Building Evidence for Advancing New Treatment for Rifampicin Resistant Tuberculosis (RR-TB) Comparing a Short Course of Treatment (Containing Bedaquiline, Delamanid and Linezolid) With the Current South African Standard of Care
NCT ID: NCT04062201
Last Updated: 2024-08-28
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
COMPLETED
PHASE3
402 participants
INTERVENTIONAL
2019-08-22
2024-04-15
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
Related Clinical Trials
Explore similar clinical trials based on study characteristics and research focus.
A Phase 3 Trial Assessing Safety and Efficacy of B-Pa-L in Participants With DR-TB
NCT02333799
6 Months of Bedaquiline(BDQ), Delamanid(DLM), Linezolid(LZD) and Levofloxacin(LFX) in RR-TB Patients in Hubei Province
NCT07198685
Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients
NCT03338621
Bedaquiline Enhanced Post ExpOsure Prophylaxis for Leprosy
NCT05597280
Linezolid Dosing Strategies in Drug-Resistant TB
NCT05007821
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
The current short injectable-free treatment regimen for RR-TB in South Africa is based on these WHO recommendations. This South African standard of care, referred to as the Control Strategy, is given for a duration of 40 to 48 weeks and consists of BDQ, LNZ, Isoniazid (high dose), LVX, ethambutol, pyrazinamide and CFZ. Should a patient have resistance to the fluoroquinolones and/or the injectable, the patient is started on a strengthened regimen that may include BDQ, LNZ and DLM with other added agents depending on prior exposure and any other available resistance testing.
In addition to the shorter RR-TB regimen recommended by the WHO, there are other shorter regimens currently being evaluated in clinical trials. Many of these regimens employ new or re-purposed medicines such as BDQ, DLM, and LNZ, which have each been shown to be effective in clinical trials. Some of the regimens forgo the use of a second-line injectable, which is associated with a high rate of adverse events and is programmatically difficult to administer. Although these regimens are currently undergoing testing in clinical trials, the programmatic use of these regimens under operational and pragmatic research conditions can also provide important data to the global TB community about their effectiveness and safety, while also providing more information about programmatic implementation and expanding access to their potential benefits.
For this reason, BEAT Tuberculosis aims to be as pragmatic as possible, with broad eligibility criteria including almost all participants diagnosed with RR-TB. It aligns itself with the SANTP's goal to investigate an effective treatment regimen for RR-TB, while strictly adhering to the high standards of ethical conduct in clinical research. The primary objective of the trial is to evaluate the efficacy and safety of the Study Strategy, specifically to demonstrate that the intervention or Study Strategy has non-inferior efficacy to the Control Strategy.
The principle behind the Study Strategy is to "hit early and to hit hard" with the agents most likely to be effective- it is common that upon the diagnosis of RR-TB, fluoroquinolone resistance is unknown. Therefore, the Study Strategy contains three novel agents as core drugs -BDQ, LNZ, and DLM against which there is no expected Mtb resistance in the community. In addition, there are two other support medications- LVX and CFZ. Treatment will be changed on receipt of the second-line line probe assay (LPA) results. The Study Strategy has been designed to cover all possible eventualities from rifampicin mono resistant TB to Extensively Drug Resistant (XDR-TB) with an all oral regimen. The Study Strategy is given for 24 weeks but if culture conversion has not occurred by week 16, the full treatment duration can be extended to 36 weeks.
Participants include children from 6 years of age and adults diagnosed with RR-TB with or without resistance to isoniazid (INH) and/or fluoroquinolones. A total of 400 participants will be enrolled into the clinical trial. Participants will be randomized in a 1:1 ratio to receive either the Study Strategy or Control Strategy, with a stratification by clinical site and HIV status. All participants will be followed up for 76 weeks from randomization.
All patients in South Africa who are diagnosed with RR-TB are managed by the SANTP. All study tests will therefore be performed by the National Health Laboratory Services, including mycobacteriology, blood screening and safety testing and point of contact testing. These tests will be done in line with the national programme's schedule of events.
The trial will be open label, as blinding is not feasible. It is not possible to formulate placebos with multiple drugs and durations of treatment. However, the trial will be treated as if it were a blinded trial in all ways other than the physician and the participant having knowledge of the treatment assignment. Individuals assessing x-rays, cultures, ECGs and other participant information will be blinded to treatment assignment.
BEAT Tuberculosis will be conducted in Port Elizabeth in the Eastern Cape, and in Durban, KwaZulu Natal, where there is a high burden of drug resistant TB (DR TB). The clinical trial sites are established DR-TB initiation and treating sites and have been approved by the national, provincial and district TB program with the capacity for long term follow up for safety evaluation. This trial will strengthen the drug resistant TB research capacity in an under-researched area such as the Eastern Cape.
All participants will be offered an HIV test, as is standard in South Africa, and must be willing to take antiretroviral treatment, should they test positive. Wherever possible, participants who are co-infected with HIV will be managed in a joint treatment clinic to ensure close co-ordination of management of the two conditions, and to ensure that appropriate decisions can be made concerning the management of drug interactions and side effects.
Additionally, there is a pharmacokinetics/pharmacodynamics (PK-PD) aspect to the trial. There are limited data describing the association of drug concentrations with efficacy and treatment related toxicities of many of the anti-TB drugs used in the treatment of RR-TB. Understanding these PK-PD relationships can result in dose optimization to improve outcomes in the relevant patient populations. BEAT Tuberculosis is a unique opportunity to explore these relationships.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Study Strategy
Bedaquiline Oral Tablet
Weight Group 16 - 29.9kg: 200mg daily for two weeks; followed by 100mg three times weekly for weeks 3 - 24 Weight Group: 30 - \>50kg: 400mg once daily for 14 days followed by 200mg three times weekly for weeks 3 - 24
Linezolid Oral Tablet
Weight Group 16 - 23kg: 180 - 210mg (crush 1 tab and mix in 10ml water, administer 3-3.5ml. Discard rest) Weight Group 23.1 - 29.9kg: 300mg daily Weight Group 30 - 33.9kg: 450mg daily Weight Group 34 - \>50kg: 600mg daily
Delamanid in Oral Dosage Form
Weight Group 16 - 23kg: 25mg twice daily for 24 weeks Weight Group 23.1 - 33.9kg: 50mg twice daily for 24 weeks Weight Group 34 - \>50kg: 100mg twice daily for 8 weeks followed by 200 mg daily for 16 weeks
Clofazimine Oral Product
Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - \>50kg: 100mg daily
Levofloxacin Oral Tablet
Weight Group 16 - 23kg: 375 - 500mg daily Weight Group 23.1 - 33.9kg: 500mg once daily Weight Group 34 - 50kg: 750mg daily Weight Group \>50kg:1000mg daily
Control Strategy
Bedaquiline Oral Tablet
Weight Group 16 - 29.9kg: 200mg daily for two weeks; followed by 100mg three times weekly for weeks 3 - 24 Weight Group: 30 - \>50kg: 400mg once daily for 14 days followed by 200mg three times weekly for weeks 3 - 24
Isoniazid Oral Product
Weight Group 16 - 23kg: 300mg daily Weight Group 23.1 - 50kg: 400mg daily Weight Group \>50kg: 600mg daily
Ethambutol Oral Product
Weight Group 16 - 23kg: 400mg daily Weight Group 23.1 - 29.9kg: 600mg daily Weight Group 30 - 50kg: 800mg daily Weight Group \>50kg: 1200mg daily
Pyrazinamide Oral Product
Weight Group 16 - 23kg: 750mg daily Weight Group 23.1 - 29.9kg: 1000mg daily Weight Group 30 - 33.9kg: 1250mg daily Weight Group 34 - 50kg: 1500mg daily Weight Group \>50kg: 2000mg daily
Linezolid Oral Tablet
Weight Group 16 - 23kg: 180 - 210mg (crush 1 tab and mix in 10ml water, administer 3-3.5ml. Discard rest) Weight Group 23.1 - 29.9kg: 300mg daily Weight Group 30 - 33.9kg: 450mg daily Weight Group 34 - \>50kg: 600mg daily
Clofazimine Oral Product
Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - \>50kg: 100mg daily
Levofloxacin Oral Tablet
Weight Group 16 - 23kg: 375 - 500mg daily Weight Group 23.1 - 33.9kg: 500mg once daily Weight Group 34 - 50kg: 750mg daily Weight Group \>50kg:1000mg daily
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Bedaquiline Oral Tablet
Weight Group 16 - 29.9kg: 200mg daily for two weeks; followed by 100mg three times weekly for weeks 3 - 24 Weight Group: 30 - \>50kg: 400mg once daily for 14 days followed by 200mg three times weekly for weeks 3 - 24
Linezolid Oral Tablet
Weight Group 16 - 23kg: 180 - 210mg (crush 1 tab and mix in 10ml water, administer 3-3.5ml. Discard rest) Weight Group 23.1 - 29.9kg: 300mg daily Weight Group 30 - 33.9kg: 450mg daily Weight Group 34 - \>50kg: 600mg daily
Delamanid in Oral Dosage Form
Weight Group 16 - 23kg: 25mg twice daily for 24 weeks Weight Group 23.1 - 33.9kg: 50mg twice daily for 24 weeks Weight Group 34 - \>50kg: 100mg twice daily for 8 weeks followed by 200 mg daily for 16 weeks
Clofazimine Oral Product
Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - \>50kg: 100mg daily
Levofloxacin Oral Tablet
Weight Group 16 - 23kg: 375 - 500mg daily Weight Group 23.1 - 33.9kg: 500mg once daily Weight Group 34 - 50kg: 750mg daily Weight Group \>50kg:1000mg daily
Isoniazid Oral Product
Weight Group 16 - 23kg: 300mg daily Weight Group 23.1 - 50kg: 400mg daily Weight Group \>50kg: 600mg daily
Ethambutol Oral Product
Weight Group 16 - 23kg: 400mg daily Weight Group 23.1 - 29.9kg: 600mg daily Weight Group 30 - 50kg: 800mg daily Weight Group \>50kg: 1200mg daily
Pyrazinamide Oral Product
Weight Group 16 - 23kg: 750mg daily Weight Group 23.1 - 29.9kg: 1000mg daily Weight Group 30 - 33.9kg: 1250mg daily Weight Group 34 - 50kg: 1500mg daily Weight Group \>50kg: 2000mg daily
Linezolid Oral Tablet
Weight Group 16 - 23kg: 180 - 210mg (crush 1 tab and mix in 10ml water, administer 3-3.5ml. Discard rest) Weight Group 23.1 - 29.9kg: 300mg daily Weight Group 30 - 33.9kg: 450mg daily Weight Group 34 - \>50kg: 600mg daily
Clofazimine Oral Product
Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - \>50kg: 100mg daily
Levofloxacin Oral Tablet
Weight Group 16 - 23kg: 375 - 500mg daily Weight Group 23.1 - 33.9kg: 500mg once daily Weight Group 34 - 50kg: 750mg daily Weight Group \>50kg:1000mg daily
Other Intervention Names
Discover alternative or legacy names that may be used to describe the listed interventions across different sources.
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* Willing and able to adhere to the complete follow-up schedule and to study procedures
* Male or female, aged 6 years or older, including breastfeeding and/or pregnant women
* Weigh more than or equal to 16kg
* Participants above the age of 12 years, must have confirmed pulmonary TB with initial laboratory result of resistance to at least rifampicin as confirmed by genotypic or phenotypic susceptibility testing in the last three months
* Willing to use effective contraception for females of childbearing potential if sexually active; must be willing to use either an intrauterine contraceptive device or a hormonal method for the duration of the treatment regimen and for three months thereafter
* Willing to have an HIV test, and if positive, is willing to be treated with appropriate antiretroviral therapy
* Participants between the ages of 6 - 12 years, must have either confirmed pulmonary RR-TB or probable pulmonary RR-TB and a decision has been made by the referring clinician or investigator to treat the child for RR-TB
* Participants who are pregnant, should have an ultrasound done to confirm a viable intrauterine pregnancy prior to enrolment
Exclusion Criteria
Please note: Participants with prior successfully treated episodes of DR TB are permitted to enroll.
* Has complicated or severe extra-pulmonary manifestations of TB, including osteo-articular, pericardial and central nervous system infection as per investigators opinion
* Is unable to take oral medication
* Is taking any prohibited medications as referred to in the protocol
* Has a known allergy or hypersensitivity to any of the medicines in the regimens
* Is currently taking part in another clinical trial of any medicinal product
* Has a QTcF interval of greater than 480 ms. Please note: If the QTcF interval is greater than 480 ms, it may be repeated if participant has reversible contributory factors, i.e. low potassium or to allow washout of previous QT prolonging drugs.
* Has clinically significant ECG abnormality in the opinion of the site investigator within 60 days prior to entry, including but not limited to second or third degree atrioventricular (AV) block or clinically important arrhythmia
* Participants with the following laboratory abnormality at screening.
1. Haemoglobin level of \< 8.0 g/dL
2. Platelet count \< 75,000/mm\^3
3. Absolute neutrophil count (ANC) \< 1000/ mm\^3
4. An estimated creatinine clearance (CrCl) less than 30 mL/min as calculated by the National Health Laboratory Service (NHLS) equation
5. Alanine aminotransferase (ALT) ≥3 x upper limit of normal (ULN)
6. Total bilirubin grade 3 or greater (\>2.0 x ULN, or \>1.50 x ULN when accompanied by any increase in other liver function test)
7. Serum potassium less than 3.2 mmol/l
* Peripheral neuropathy of grade 3 or 4 using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events
* If in the investigator's opinion, the participant is unable to commit to study related procedures or it is unsafe for the participant to take part in the study
6 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
Regents of the University of California
OTHER
University of Cape Town
OTHER
Perinatal HIV Research Unit of the University of the Witswatersrand
OTHER
Wits Health Consortium (Pty) Ltd
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Francesca Conradie
Deputy Director
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Francesca M Conradie
Role: PRINCIPAL_INVESTIGATOR
Clinical HIV Research Unit t/a Wits Health Consortium
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Jose Pearson TB Hospital
Port Elizabeth, Eastern Cape, South Africa
King DinuZulu Hospital Complex
Durban, KwaZulu-Natal, South Africa
Countries
Review the countries where the study has at least one active or historical site.
References
Explore related publications, articles, or registry entries linked to this study.
Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, De Paepe E, van Heeswijk RP, Dannemann B; TMC207-C208 Study Group. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014 Aug 21;371(8):723-32. doi: 10.1056/NEJMoa1313865.
Schnippel K, Ndjeka N, Maartens G, Meintjes G, Master I, Ismail N, Hughes J, Ferreira H, Padanilam X, Romero R, Te Riele J, Conradie F. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. Lancet Respir Med. 2018 Sep;6(9):699-706. doi: 10.1016/S2213-2600(18)30235-2. Epub 2018 Jul 11.
Sotgiu G, Centis R, D'Ambrosio L, Alffenaar JW, Anger HA, Caminero JA, Castiglia P, De Lorenzo S, Ferrara G, Koh WJ, Schecter GF, Shim TS, Singla R, Skrahina A, Spanevello A, Udwadia ZF, Villar M, Zampogna E, Zellweger JP, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012 Dec;40(6):1430-42. doi: 10.1183/09031936.00022912. Epub 2012 Apr 10.
Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeva I, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van Baelen B, van Heeswijk RP, Dannemann B; TMC207-C209 Study Group. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016 Feb;47(2):564-74. doi: 10.1183/13993003.00724-2015. Epub 2015 Dec 2.
Drusano GL, Neely M, Van Guilder M, Schumitzky A, Brown D, Fikes S, Peloquin C, Louie A. Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis. PLoS One. 2014 Jul 8;9(7):e101311. doi: 10.1371/journal.pone.0101311. eCollection 2014.
Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2012 Apr;16(4):447-54. doi: 10.5588/ijtld.11.0451.
Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-10. doi: 10.1159/000334441. Epub 2011 Dec 13.
Noel GJ, Goodman DB, Chien S, Solanki B, Padmanabhan M, Natarajan J. Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings. J Clin Pharmacol. 2004 May;44(5):464-73. doi: 10.1177/0091270004264643.
Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, van Niekerk C, Everitt D, Hutchings J, Burger DA, Schall R, Mendel CM. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med. 2015 Apr 15;191(8):943-53. doi: 10.1164/rccm.201410-1801OC.
Denti P, Garcia-Prats AJ, Draper HR, Wiesner L, Winckler J, Thee S, Dooley KE, Savic RM, McIlleron HM, Schaaf HS, Hesseling AC. Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis. Antimicrob Agents Chemother. 2018 Jan 25;62(2):e01521-17. doi: 10.1128/AAC.01521-17. Print 2018 Feb.
Svensson EM, Dosne AG, Karlsson MO. Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin. CPT Pharmacometrics Syst Pharmacol. 2016 Dec;5(12):682-691. doi: 10.1002/psp4.12147. Epub 2016 Nov 8.
Svensson EM, Karlsson MO. Modelling of mycobacterial load reveals bedaquiline's exposure-response relationship in patients with drug-resistant TB. J Antimicrob Chemother. 2017 Dec 1;72(12):3398-3405. doi: 10.1093/jac/dkx317.
Gumbo T, Pasipanodya JG, Wash P, Burger A, McIlleron H. Redefining multidrug-resistant tuberculosis based on clinical response to combination therapy. Antimicrob Agents Chemother. 2014 Oct;58(10):6111-5. doi: 10.1128/AAC.03549-14. Epub 2014 Aug 4.
Chigutsa E, Pasipanodya JG, Visser ME, van Helden PD, Smith PJ, Sirgel FA, Gumbo T, McIlleron H. Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):38-45. doi: 10.1128/AAC.03931-14. Epub 2014 Oct 13.
Related Links
Access external resources that provide additional context or updates about the study.
U.S. Food and Drug Administration. SIRTURO Prescribing Information
Bedaquiline- and delamanid- containing regimens achieve excellent interim treatment response without safety concerns
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
72067418CA00006
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
BEAT Tuberculosis
Identifier Type: -
Identifier Source: org_study_id
More Related Trials
Additional clinical trials that may be relevant based on similarity analysis.