- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04081077
PRACTECAL-PKPD Sub Study (PRACTECAL-PKPD)
Pharmacokinetics and Pharmacodynamics Sub-study for TB-PRACTECAL Clinical Trial ( PRACTECAL-PKPD)
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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Minsk, Belarus
- Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
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Gauteng
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Johannesburg, Gauteng, South Africa, 2092
- Helen Jospeh Hospital
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KwaZulu Natal
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Pietermaritzburg, KwaZulu Natal, South Africa
- Doris Goodwin Hospital
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KwaZulu-Natal
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Durban, KwaZulu-Natal, South Africa, 3650
- THINK Clinical Trial Unit, Hillcrest
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Durban, KwaZulu-Natal, South Africa, 4091
- King DinuZulu Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Regimen 3: Bedaquiline, Pretomanid, 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)
|
Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria.
This in turn blocks the ATP production required for cellular energy production and leading to cell death.
Other Names:
Linezolid, an oxazolidinone class antimicrobial which works by inhibiting ribosomal protein synthesis.
It is approved for Gram-positive bacterial infections, and is increasingly being used for drug resistant TB disease.
Other Names:
Pretomanid is an nitroimidazole class antimicrobial which interferes with cell wall biosynthesis in mycobacteria.
It may have other mechanisms of action as well in non-replicating mycobacteria.
Other Names:
|
Experimental: Regimen 1: Bedaquiline, Pretomanid, Linezolid, 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
|
Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria.
This in turn blocks the ATP production required for cellular energy production and leading to cell death.
Other Names:
Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria
Other Names:
Linezolid, an oxazolidinone class antimicrobial which works by inhibiting ribosomal protein synthesis.
It is approved for Gram-positive bacterial infections, and is increasingly being used for drug resistant TB disease.
Other Names:
Pretomanid is an nitroimidazole class antimicrobial which interferes with cell wall biosynthesis in mycobacteria.
It may have other mechanisms of action as well in non-replicating mycobacteria.
Other Names:
|
Experimental: Regimen 2:Bedaquiline, Pretomanid, Linezolid, 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
|
Bedaquiline is a diarylquinoline class antimicrobial which blocks the proton pump for ATP synthase of mycobacteria.
This in turn blocks the ATP production required for cellular energy production and leading to cell death.
Other Names:
Linezolid, an oxazolidinone class antimicrobial which works by inhibiting ribosomal protein synthesis.
It is approved for Gram-positive bacterial infections, and is increasingly being used for drug resistant TB disease.
Other Names:
Pretomanid is an nitroimidazole class antimicrobial which interferes with cell wall biosynthesis in mycobacteria.
It may have other mechanisms of action as well in non-replicating mycobacteria.
Other Names:
Clofazimine (Cfz) is a lipophilic riminophenazine licensed for treatment of leprosy.
Its mechanism(s) of action remains unclear, but existing evidence suggests production of reactive oxygen species within Mycobacterium tuberculosis is one mechanism.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacokinetic: Cmax
Time Frame: 72 weeks
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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)
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72 weeks
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Pharmacokinetic: AUC
Time Frame: 72 weeks
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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)
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72 weeks
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Pharmacokinetic: T1/2
Time Frame: 72 weeks
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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)
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72 weeks
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Pharmacokinetic: Tmax
Time Frame: 72 weeks
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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)
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72 weeks
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Pharmacodynamics: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame: 72 weeks
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Number of patients with serious adverse events (SAE), adverse events of special interest (AESI) and other AEs with their respective severity grading.
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72 weeks
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Pharmacodynamics: Culture Conversion 24 weeks post treatment [Efficacy]
Time Frame: 24 weeks
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Percentage of patients with culture conversion in liquid media at 24 weeks post randomisation
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24 weeks
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Bern Nyang'wa, MB BS, MPH, Medecins Sans Frontieres, Netherlands
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Lung Diseases
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Tuberculosis, Pulmonary
- Tuberculosis, Multidrug-Resistant
- Extensively Drug-Resistant Tuberculosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antineoplastic Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Anti-Bacterial Agents
- Leprostatic Agents
- Protein Synthesis Inhibitors
- Antitubercular Agents
- Linezolid
- Moxifloxacin
- Bedaquiline
- Clofazimine
Other Study ID Numbers
- PRACTECAL-PKPD
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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