Global tuberculosis report 2016. Geneva: WHO; 2016
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citation: Svensson EM, Dooley KE, Karlsson MO. Impact of lopinavir-ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis-HIV coinfection. Antimicrob Agents Chemother. 2014 Nov;58(11):6406-12. doi: 10.1128/AAC.03246-14. Epub 2014 Aug 11.
PMID: 25114140
citation: Svensson EM, Aweeka F, Park JG, Marzan F, Dooley KE, Karlsson MO. Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2780-7. doi: 10.1128/AAC.00191-13. Epub 2013 Apr 9.
PMID: 23571542
citation: Pandie M, Wiesner L, McIlleron H, Hughes J, Siwendu S, Conradie F, Variava E, Maartens G. Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB. J Antimicrob Chemother. 2016 Apr;71(4):1037-40. doi: 10.1093/jac/dkv447. Epub 2016 Jan 7.
PMID: 26747099
citation: Mallikaarjun S, Wells C, Petersen C, Paccaly A, Shoaf SE, Patil S, Geiter L. Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects. Antimicrob Agents Chemother. 2016 Sep 23;60(10):5976-85. doi: 10.1128/AAC.00509-16. Print 2016 Oct.
PMID: 27458223
citation: Chigutsa E, Patel K, Denti P, Visser M, Maartens G, Kirkpatrick CM, McIlleron H, Karlsson MO. A time-to-event pharmacodynamic model describing treatment response in patients with pulmonary tuberculosis using days to positivity in automated liquid mycobacterial culture. Antimicrob Agents Chemother. 2013 Feb;57(2):789-95. doi: 10.1128/AAC.01876-12. Epub 2012 Nov 26.
PMID: 23183433
citation: Svensson E. A model-based analysis to describe bedaquiline's exposure-response relationship and predict the impact of drug-drug interactions. 9th Int workshop on Clinical Pharmacology of Tuberculosis Drugs 2016, Liverpool October 2016; Abstract O_01.
citation: Taubel J, Naseem A, Harada T, Wang D, Arezina R, Lorch U, Camm AJ. Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers. Br J Clin Pharmacol. 2010 Apr;69(4):391-400. doi: 10.1111/j.1365-2125.2009.03595.x.
PMID: 20406223
citation: Naidoo A, Chirehwa M, McIlleron H, Naidoo K, Essack S, Yende-Zuma N, Kimba-Phongi E, Adamson J, Govender K, Padayatchi N, Denti P. Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB. J Antimicrob Chemother. 2017 May 1;72(5):1441-1449. doi: 10.1093/jac/dkx004.
PMID: 28175315
responsible party type: Principal Investigator
investigator affiliation: University of Cape Town
investigator full name: Helen Margaret McIlleron
investigator title: Professor
mesh term: Tuberculosis
mesh term: Tuberculosis, Multidrug-Resistant
sharing ipd: Undecided