Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)
- Conditions
- Tuberculosis, Multidrug-ResistantExtensively Drug-Resistant TuberculosisTuberculosis, Pulmonary
- Interventions
- Drug: Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.
- Registration Number
- NCT02589782
- Lead Sponsor
- Medecins Sans Frontieres, Netherlands
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 552
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control Regimen Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB. Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB. Regimen 1 Bedaquiline 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 Regimen 1 Moxifloxacin 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 Regimen 1 Linezolid 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 Regimen 2 Bedaquiline 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 Regimen 2 Linezolid 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 Regimen 3 Bedaquiline 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) Regimen 3 Linezolid 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) Regimen 2 Clofazimine 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 Regimen 1 Pretomanid 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 Regimen 2 Pretomanid 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 Regimen 3 Pretomanid 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)
- Primary Outcome Measures
Name Time Method Stage 1: Percentage of patients who discontinue treatment for any reason or die 8 weeks post randomisation Stage 2: Percentage of patients with an unfavourable outcome (failure, death, recurrence, loss to follow-up) 72 weeks post-randomisation Stage 1:Percentage of patients with culture conversion in liquid media at 8 weeks post randomisation. 8 weeks post randomisation
- Secondary Outcome Measures
Name Time Method Stage 2: Percentage of patients with culture conversion 12 weeks post randomisation Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE 108 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) 108 weeks post randomisation Stage 1: Percentage of patients with grade 3 or higher QT prolongation within 8 weeks post randomisation Stage 1: Percentage of patients experiencing at least one Serious Adverse Event (SAE) within 8 weeks post randomisation Stage 1:Percentage of patients experiencing at least one new grade 3 or higher Adverse Event within 8 weeks post randomisation Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up) 24 weeks post randomisation Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment 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 24 weeks post randomisation Stage 2: Percentage of patients experiencing recurrence week 48 in investigational arms Stage 2: TB drug hair levels In relation to dose intake and start of treatment over a 72 week period Stage 2: Median time to culture conversion 108 weeks Stage 2: Plasma drug concentrations In relation to dose intake and start of treatment over a 72 week period
Trial Locations
- Locations (7)
King DinuZulu Hospital
🇿🇦Durban, KwaZulu-Natal, South Africa
Republican TB Hospital No. 2
🇺🇿Nukus, Karakalpakstan, Uzbekistan
Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
🇧🇾Minsk, Belarus
THINK Clinical Trial Unit, Hillcrest
🇿🇦Durban, KwaZulu-Natal, South Africa
Helen Jospeh Hospital
🇿🇦Johannesburg, Gauteng, South Africa
Doris Goodwin Hospital
🇿🇦Pietermaritzburg, KwaZulu Natal, South Africa
Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital
🇺🇿Tashkent, Uzbekistan