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ClinicalTrials.gov ID

NCT03827811

Lead Sponsor

University of Cape TownOTHER

Overall Status

Unknown status

Study Type

Observational

Enrollment

625Estimated

Last Update Posted

Nov 4, 2022Actual

Start Date

Jan 30, 2020Actual

Primary Completion Date

Apr 30, 2023Estimated

Completion Date

Apr 30, 2023Estimated

Official Title

Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis

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).

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.

• Multi-drug Resistant Tuberculosis

Ages Eligible for Study

Child (0-17)Adult (18-64)Older Adult (65+)

Sexes Eligible for Study

All

Accepts Healthy Volunteers

No

Eligibility 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:

-

Observational Model

Cohort

Time Perspective

Prospective

Lead Sponsor

University of Cape TownOTHER

Collaborators

Partners in HealthOTHER

EpicentreOTHER

Medecins Sans Frontieres, NetherlandsOTHER

Institute of Tropical Medicine, BelgiumOTHER

Interactive Research and DevelopmentOTHER

sperea_ses@pih.org

sperea_ses@pih.org