Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)

  • STATUS
    Recruiting
  • End date
    Feb 26, 2023
  • participants needed
    630
  • sponsor
    Medecins Sans Frontieres, Netherlands
Updated on 26 January 2021
linezolid
moxifloxacin
treatment regimen
rifampin
drug-resistant tuberculosis
extensively drug-resistant tuberculosis
bedaquiline
clofazimine
pretomanid

Summary

TB PRACTECAL is a multi-centre, open label, multi-arm, randomised, controlled, phase II-III trial; evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary multi drug-resistant TB (MDR-TB).

Description

This is a multi-centre, open label, multi-arm, randomised, controlled, phase II-III trial; evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary multidrug-resistant TB (MDR-TB).

The study will be divided into two stages, with a seamless transition between the stages, meaning recruitment into an arm will only stop after a decision has been taken following stage 1 primary end point data analysis. All recruited patients will be followed up to 108 weeks post randomisation unless they die or withdraw consent. The local standard of care (SOC) MDR-TB regimen will be used as the internal control for both safety and efficacy.

The first stage corresponds to a Phase II trial of safety and preliminary efficacy in patients with MDR-TB. Patients will be recruited into 3 parallel B and Pa containing regimen arms plus a SOC control. The main objective of Stage 1 is to select drug regimens for evaluation in Stage 2 based on 8 week safety and efficacy endpoints. All stage 1 patients will be hospitalised for 8 weeks for intensive cardiological evaluations to establish the QT-specific liability of the regimens.

Investigational arms that do not meet predefined safety and efficacy criteria (percentage culture conversion >40%; percentage discontinuation and death <45%) will not be considered for further evaluation. The regimens that do not meet these pre-defined safety and/or efficacy criteria will be eligible to be evaluated for long term safety, tolerability and efficacy in Stage 2.

If less than two investigational arms are available for stage two assessment, the SAC will make recommendations on whether new arms should be introduced in the study. If more than two arms are available for the Stage 2 assessment, two regimens will be chosen. The SAC will make recommendations on which arms to take forward to the trial steering committee.

The second stage corresponds to a phase III trial. Patients in this stage will be recruited into the arms chosen from stage 1 plus the SOC. The regimens will primarily be evaluated for safety and efficacy in comparison with the SOC arm at 72 weeks post randomisation. The primary efficacy outcome will be a composite endpoint of the percentage of unfavourable outcomes. The secondary outcomes will include safety outcomes and in particular the percentage of Grade 3 or 4 AEs and SAEs in the investigational regimens compared with the SOC.

Details
Condition drug-resistant tuberculosis, Extremely Drug-Resistant Tuberculosis, Pulmonary tuberculosis, extensively drug-resistant tuberculosis
Treatment moxifloxacin, bedaquiline, linezolid, pretomanid, Clofazimine, Clofazimine, Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.
Clinical Study IdentifierNCT02589782
SponsorMedecins Sans Frontieres, Netherlands
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 15 yrs?
Gender: Male or Female
Do you have any of these conditions: drug-resistant tuberculosis or Extremely Drug-Resistant Tuberculosis or Pulmonary tuberculosis?
Do you have any of these conditions: Extremely Drug-Resistant Tuberculosis or Pulmonary tuberculosis or drug-resistant tuberculosis or extensively drug-resistant tuberculosis?
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)

Exclusion Criteria

Patients will not be eligible for inclusion in the trial if they meet any of
the following
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 (AST or ALT)
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 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
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