search
Back to results

PRACTECAL-PKPD Sub Study (PRACTECAL-PKPD)

Primary Purpose

Multi-drug Resistant Tuberculosis, Extensively Drug-Resistant Tuberculosis, Pulmonary Tuberculosis

Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Bedaquiline
Pretomanid
Moxifloxacin
Linezolid
Clofazimine
Sponsored by
Medecins Sans Frontieres, Netherlands
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multi-drug Resistant Tuberculosis focused on measuring Pharmacokinetics, Pharmcogenomics, Pharmacodynamics, Bedaquiline, Pretomanid, Linezolid, Clofazimine, Moxifloxacin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
  • Helen Jospeh Hospital
  • Doris Goodwin Hospital
  • THINK Clinical Trial Unit, Hillcrest
  • King DinuZulu Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin

Regimen 2:Bedaquiline, Pretomanid, Linezolid, Clofazimine

Regimen 3: Bedaquiline, Pretomanid, Linezolid

Arm Description

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: 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: 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)

Outcomes

Primary Outcome Measures

Pharmacokinetic: Cmax
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)
Pharmacokinetic: AUC
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: T1/2
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: Tmax
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)
Pharmacodynamics: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
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]
Percentage of patients with culture conversion in liquid media at 24 weeks post randomisation

Secondary Outcome Measures

Full Information

First Posted
August 29, 2019
Last Updated
May 12, 2021
Sponsor
Medecins Sans Frontieres, Netherlands
Collaborators
London School of Hygiene and Tropical Medicine, Global Alliance for TB Drug Development, University College, London, Drugs for Neglected Diseases, Swiss Tropical & Public Health Institute, eResearch Technology, Inc., Ministry of Health, Republic of Uzbekistan, World Health Organization, Ministry of Public Health, Republic of Belarus, THINK TB & HIV Investigative Network, University of Liverpool, Wits Health Consortium (Pty) Ltd, Hackensack Meridian Health, University of California, San Francisco, Minsk Republican Research and Practical Centre for Pulmonology and Tuberculosis
search

1. Study Identification

Unique Protocol Identification Number
NCT04081077
Brief Title
PRACTECAL-PKPD Sub Study
Acronym
PRACTECAL-PKPD
Official Title
Pharmacokinetics and Pharmacodynamics Sub-study for TB-PRACTECAL Clinical Trial ( PRACTECAL-PKPD)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Unknown status
Study Start Date
August 6, 2019 (Actual)
Primary Completion Date
September 30, 2022 (Anticipated)
Study Completion Date
September 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Medecins Sans Frontieres, Netherlands
Collaborators
London School of Hygiene and Tropical Medicine, Global Alliance for TB Drug Development, University College, London, Drugs for Neglected Diseases, Swiss Tropical & Public Health Institute, eResearch Technology, Inc., Ministry of Health, Republic of Uzbekistan, World Health Organization, Ministry of Public Health, Republic of Belarus, THINK TB & HIV Investigative Network, University of Liverpool, Wits Health Consortium (Pty) Ltd, Hackensack Meridian Health, University of California, San Francisco, Minsk Republican Research and Practical Centre for Pulmonology and Tuberculosis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multi-drug Resistant Tuberculosis, Extensively Drug-Resistant Tuberculosis, Pulmonary Tuberculosis
Keywords
Pharmacokinetics, Pharmcogenomics, Pharmacodynamics, Bedaquiline, Pretomanid, Linezolid, Clofazimine, Moxifloxacin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
240 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin
Arm Type
Experimental
Arm Description
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
Arm Title
Regimen 2:Bedaquiline, Pretomanid, Linezolid, Clofazimine
Arm Type
Experimental
Arm Description
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
Arm Title
Regimen 3: Bedaquiline, Pretomanid, Linezolid
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Bedaquiline
Other Intervention Name(s)
Sirturo, R207910, TMC207
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Pretomanid
Other Intervention Name(s)
PA-824
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Moxifloxacin
Other Intervention Name(s)
Avelox, BAY 12-8039
Intervention Description
Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria
Intervention Type
Drug
Intervention Name(s)
Linezolid
Other Intervention Name(s)
Zyvox
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Clofazimine
Other Intervention Name(s)
Lamprene
Intervention Description
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.
Primary Outcome Measure Information:
Title
Pharmacokinetic: Cmax
Description
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)
Time Frame
72 weeks
Title
Pharmacokinetic: AUC
Description
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)
Time Frame
72 weeks
Title
Pharmacokinetic: T1/2
Description
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)
Time Frame
72 weeks
Title
Pharmacokinetic: Tmax
Description
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)
Time Frame
72 weeks
Title
Pharmacodynamics: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Description
Number of patients with serious adverse events (SAE), adverse events of special interest (AESI) and other AEs with their respective severity grading.
Time Frame
72 weeks
Title
Pharmacodynamics: Culture Conversion 24 weeks post treatment [Efficacy]
Description
Percentage of patients with culture conversion in liquid media at 24 weeks post randomisation
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bern Nyang'wa, MB BS, MPH
Organizational Affiliation
Medecins Sans Frontieres, Netherlands
Official's Role
Principal Investigator
Facility Information:
Facility Name
Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
City
Minsk
Country
Belarus
Facility Name
Helen Jospeh Hospital
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2092
Country
South Africa
Facility Name
Doris Goodwin Hospital
City
Pietermaritzburg
State/Province
KwaZulu Natal
Country
South Africa
Facility Name
THINK Clinical Trial Unit, Hillcrest
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
3650
Country
South Africa
Facility Name
King DinuZulu Hospital
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
4091
Country
South Africa

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34489274
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.
Results Reference
derived

Learn more about this trial

PRACTECAL-PKPD Sub Study

We'll reach out to this number within 24 hrs