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

NCT04062201 | Completed Phase 3 DMC

• 2 other identifiers: BEAT Tuberculosis72067418CA00006
• Study Type: interventional
• Target: 402
• Locations: 1 country
• Sites: 2

Brief Summary

BEAT Tuberculosis is a phase 3, open label, multi-centre, randomized controlled trial. The purpose of this trial is to compare the efficacy and safety of a Study Strategy consisting of 6 months of bedaquiline (BDQ), delamanid (DLM), and linezolid (LNZ), with levofloxacin (LVX) and clofazimine (CFZ) compared to the current South African Standard of Care (Control Strategy) for 9 months for the treatment of rifampicin resistant (RR-TB) Tuberculosis.

Conditions

Tuberculosis; Pre-XDR-TB; Extensively Drug-Resistant Tuberculosis; Multi Drug Resistant Tuberculosis; Rifampicin Resistant Tuberculosis

Keywords

Tuberculosis; Drug-resistant Tuberculosis; Randomized Controlled Trial; Rifampicin Resistant Tuberculosis; Multi Drug Resistant Tuberculosis; Extensively Drug-Resistant Tuberculosis; Pre-XDR-TB (fluoroquinolone resistant); Open label; South Africa

Outcome Measures

Primary Outcomes (3)

• The proportion of participants with a successful outcome at the end of treatment

  A successful treatment outcome measured at the end of treatment is defined as either Cured or Treatment Completed. Cured: Adequate treatment adherence (at least 80% of doses taken) as per protocol without evidence of failure and the last two negative sputum specimens at the end of treatment being culture negative. These specimens must be separated by at least 14 days. Treatment completed: Adequate treatment adherence (at least 80% of doses taken) as per protocol without evidence of failure but no record that two or more consecutive cultures taken at least 14 days apart are negative.

  From 24 weeks to 76 weeks depending on assigned strategy and type of TB

• The proportion of participants with a successful outcome at the end of follow up at 76 weeks post treatment initiation

  A successful end of follow up outcome measured at 76 weeks post treatment initiation is defined as either Cured or Culture negative when last seen. Cured: Sputum Culture negative at the end of follow up at 76 weeks post treatment initiation. Culture negative when last seen: if the participant is lost before the end of follow up at 76 weeks and provided they have a successful treatment outcome at the last study visit attended.

  At the end of follow up at 76 weeks post treatment initiation

• The proportion of participants who experience grade 3 or greater adverse events during treatment and up to 30 days following the end of treatment

  Adverse events are graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events

  From treatment initiation to 30 days following the end of treatment

Secondary Outcomes (17)

• The proportion of participants with a successful composite outcome at 76 weeks post treatment initiation

  At the end of follow up at 76 weeks post treatment initiation

• PK/PD model of clofazimine exposure

  Week 4

• PK/PD model of clofazimine exposure

  Week 4

• PK/PD model of clofazimine exposure

  Week 4

• PK/PD model of clofazimine exposure

  Week 4

Study Arms (2)

Study Strategy

EXPERIMENTAL

Drug: Bedaquiline Oral Tablet; Drug: Linezolid Oral Tablet; Drug: Delamanid in Oral Dosage Form; Drug: Clofazimine Oral Product; Drug: Levofloxacin Oral Tablet

Control Strategy

ACTIVE COMPARATOR

Drug: Bedaquiline Oral Tablet; Drug: Isoniazid Oral Product; Drug: Ethambutol Oral Product; Drug: Pyrazinamide Oral Product; Drug: Linezolid Oral Tablet; Drug: Clofazimine Oral Product; Drug: Levofloxacin Oral Tablet

Interventions

Bedaquiline Oral Tablet DRUG

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

Also known as: Sirturo

Control Strategy; Study Strategy

Linezolid Oral Tablet DRUG

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

Also known as: Zyvox

Study Strategy

Delamanid in Oral Dosage Form DRUG

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

Also known as: Deltyba

Study Strategy

Clofazimine Oral Product DRUG

Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - \>50kg: 100mg daily

Also known as: Lamprene

Study Strategy

Levofloxacin Oral Tablet DRUG

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

Study Strategy

Isoniazid Oral Product DRUG

Weight Group 16 - 23kg: 300mg daily Weight Group 23.1 - 50kg: 400mg daily Weight Group \>50kg: 600mg daily

Also known as: INH

Control Strategy

Ethambutol Oral Product DRUG

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

Control Strategy

Pyrazinamide Oral Product DRUG

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

Control Strategy

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give informed consent to be enrolled in the research study prior to any study related procedures (signed or witnessed consent if the participant is unable to read and understand the informed consent document; signed or witnessed consent from a child's biological parent, legal guardian or primary caregiver) and if the participant is a child (6-17 years) is willing to sign assent
• 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

You may not qualify if:

• Had taken more than 28 days but less than 24 weeks of second line TB drugs including BDQ, LNZ, CFZ, fluoroquinolones or DLM.
• 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.
• Haemoglobin level of \< 8.0 g/dL
• Platelet count \< 75,000/mm\^3
• Absolute neutrophil count (ANC) \< 1000/ mm\^3
• An estimated creatinine clearance (CrCl) less than 30 mL/min as calculated by the National Health Laboratory Service (NHLS) equation
• Alanine aminotransferase (ALT) ≥3 x upper limit of normal (ULN)

Sponsors & Collaborators

• Wits Health Consortium (Pty) Ltd: lead
• Regents of the University of California: collaborator
• University of Cape Town: collaborator
• Perinatal HIV Research Unit of the University of the Witswatersrand: collaborator

Study Sites (2)

Jose Pearson TB Hospital

Port Elizabeth, Eastern Cape, 6003, South Africa

Location

King DinuZulu Hospital Complex

Durban, KwaZulu-Natal, 4015, South Africa

Location

Related Publications (14)

• 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.

  PMID: 25140958 BACKGROUND

• 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.

  PMID: 30001994 BACKGROUND

• 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.

  PMID: 22496332 BACKGROUND

• 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.

  PMID: 26647431 BACKGROUND

• 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.

  PMID: 25003557 BACKGROUND

• 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.

  PMID: 22325685 BACKGROUND

• 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.

  PMID: 22156660 BACKGROUND

• 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.

  PMID: 15102866 BACKGROUND

• 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.

  PMID: 25622149 BACKGROUND

• 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.

  PMID: 29133560 BACKGROUND

• 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.

  PMID: 27863179 BACKGROUND

• 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.

  PMID: 28961790 BACKGROUND

• 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.

  PMID: 25092691 BACKGROUND

• 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.

  PMID: 25313213 BACKGROUND

Related Links

• U.S. Food and Drug Administration. SIRTURO Prescribing Information
• Bedaquiline- and delamanid- containing regimens achieve excellent interim treatment response without safety concerns
• Deltyba package insert

MeSH Terms

Conditions

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

Interventions

bedaquiline; Linezolid; OPC-67683; Dosage Forms; Clofazimine; Levofloxacin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

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

Study Officials

• Francesca M Conradie

  Clinical HIV Research Unit t/a Wits Health Consortium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy Director

Study Record Dates

• First Submitted: August 6, 2019
• First Posted: August 20, 2019
• Study Start: August 22, 2019
• Primary Completion: April 15, 2024
• Study Completion: April 15, 2024
• Last Updated: August 28, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: August 2019 - August 2030
• Access Criteria: There will be controlled access to the data/documents with the gatekeepers being the Principal Investigator (PI) and the chair of the Trial Steering Committee (TSC), who will be responsible for deciding who may have access. Access to the data/documents must include prior ethical approval for secondary data analysis and the statistical methods for secondary data analysis must be vetted by a statistician. If access is requested during the conduct of the trial, it must be directed to all the members of the TSC via the chair.

Locations

ZA (2)