Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s)
NCT ID: NCT02589782
Last Updated: 2024-05-01
Study Results
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Basic Information
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COMPLETED
PHASE2/PHASE3
552 participants
INTERVENTIONAL
2017-01-31
2022-08-05
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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
Bedaquiline
Pretomanid
Moxifloxacin
Linezolid
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
Bedaquiline
Pretomanid
Linezolid
Clofazimine
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)
Bedaquiline
Pretomanid
Linezolid
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.
Interventions
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Bedaquiline
Pretomanid
Moxifloxacin
Linezolid
Clofazimine
Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.
Other Intervention Names
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Eligibility Criteria
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Inclusion 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
* 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.
15 Years
ALL
No
Sponsors
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London School of Hygiene and Tropical Medicine
OTHER
Global Alliance for TB Drug Development
OTHER
University College, London
OTHER
Drugs for Neglected Diseases
OTHER
Swiss Tropical & Public Health Institute
OTHER
eResearch Technology, Inc.
INDUSTRY
Ministry of Health, Republic of Uzbekistan
OTHER_GOV
World Health Organization
OTHER
Ministry of Public Health, Republic of Belarus
OTHER_GOV
THINK TB & HIV Investigative Network
NETWORK
University of Liverpool
OTHER
Wits Health Consortium (Pty) Ltd
OTHER
Rutgers, The State University of New Jersey
OTHER
University of California, San Francisco
OTHER
Medecins Sans Frontieres, Netherlands
OTHER
Responsible Party
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Principal Investigators
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Bern-Thomas Nyang'wa, MD
Role: PRINCIPAL_INVESTIGATOR
Medecins Sans Frontieres, Netherlands
Locations
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Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital
Minsk, , Belarus
Helen Jospeh Hospital
Johannesburg, Gauteng, South Africa
THINK Clinical Trial Unit, Hillcrest
Durban, KwaZulu-Natal, South Africa
King DinuZulu Hospital
Durban, KwaZulu-Natal, South Africa
Doris Goodwin Hospital
Pietermaritzburg, KwaZulu-Natal, South Africa
Republican TB Hospital No. 2
Nukus, Karakalpakstan, Uzbekistan
Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital
Tashkent, , Uzbekistan
Countries
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References
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Motta I, Cusinato M, Ludman AJ, Lachenal N, Dodd M, Soe M, Abdrasuliev T, Usmanova R, Butabekov I, Nikolaevna TZ, Liverko I, Parpieva N, Moodliar R, Solodovnikova V, Kazounis E, Nyang'wa B-T, Fielding KL, Berry C. How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial. Antimicrob Agents Chemother. 2024 Jul 9;68(7):e0053624. doi: 10.1128/aac.00536-24. Epub 2024 Jun 6.
Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, Tigay Z, Moodliar R, Dodd M, Solodovnikova V, Liverko I, Rajaram S, Rassool M, McHugh T, Spigelman M, Moore DA, Ritmeijer K, du Cros P, Fielding K; TB-PRACTECAL team. Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial. Lancet Respir Med. 2024 Feb;12(2):117-128. doi: 10.1016/S2213-2600(23)00389-2. Epub 2023 Nov 16.
Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, Tigay Z, Solodovnikova V, Liverko I, Moodliar R, Dodd M, Ngubane N, Rassool M, McHugh TD, Spigelman M, Moore DAJ, Ritmeijer K, du Cros P, Fielding K; TB-PRACTECAL Study Collaborators. A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis. N Engl J Med. 2022 Dec 22;387(25):2331-2343. doi: 10.1056/NEJMoa2117166.
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.
Other Identifiers
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1541
Identifier Type: -
Identifier Source: org_study_id
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