Clinical trial NCT03827811: Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis-PandrTB Tuberculosis
Official title: Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Multi-drug Resistant Tuberculosis
Keywords: MDR
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Partners in Health
name: Epicentre
name: Medecins Sans Frontieres, Netherlands
name: Institute of Tropical Medicine, Belgium
name: Interactive Research and Development
First posted: 2019-02-01
Enrollment: 625
Sex: ALL
Minimum age (years): 15
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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:

-

Primary outcomes:
measure: Drug exposure (AUC)
timeFrame: 5 years
measure: Rate of decline of viable M.tubercolosis in sputum
timeFrame: 5 years
measure: Collecting adverse events as a measure of safety
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Almaty
country: Kazakhstan
facility: National Scientific Center of Phthisiopulmonology
city: Maseru
country: Lesotho
facility: Partners in Health Lesotho House 233 Corner Lancers and Caldwell Roads
city: Karachi
country: Pakistan
facility: Indus Hospital
city: Lima
country: Peru
facility: Peru-1
city: Lima
country: Peru
facility: Peru_2
city: Cape Town
country: South Africa
facility: Khayelitsha Town 2 Clinic
state: Western Cape
city: Hanoi
country: Vietnam
facility: Hanoi Lung Hospital
Study officials:
affiliation: University of Cape Town
name: Helen McIlleron, PhD
role: PRINCIPAL_INVESTIGATOR
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