AzTrials
AzTrials

Multi-drug Resistant TuberculosisPhase 2/3PRACTECAL-PKPDNCT04081077

PRACTECAL-PKPD Sub Study

A Phase 2/3 study testing Bedaquiline, Pretomanid and Moxifloxacin in people with Multi-drug Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis, run by Medecins Sans Frontieres, Netherlands at 5 sites in 2 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bedaquiline, Pretomanid and Moxifloxacin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
240 participants
Where
5 sitesin 2 countries
Study dates
6 Aug 2019to 30 Sep 2022
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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.

Trial locations and contacts

5 sites in 2 countries.

5 sites in 2 countries

South Africa4 sites

  • THINK Clinical Trial Unit, Hillcrest

    Durban, KwaZulu-Natal, 3650

  • King DinuZulu Hospital

    Durban, KwaZulu-Natal, 4091

  • Helen Jospeh Hospital

    Johannesburg, Gauteng, 2092

  • Doris Goodwin Hospital

    Pietermaritzburg, KwaZulu-Natal

Other trials in South Africa

Belarus1 site

  • Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital

    Minsk

Other trials in Belarus

About this study

Official title: Pharmacokinetics and Pharmacodynamics Sub-study for TB-PRACTECAL Clinical Trial ( PRACTECAL-PKPD)

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.

Read the 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.

Being tested
Bedaquiline, Pretomanid, Moxifloxacin, Linezolid, Clofazimine
Keywords
Pharmacokinetics, Pharmcogenomics, Pharmacodynamics, Bedaquiline, Pretomanid, Linezolid, Clofazimine, Moxifloxacin
Medical subject headings
Tuberculosis, Multidrug-Resistant, Extensively Drug-Resistant Tuberculosis, Tuberculosis, Pulmonary

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BedaquilineDrug

    Also called Sirturo, R207910, TMC207

    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.

  • PretomanidDrug

    Also called PA-824

    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.

  • MoxifloxacinDrug

    Also called Avelox, BAY 12-8039

    Moxifloxacin is an 8-methoxyquinolone class antimicrobial that is a potent inhibitor of DNA gyrase and topoisomerase IV in bacteria

  • LinezolidDrug

    Also called Zyvox

    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.

  • ClofazimineDrug

    Also called Lamprene

    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.

Study groups in NCT04081077
Study groupRoleWhat they receive
Regimen 1: Bedaquiline, Pretomanid, Linezolid, MoxifloxacinExperimentalBedaquiline: 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
Receives: Drug: Bedaquiline; Drug: Pretomanid; Drug: Moxifloxacin; Drug: Linezolid
Regimen 2:Bedaquiline, Pretomanid, Linezolid, ClofazimineExperimentalBedaquiline: 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
Receives: Drug: Bedaquiline; Drug: Pretomanid; Drug: Linezolid; Drug: Clofazimine
Regimen 3: Bedaquiline, Pretomanid, LinezolidExperimentalBedaquiline: 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)
Receives: Drug: Bedaquiline; Drug: Pretomanid; Drug: Linezolid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: 72 weeks

  2. 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)

    Measured: 72 weeks

  3. 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)

    Measured: 72 weeks

  4. 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)

    Measured: 72 weeks

  5. 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.

    Measured: 72 weeks

  6. Pharmacodynamics: Culture Conversion 24 weeks post treatment [Efficacy]

    Percentage of patients with culture conversion in liquid media at 24 weeks post randomisation

    Measured: 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Sep 2019
  2. Study start6 Aug 2019
  3. Primary completion30 Sep 2022 (estimated)
  4. Study completion30 Sep 2022 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
240 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04081077
Sponsor's protocol ID
PRACTECAL-PKPD
Acronym
PRACTECAL-PKPD
Status last verified
May 2021
First submitted
29 Aug 2019
Last updated
14 May 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Nyang'wa BT, Motta I, Moodliar R, Solodovnikova V, Rajaram S, Rasool M, Berry C, Moore DAJ, Davies G, Kloprogge F. Pharmacokinetics, bactericidal activity and toxicity of short oral regimens for rifampicin-resistant tuberculosis treatment. Nat Commun. 2026 Jun 10;17(1):7830. doi: 10.1038/s41467-026-74335-y.

    PubMed 42270675

  • Nyang'wa BT, Motta I, Moodliar R, Solodovnikova V, Rajaram S, Rasool M, Berry C, Huang Z, Davies G, Moore DAJ, Kloprogge F. Population pharmacokinetics and target attainment of pretomanid in rifampicin-resistant tuberculosis patients. Sci Rep. 2026 Mar 31;16(1):15255. doi: 10.1038/s41598-026-46217-2.

    PubMed 41917253

  • 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.

    PubMed 34489274

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Bedaquiline, Pretomanid and Moxifloxacin in people with Multi-drug Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis, run by Medecins Sans Frontieres, Netherlands at 5 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in South Africa, Belarus. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pharmacokinetic: Cmax (time frame: 72 weeks). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04081077, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2021.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Keep searching with a free account

You’ve used your 3 free searches for this session. Log in or create a free AzTrials account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in