PRACTECAL-PKPD Sub Study
PRACTECAL-PKPD
Pharmacokinetics and Pharmacodynamics Sub-study for TB-PRACTECAL Clinical Trial ( PRACTECAL-PKPD)
1 other identifier
interventional
240
2 countries
5
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Aug 2019
Typical duration for phase_2
5 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
August 6, 2019
CompletedFirst Submitted
Initial submission to the registry
August 29, 2019
CompletedFirst Posted
Study publicly available on registry
September 9, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 30, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
September 30, 2022
CompletedMay 14, 2021
May 1, 2021
3.2 years
August 29, 2019
May 12, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (6)
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)
72 weeks
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)
72 weeks
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)
72 weeks
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)
72 weeks
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.
72 weeks
Pharmacodynamics: Culture Conversion 24 weeks post treatment [Efficacy]
Percentage of patients with culture conversion in liquid media at 24 weeks post randomisation
24 weeks
Study Arms (3)
Regimen 1: Bedaquiline, Pretomanid, Linezolid, Moxifloxacin
EXPERIMENTALBedaquiline: 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
EXPERIMENTALBedaquiline: 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
EXPERIMENTALBedaquiline: 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)
Interventions
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.
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.
Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria
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.
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.
Eligibility Criteria
You may qualify if:
- 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);
You may not qualify if:
- 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.
- +3 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Medecins Sans Frontieres, Netherlandslead
- London School of Hygiene and Tropical Medicinecollaborator
- Global Alliance for TB Drug Developmentcollaborator
- University College, Londoncollaborator
- Drugs for Neglected Diseasescollaborator
- Swiss Tropical & Public Health Institutecollaborator
- eResearch Technology, Inc.collaborator
- Ministry of Health, Republic of Uzbekistancollaborator
- World Health Organizationcollaborator
- Ministry of Public Health, Republic of Belaruscollaborator
- THINK TB & HIV Investigative Networkcollaborator
- University of Liverpoolcollaborator
- Wits Health Consortium (Pty) Ltdcollaborator
- Hackensack Meridian Healthcollaborator
- University of California, San Franciscocollaborator
- Minsk Republican Research and Practical Centre for Pulmonology and Tuberculosiscollaborator
Study Sites (5)
Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
Minsk, Belarus
Helen Jospeh Hospital
Johannesburg, Gauteng, 2092, South Africa
THINK Clinical Trial Unit, Hillcrest
Durban, KwaZulu-Natal, 3650, South Africa
King DinuZulu Hospital
Durban, KwaZulu-Natal, 4091, South Africa
Doris Goodwin Hospital
Pietermaritzburg, KwaZulu-Natal, South Africa
Related Publications (1)
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.
PMID: 34489274DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Bern Nyang'wa, MB BS, MPH
Medecins Sans Frontieres, Netherlands
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 29, 2019
First Posted
September 9, 2019
Study Start
August 6, 2019
Primary Completion
September 30, 2022
Study Completion
September 30, 2022
Last Updated
May 14, 2021
Record last verified: 2021-05
Data Sharing
- IPD Sharing
- Will not share