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

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ClinicalTrials.gov Identifier: NCT02589782
Recruitment Status : Recruiting
First Posted : October 28, 2015
Last Update Posted : October 22, 2020
Sponsor:
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
Liverpool School of Tropical Medicine
Wits Health Consortium (Pty) Ltd
Rutgers, The State University of New Jersey
University of California, San Francisco
Information provided by (Responsible Party):
Medecins Sans Frontieres, Netherlands

Tracking Information
First Submitted Date  ICMJE October 15, 2015
First Posted Date  ICMJE October 28, 2015
Last Update Posted Date October 22, 2020
Actual Study Start Date  ICMJE January 2017
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 27, 2015)
  • Stage 1:Percentage of patients with culture conversion in liquid media at 8 weeks post randomisation. [ Time Frame: 8 weeks post randomisation ]
  • Stage 1: Percentage of patients who discontinue treatment for any reason or die [ Time Frame: 8 weeks post randomisation ]
  • Stage 2: Percentage of patients with an unfavourable outcome (failure, death, recurrence, loss to follow-up) [ Time Frame: 72 weeks post-randomisation ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2019)
  • Stage 1: Percentage of patients with grade 3 or higher QT prolongation [ Time Frame: within 8 weeks post randomisation ]
  • Stage 1: Percentage of patients experiencing at least one Serious Adverse Event (SAE) [ Time Frame: within 8 weeks post randomisation ]
  • Stage 1:Percentage of patients experiencing at least one new grade 3 or higher Adverse Event [ Time Frame: within 8 weeks post randomisation ]
  • Stage 2: Percentage of patients with culture conversion [ Time Frame: 12 weeks post randomisation ]
  • Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up) [ Time Frame: 24 weeks post randomisation ]
  • Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up, still on treatment at censure and recurrence) [ Time Frame: 108 weeks post randomisation ]
  • Stage 2: Median time to culture conversion [ Time Frame: 108 weeks ]
  • Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE [ Time Frame: 72 weeks post randomisation ]
  • Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE [ Time Frame: 108 weeks post randomisation ]
  • Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment [ Time Frame: 24 weeks in investigational arms and 108 weeks in SOC arm ]
    The percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment in the investigational arms (maximum of 24 weeks) and the SOC arm which varies in length (maximum 108 weeks).
  • Stage 2: Mean single ΔQTcF [ Time Frame: 24 weeks post randomisation ]
  • Stage 2: Percentage of patients experiencing recurrence [ Time Frame: week 48 in investigational arms ]
  • Stage 2: Plasma drug concentrations [ Time Frame: In relation to dose intake and start of treatment over a 72 week period ]
  • Stage 2: TB drug hair levels [ Time Frame: In relation to dose intake and start of treatment over a 72 week period ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2015)
  • Stage 1: Percentage of patients with grade 3 or higher QT prolongation [ Time Frame: within 8 weeks post randomisation ]
  • Stage 1: Percentage of patients experiencing at least one Serious Adverse Event (SAE) [ Time Frame: within 8 weeks post randomisation ]
  • Stage 1:Percentage of patients experiencing at least one new grade 3 or higher Adverse Event [ Time Frame: within 8 weeks post randomisation ]
  • Stage 2: Percentage of patients with culture conversion [ Time Frame: 12 weeks post randomisation ]
  • Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up) [ Time Frame: 24 weeks post randomisation ]
  • Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up, still on treatment at censure and recurrence) [ Time Frame: 108 weeks post randomisation ]
  • Stage 2: Median time to culture conversion [ Time Frame: 108 weeks ]
  • Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE [ Time Frame: 72 weeks post randomisation ]
  • Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE [ Time Frame: 108 weeks post randomisation ]
  • Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment [ Time Frame: 24 weeks in investigational arms and 108 weeks in SOC arm ]
    We will evaluate the percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment in the investigational arms (maximum of 24 weeks) and the SOC arm which varies in length (maximum 108 weeks).
  • Stage 2: Mean single ΔQTcF [ Time Frame: 24 weeks post randomisation ]
  • Stage 2: Percentage of patients experiencing recurrence [ Time Frame: week 48 in investigational arms ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)
Official Title  ICMJE A Randomised, Controlled, Open-Label, Phase II-III Trial to Evaluate the Safety and Efficacy of Regimens Containing Bedaquiline and Pretomanid for the Treatment of Adult Patients With Pulmonary Multidrug Resistant Tuberculosis
Brief 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).
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Tuberculosis, Multidrug-Resistant
  • Extensively Drug-Resistant Tuberculosis
  • Tuberculosis, Pulmonary
Intervention  ICMJE
  • Drug: Bedaquiline
    Other Names:
    • Sirturo
    • R207910
    • TMC207
  • Drug: Pretomanid
    Other Name: PA-824
  • Drug: Moxifloxacin
    Other Name: Avelox
  • Drug: Linezolid
    Other Name: Zyvox
  • Drug: Clofazimine
    Other Name: Lamprene
  • Drug: Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.
Study Arms  ICMJE
  • Experimental: Regimen 1
    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
    Interventions:
    • Drug: Bedaquiline
    • Drug: Pretomanid
    • Drug: Moxifloxacin
    • Drug: Linezolid
  • Experimental: Regimen 2
    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
    Interventions:
    • Drug: Bedaquiline
    • Drug: Pretomanid
    • Drug: Linezolid
    • Drug: Clofazimine
  • Experimental: Regimen 3
    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)
    Interventions:
    • Drug: Bedaquiline
    • Drug: Pretomanid
    • Drug: Linezolid
  • Active Comparator: Control Regimen
    Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.
    Intervention: Drug: Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 27, 2015)
630
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2023
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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);

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nicola James, MSc +44 2070674255 nicola.james@london.msf.org
Contact: Charlotte Batts Charlotte.Batts@london.msf.org
Listed Location Countries  ICMJE Belarus,   South Africa,   Uzbekistan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02589782
Other Study ID Numbers  ICMJE 1541
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Medecins Sans Frontieres, Netherlands
Study Sponsor  ICMJE Medecins Sans Frontieres, Netherlands
Collaborators  ICMJE
  • 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
  • Liverpool School of Tropical Medicine
  • Wits Health Consortium (Pty) Ltd
  • Rutgers, The State University of New Jersey
  • University of California, San Francisco
Investigators  ICMJE
Principal Investigator: Bern-Thomas Nyang'wa, MD Medecins Sans Frontieres, Netherlands
PRS Account Medecins Sans Frontieres, Netherlands
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP