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

NCT02589782 | Completed Phase 2 DMC

• 1 other identifier: 1541
• Study Type: interventional
• Target: 552
• Locations: 3 countries
• Sites: 7

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).

Conditions

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

Keywords

bedaquiline; Nitroimidazoles; diarylquinolines; linezolid; clofazimine; pretomanid; moxifloxacin

Outcome Measures

Primary Outcomes (3)

• Stage 1:Percentage of patients with culture conversion in liquid media at 8 weeks post randomisation.

  8 weeks post randomisation

• 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

Secondary Outcomes (14)

• 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 culture conversion

  12 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

Study Arms (4)

Regimen 1

EXPERIMENTAL

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

Drug: Bedaquiline; Drug: Pretomanid; Drug: Moxifloxacin; Drug: Linezolid

Regimen 2

EXPERIMENTAL

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

Drug: Bedaquiline; Drug: Pretomanid; Drug: Linezolid; Drug: Clofazimine

Regimen 3

EXPERIMENTAL

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)

Drug: Bedaquiline; Drug: Pretomanid; Drug: Linezolid

Control Regimen

ACTIVE COMPARATOR

Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.

Drug: Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.

Interventions

Bedaquiline DRUG

Also known as: Sirturo, R207910, TMC207

Regimen 1; Regimen 2; Regimen 3

Pretomanid DRUG

Also known as: PA-824

Regimen 1; Regimen 2; Regimen 3

Moxifloxacin DRUG

Also known as: Avelox

Regimen 1

Linezolid DRUG

Also known as: Zyvox

Regimen 1; Regimen 2; Regimen 3

Clofazimine DRUG

Also known as: Lamprene

Regimen 2

Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB. DRUG

Control Regimen

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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);

You may not qualify if:

• 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

Sponsors & Collaborators

• Medecins Sans Frontieres, Netherlands: lead
• London School of Hygiene and Tropical Medicine: collaborator
• Global Alliance for TB Drug Development: collaborator
• University College, London: collaborator
• Drugs for Neglected Diseases: collaborator
• Swiss Tropical & Public Health Institute: collaborator
• eResearch Technology, Inc.: collaborator
• Ministry of Health, Republic of Uzbekistan: collaborator
• World Health Organization: collaborator
• Ministry of Public Health, Republic of Belarus: collaborator
• THINK TB & HIV Investigative Network: collaborator
• University of Liverpool: collaborator
• Wits Health Consortium (Pty) Ltd: collaborator
• Rutgers, The State University of New Jersey: collaborator
• University of California, San Francisco: collaborator

Study Sites (7)

Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital

Minsk, Belarus

Location

Helen Jospeh Hospital

Johannesburg, Gauteng, 2092, South Africa

Location

THINK Clinical Trial Unit, Hillcrest

Durban, KwaZulu-Natal, 3650, South Africa

Location

King DinuZulu Hospital

Durban, KwaZulu-Natal, 4091, South Africa

Location

Doris Goodwin Hospital

Pietermaritzburg, KwaZulu-Natal, South Africa

Location

Republican TB Hospital No. 2

Nukus, Karakalpakstan, Uzbekistan

Location

Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital

Tashkent, Uzbekistan

Location

Related Publications (4)

• 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.

  PMID: 38842323 DERIVED

• 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.

  PMID: 37980911 DERIVED

• 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.

  PMID: 36546625 DERIVED

• 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.

  PMID: 35698158 DERIVED

MeSH Terms

Conditions

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

Interventions

bedaquiline; pretomanid; Moxifloxacin; Linezolid; Clofazimine

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Phenazines; Heterocyclic Compounds, 3-Ring

Study Officials

• Bern-Thomas Nyang'wa, MD

  Medecins Sans Frontieres, Netherlands

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2015
• First Posted: October 28, 2015
• Study Start: January 1, 2017
• Primary Completion: August 5, 2022
• Study Completion: August 5, 2022
• Last Updated: May 1, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Q3 2024

Locations

ZA (4); UZ (2); BE (1)