PRACTECAL-PKPD Sub Study

PRACTECAL-PKPD is an exploratory pharmacokinetic and pharmacodynamic sub-study investigating the relationship between the patients' exposure to anti- tuberculosis (TB) drugs in the TB-PRACTECAL trial investigational regimens and their respective treatment outcomes.

PRACTECAL-PKPD is a sub-study of the main TB-PRACTECAL phase II-III trial for the treatment of biologically confirmed pulmonary multi drug or extensively drug-resistant TB (M/XDR-TB). TB-PRACTECAL is a multicentre, open label, phase 2-3 randomised controlled trial evaluating 6 months, exclusively oral regimens containing bedaquiline (B), pretomanid (Pa), linezolid (Lzd) +/- moxifloxacin (Mfx) or clofazimine (Cfz) for the treatment of microbiologically confirmed pulmonary M/XDR-TB.

Primary objective Measure the plasma concentrations of pretomanid, linezolid, bedaquiline, clofazimine and moxifloxacin in a sub-set of patients in the TB-PRACTECAL trial and using population pharmacokinetic (PK) models, estimate the population exposure metrics (minimum plasma concentration (Cmin), mean plasma concentration (Cmean), maximum plasma concentration (Cmax), plasma concentration versus time curve (AUC)) for the individual drugs in the TB-PRACTECAL trial.

Secondary objectives Develop a population pharmacodynamic model to explore the relationship between drug exposure, baseline minimum inhibitory concentrations and both mycobacteriological and clinical treatment success Develop a population pharmacodynamics model and identify PK parameters that are associated with treatment emergent toxicity Explore covariates specific to the regimens and study population Use results of above objectives to develop a hypothesis on the optimal dosing of linezolid and clofazimine Explore the pharmacogenomic factors associated with efficacy and toxicity of the investigational drugs Analyse adherence/exposure to the investigational regimen(s) by analysing anti-TB drug levels in small hair samples Assess the potential of using hair drug levels to develop safety and efficacy pharmacodynamic models Conduct clinical validation of a dried blood quantification method using volumetric absorptive microsampling.

Procedures:

4 ml (vacutainer tube, lithium heparin) of blood will be collected from the hand, forearm or antecubital vein at each sampling occasion and moment for the PK. The sampling occasions are on Day 1, Weeks 8, 12, 16, 20, 24, 32 and 72. On Day 1, blood will be collected just before drugs intake, then 2 and 23 hours after drugs intake. On week 8, blood will be collected just before drugs intake, then 6.5 and 23 hours post dose. At weeks 12, 16, 20 and 24 the blood will be collected within 30 minutes before taking the dose. Samples from week 32 and 72 will be collected whenever feasible after the patients have completed their treatment so blood collection is not relative to drug intake on that occasion. These have been included to capture the elimination phases of the drugs which have long terminal half-lives.

A subgroup of patients will also participate to the clinical validation study of a dried blood quantification method using volumetric absorptive microsampling. 2ml of blood and a drop of blood from the finger tips will be collected at the following sampling occasions: day 1, week 8, 12 and 16.

In the small hair study, a small thatch of hair will be cut as close as possible to the scalp from the occiput at weeks 8, 16, 24, 32 and 72.

Eligibility Criteria:
Main study inclusion criteria\*:

Patients eligible for inclusion in the trial must fulfil all of the following criteria:

* Male or female subjects aged 15 years of age or above, regardless of HIV status;
* Microbiological test (molecular or phenotypic) confirming presence of M. tuberculosis;
* Resistant to at least rifampicin by either molecular or phenotypic drug susceptibility test;
* Completed informed consent form (ICF);

Main study exclusion criteria:

* Known allergies, hypersensitivity, or intolerance to any of the study drugs;
* Pregnant or breast-feeding; or unwilling to use appropriate contraceptive measures
* Liver enzymes \>3 times the upper limit of normal;
* Any condition (social or medical) which, in the opinion of the investigator, would make study participation unsafe;
* Taking any medications contraindicated with the medicines in the trial; QTcF \> 450ms;
* One or more risk factors for QT prolongation (excluding age and gender) or other uncorrected risk factors for TdP;
* History of cardiac disease, syncopal episodes, symptomatic or asymptomatic arrhythmias (with the exception of sinus arrhythmia);
* Any baseline biochemical laboratory value consistent with Grade 4 toxicity.
* Moribund
* Known resistance to bedaquiline, pretomanid, delamanid or linezolid.
* Prior use of bedaquiline and/or pretomanid and/or linezolid and/or delamanid for one or more months.
* Patients not eligible to start a new course of MDR-TB/XDR-TB treatment according to local protocol, including but not limited to:

  * currently on MDR-TB treatment for more than 2 weeks (and not failing)
  * unstable address
  * loss to follow-up in previous treatment with no change in circumstance and motivation.
* Tuberculous meningoencephalitis, brain abscesses, osteomyelitis or arthritis.

  \*PKPD inclusion/exclusion:
* Adult patients (aged 18 years or above) recruited into the investigational arms of the TB-PRACTECAL trial in the approved sites.
* Willing to sign the sub-study informed consent form after agreeing to the additional blood draws.