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

• ClinicalTrials.gov Identifier: NCT02589782
• Recruitment Status: Unknown
• First Posted: October 28, 2015
• Last Update Posted: May 14, 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; 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: October 15, 2015
• First Posted Date: October 28, 2015
• Last Update Posted Date: May 14, 2021
• Actual Study Start Date: January 2017
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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 (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: Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)
• Official Title: 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: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Tuberculosis, Multidrug-Resistant
• Extensively Drug-Resistant Tuberculosis
• Tuberculosis, Pulmonary

Intervention

• 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

• 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 *: Berry C, du Cros P, Fielding K, Gajewski S, Kazounis E, McHugh TD, Merle C, Motta I, Moore DAJ, Nyang'wa BT. TB-PRACTECAL: study protocol for 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. Trials. 2022 Jun 13;23(1):484. doi: 10.1186/s13063-022-06331-8.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: May 12, 2021): 552
• Original Estimated Enrollment (submitted: October 27, 2015): 630
• Estimated Study Completion Date: December 2022
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 (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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, South Africa, Uzbekistan

Administrative Information

• NCT Number: NCT02589782
• Other Study ID Numbers: 1541
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Medecins Sans Frontieres, Netherlands
• Original Responsible Party: Same as current
• Current Study Sponsor: Medecins Sans Frontieres, Netherlands
• Original Study Sponsor: Same as current

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
• Rutgers, The State University of New Jersey
• University of California, San Francisco

Investigators

• Principal Investigator: Bern-Thomas Nyang'wa, MD; Medecins Sans Frontieres, Netherlands

• PRS Account: Medecins Sans Frontieres, Netherlands
• Verification Date: May 2021