Clinical trial NCT04081077: PRACTECAL-PKPD Sub Study
Official title: Pharmacokinetics and Pharmacodynamics Sub-study for TB-PRACTECAL Clinical Trial ( PRACTECAL-PKPD)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Multi-drug Resistant Tuberculosis
Extensively Drug-Resistant Tuberculosis
Pulmonary Tuberculosis
Keywords: Pharmacokinetics
Pharmcogenomics
Pharmacodynamics
Bedaquiline
Pretomanid
Linezolid
Clofazimine
Moxifloxacin
Lead sponsor: Medecins Sans Frontieres, Netherlands
Sponsor class: OTHER
Collaborators: name: London School of Hygiene and Tropical Medicine
name: Global Alliance for TB Drug Development
name: University College, London
name: Drugs for Neglected Diseases
name: Swiss Tropical & Public Health Institute
name: eResearch Technology, Inc.
name: Ministry of Health, Republic of Uzbekistan
name: World Health Organization
name: Ministry of Public Health, Republic of Belarus
name: THINK TB & HIV Investigative Network
name: University of Liverpool
name: Wits Health Consortium (Pty) Ltd
name: Hackensack Meridian Health
name: University of California, San Francisco
name: Minsk Republican Research and Practical Centre for Pulmonology and Tuberculosis
First posted: 2019-09-09
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Pharmacokinetic: Cmax
timeFrame: 72 weeks
measure: Pharmacokinetic: AUC
timeFrame: 72 weeks
measure: Pharmacokinetic: T1/2
timeFrame: 72 weeks
measure: Pharmacokinetic: Tmax
timeFrame: 72 weeks
measure: Pharmacodynamics: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: 72 weeks
measure: Pharmacodynamics: Culture Conversion 24 weeks post treatment [Efficacy]
timeFrame: 24 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Minsk
country: Belarus
facility: Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
city: Johannesburg
country: South Africa
facility: Helen Jospeh Hospital
state: Gauteng
city: Pietermaritzburg
country: South Africa
facility: Doris Goodwin Hospital
state: KwaZulu Natal
city: Durban
country: South Africa
facility: THINK Clinical Trial Unit, Hillcrest
state: KwaZulu-Natal
city: Durban
country: South Africa
facility: King DinuZulu Hospital
state: KwaZulu-Natal
Study officials:
affiliation: Medecins Sans Frontieres, Netherlands
name: Bern Nyang'wa, MB BS, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nyang'wa BT, Kloprogge F, Moore DAJ, Bustinduy A, Motta I, Berry C, Davies GR. Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomised controlled trial. BMJ Open. 2021 Sep 6;11(9):e047185. doi: 10.1136/bmjopen-2020-047185.