PRACTECAL-PKPD Sub Study
- Conditions
- Multi-drug Resistant TuberculosisExtensively Drug-Resistant TuberculosisPulmonary Tuberculosis
- Interventions
- Registration Number
- NCT04081077
- Lead Sponsor
- Medecins Sans Frontieres, Netherlands
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 240
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Regimen 3: Bedaquiline, Pretomanid, Linezolid Linezolid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated) Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin Pretomanid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Moxifloxacin: 400 mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin Bedaquiline Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Moxifloxacin: 400 mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin Moxifloxacin Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Moxifloxacin: 400 mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin Linezolid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Moxifloxacin: 400 mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Regimen 2:Bedaquiline, Pretomanid, Linezolid, Clofazimine Linezolid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Clofazimine: 50 mg (less than 33 kg), 100 mg (more than 33 kg) for 24 weeks Regimen 2:Bedaquiline, Pretomanid, Linezolid, Clofazimine Bedaquiline Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Clofazimine: 50 mg (less than 33 kg), 100 mg (more than 33 kg) for 24 weeks Regimen 2:Bedaquiline, Pretomanid, Linezolid, Clofazimine Clofazimine Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Clofazimine: 50 mg (less than 33 kg), 100 mg (more than 33 kg) for 24 weeks Regimen 3: Bedaquiline, Pretomanid, Linezolid Bedaquiline Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated) Regimen 2:Bedaquiline, Pretomanid, Linezolid, Clofazimine Pretomanid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated Clofazimine: 50 mg (less than 33 kg), 100 mg (more than 33 kg) for 24 weeks Regimen 3: Bedaquiline, Pretomanid, Linezolid Pretomanid Bedaquiline: 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks Pretomanid: 200mg once daily for 24 weeks Linezolid: 600mg daily for 16 weeks then 300mg daily (or 600mg x3/wk) for the remaining 8 weeks or earlier when moderately tolerated)
- Primary Outcome Measures
Name Time Method Pharmacokinetic: T1/2 72 weeks Plasma concentrations, their timing in relation to dose intake and start of treatment will be used in a population PK model to estimate the elimnation half life (T1/2)
Pharmacokinetic: Cmax 72 weeks Plasma concentrations, their timing in relation to dose intake and start of treatment will be used in a population PK model to estimate Peak Plasma Concentration (Cmax)
Pharmacodynamics: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] 72 weeks Number of patients with serious adverse events (SAE), adverse events of special interest (AESI) and other AEs with their respective severity grading.
Pharmacodynamics: Culture Conversion 24 weeks post treatment [Efficacy] 24 weeks Percentage of patients with culture conversion in liquid media at 24 weeks post randomisation
Pharmacokinetic: AUC 72 weeks Plasma concentrations, their timing in relation to dose intake and start of treatment will be used in a population PK model to estimate the area under the plasma concentration versus time curve (AUC)
Pharmacokinetic: Tmax 72 weeks Plasma concentrations, their timing in relation to dose intake and start of treatment will be used in a population PK model to estimate the time present at maximum plamsa concentration (Tmax)
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (5)
Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
š§š¾Minsk, Belarus
King DinuZulu Hospital
šæš¦Durban, KwaZulu-Natal, South Africa
THINK Clinical Trial Unit, Hillcrest
šæš¦Durban, KwaZulu-Natal, South Africa
Doris Goodwin Hospital
šæš¦Pietermaritzburg, KwaZulu Natal, South Africa
Helen Jospeh Hospital
šæš¦Johannesburg, Gauteng, South Africa