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Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis-PandrTB Tuberculosis (PandrTB)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03827811
Recruitment Status : Recruiting
First Posted : February 1, 2019
Last Update Posted : March 31, 2020
Sponsor:
Collaborators:
Partners in Health
Harvard Medical School
Medicines Sans Frontieres
Information provided by (Responsible Party):
Helen Margaret McIlleron, University of Cape Town

Brief Summary:
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).

Condition or disease
Multi-drug Resistant Tuberculosis

Detailed Description:
PandrTB is an observational study nested in the endTB trial, a randomized study that will evaluate five 9-month, injectable-sparing regimens that could transform the treatment of MDR-TB. 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.

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Study Type : Observational
Estimated Enrollment : 625 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis
Actual Study Start Date : January 30, 2020
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : January 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Group/Cohort
PandrTB cohort
endTB participants on experimental regimen



Primary Outcome Measures :
  1. Drug exposure (AUC) [ Time Frame: 5 years ]
    drug exposures derived using population PK models

  2. Rate of decline of viable M.tubercolosis in sputum [ Time Frame: 5 years ]
    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.

  3. Collecting adverse events as a measure of safety [ Time Frame: 5 years ]
    The effect of pharmacokinetics on drug and regimen saftey will be evaluated using recursive partitioning methods.


Biospecimen Retention:   Samples With DNA
Whole blood will be stored for evaluation of genetic variants associated with drug concentrations and effects.


Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Adults and adolescents (≥15 years) will be enrolled. There is increasing recognition that adolescents have been neglected in the development of treatments for diseases like HIV and TB, given that they comprise and important population. Minors are included in the endTB clinical trial and it would be wrong to exclude them from a PK study designed to optimize doses.
Criteria

Inclusion Criteria:

All patients enrolled to the experimental arms of the endTB study and provide their written informed consent to participate in the PandrTB study.

Exclusion Criteria:

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03827811


Contacts
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Contact: Helen McIlleron, PhD 27214066779 helen.mcilleron@uct.ac.za
Contact: Marilyn Solomons 0244066779 marilyn.solomons@uct.ac.za

Locations
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Lesotho
Partners in Health Lesotho House 233 Corner Lancers and Caldwell Roads Recruiting
Maseru, Lesotho, 100
Contact: Sesomo Mohale    +266 22312399    smohale@pih.org   
Contact: Mpho Maketekete    +266 22312399    mkhesa@pih.org   
Principal Investigator: David Dr Holtzman         
Peru
Peru-1 Recruiting
Lima, Peru
Contact: Sara Perea       sperea_ses@pih.org   
Principal Investigator: Jimmy Garlarza         
Peru_2 Recruiting
Lima, Peru
Contact: Sara Perea       sperea_ses@pih.org   
Principal Investigator: Jimmy Galarza         
South Africa
Khayelitsha Town 2 Clinic Recruiting
Cape Town, Western Cape, South Africa, 7764
Contact: Nelisiwe Ntuli       msfocb-khayelitsha-endtb@brussels.msf.org   
Contact: Sehaam Jaffer       sehaam.jaffer@uct.ac.za   
Sponsors and Collaborators
University of Cape Town
Partners in Health
Harvard Medical School
Medicines Sans Frontieres
Investigators
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Principal Investigator: Helen McIlleron, PhD University of Cape Town
Additional Information:
Publications:
Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, Becerra MC, Benedetti A, Burgos M, Centis R, Chan ED, Chiang CY, Cox H, D'Ambrosio L, DeRiemer K, Dung NH, Enarson D, Falzon D, Flanagan K, Flood J, Garcia-Garcia ML, Gandhi N, Granich RM, Hollm-Delgado MG, Holtz TH, Iseman MD, Jarlsberg LG, Keshavjee S, Kim HR, Koh WJ, Lancaster J, Lange C, de Lange WC, Leimane V, Leung CC, Li J, Menzies D, Migliori GB, Mishustin SP, Mitnick CD, Narita M, O'Riordan P, Pai M, Palmero D, Park SK, Pasvol G, Peña J, Pérez-Guzmán C, Quelapio MI, Ponce-de-Leon A, Riekstina V, Robert J, Royce S, Schaaf HS, Seung KJ, Shah L, Shim TS, Shin SS, Shiraishi Y, Sifuentes-Osornio J, Sotgiu G, Strand MJ, Tabarsi P, Tupasi TE, van Altena R, Van der Walt M, Van der Werf TS, Vargas MH, Viiklepp P, Westenhouse J, Yew WW, Yim JJ; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. Epub 2012 Aug 28.
U.S. Food and Drug Administration. NDA 204-384 Sirturo™ (bedaquiline 100 mg tablets) for the treatment of adults (≥ 18 years) as part of combination therapy of pulmonary multi-drug resistant tuberculosis (MDRTB). 2012 Nov 28;1-69
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.

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Responsible Party: Helen Margaret McIlleron, Professor, University of Cape Town
ClinicalTrials.gov Identifier: NCT03827811    
Other Study ID Numbers: PandrTB
First Posted: February 1, 2019    Key Record Dates
Last Update Posted: March 31, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Helen Margaret McIlleron, University of Cape Town:
MDR
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections