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

November 1, 2022 updated by: Helen Margaret McIlleron, University of Cape Town

Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis

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).

Study Overview

Status

Recruiting

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Anticipated)

625

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Kazakhstan
      • Almaty, Kazakhstan
        • Recruiting
        • National Scientific Center of Phthisiopulmonology
        • Contact:
        • Principal Investigator:
          • Sagit Bektasov
  • Lesotho
      • Maseru, Lesotho, 100
        • Completed
        • Partners in Health Lesotho House 233 Corner Lancers and Caldwell Roads
  • Pakistan
      • Karachi, Pakistan
        • Recruiting
        • Indus Hospital
        • Contact:
        • Principal Investigator:
          • Uzma Khan
  • Peru
      • Lima, Peru
        • Recruiting
        • Peru-1
        • Contact:
        • Principal Investigator:
          • Jimmy Garlarza
      • Lima, Peru
        • Recruiting
        • Peru_2
        • Contact:
        • Principal Investigator:
          • Jimmy Galarza
  • South Africa
    • Western Cape
      • Cape Town, Western Cape, South Africa, 7764
        • Terminated
        • Khayelitsha Town 2 Clinic
  • Vietnam
      • Hanoi, Vietnam
        • Recruiting
        • Hanoi Lung Hospital
        • Contact:
        • Principal Investigator:
          • Ha Phan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years to 99 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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:

-

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
PandrTB cohort
endTB and endTB-Q study participants on experimental regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Drug exposure (AUC)
Time Frame: 5 years
drug exposures derived using population PK models
5 years
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.
5 years
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.
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Cape Town

Collaborators

Institute of Tropical Medicine, Belgium
Epicentre
Medecins Sans Frontieres, Netherlands
Partners in Health
Interactive Research and Development

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 30, 2020

Primary Completion (Anticipated)

April 30, 2023

Study Completion (Anticipated)

April 30, 2023

Study Registration Dates

First Submitted

August 7, 2018

First Submitted That Met QC Criteria

January 30, 2019

First Posted (Actual)

February 1, 2019

Study Record Updates

Last Update Posted (Actual)

November 4, 2022

Last Update Submitted That Met QC Criteria

November 1, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PandrTB

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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