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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis

Conditions
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Multi-drug Resistant Tuberculosis

Participation Criteria
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Eligibility Criteria
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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: -

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PandrTB cohort<br>endTB and endTB-Q study participants on experimental regimen | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug exposure (AUC) | drug exposures derived using population PK models | 5 years | 
| Rate of decline of viable M.tubercolosis in sputum | 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 | The effect of pharmacokinetics on drug and regimen saftey will be evaluated using recursive partitioning methods. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDR