Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04062201
Recruitment Status : Recruiting
First Posted : August 20, 2019
Last Update Posted : August 29, 2019
Sponsor:
Collaborators:
Regents of the University of California
University of Cape Town
Perinatal HIV Research Unit of the University of the Witswatersrand
Information provided by (Responsible Party):
Francesca Conradie, Wits Health Consortium (Pty) Ltd

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Pre-XDR-TB Extensively Drug-Resistant Tuberculosis Multi Drug Resistant Tuberculosis Rifampicin Resistant Tuberculosis Drug: Bedaquiline Oral Tablet Drug: Linezolid Oral Tablet Drug: Delamanid in Oral Dosage Form Drug: Clofazimine Oral Product Drug: Levofloxacin Oral Tablet Drug: Isoniazid Oral Product Drug: Ethambutol Oral Product Drug: Pyrazinamide Oral Product Phase 3

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label, Randomized Controlled Trial to Establish 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 Tuberculosis (RR-TB)
Actual Study Start Date : August 22, 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: Study Strategy Drug: Bedaquiline Oral Tablet
Days 1-14: 400mg once daily for two weeks and then 200mg three times per week for weeks 3-24
Other Name: Sirturo

Drug: Linezolid Oral Tablet
Weight Group 30-33kg: 300mg daily for 24 weeks; Weight Group 33kg or more: 600mg daily for 24 weeks. Dose reduction, interruption or permanent discontinuation of this drug is allowed per protocol.
Other Name: Zyvox

Drug: Delamanid in Oral Dosage Form
100mg twice daily for 8 weeks and then 200mg daily for 16 weeks
Other Name: Deltyba

Drug: Clofazimine Oral Product
100mg daily (duration dependent on fluoroquinolone sensitivity results) duration may be up to 24 weeks
Other Name: Lamprene

Drug: Levofloxacin Oral Tablet
Weight Group 30-33kg: 15mg/kg daily; Weight Group 33-50kg: 750mg daily; Weight Group more than 50kg: 1000mg daily. Duration dependent on fluoroquinolone sensitivity results- duration may be up to 24 weeks

Active Comparator: Control Strategy Drug: Bedaquiline Oral Tablet
Days 1-14: 400mg once daily for two weeks and then 200mg three times per week for weeks 3-24
Other Name: Sirturo

Drug: Isoniazid Oral Product
At 10 mg/kg to a maximum dose of 600mg for 16 weeks. Weight Group 30-33kg: 300mg daily for 16 weeks; Weight Group 33-50kg: 400mg daily for 16 weeks; Weight Group more than 50kg: 600mg daily for 16 weeks If the smear is positive at week 16, Isoniazid must be extended to 24 weeks
Other Name: INH

Drug: Ethambutol Oral Product
Weight Group 30-33kg: 800mg daily for 40 weeks; Weight Group 33-50kg: 800mg daily for 40 weeks; Weight Group more than 50kg: 1200mg daily for 40 weeks

Drug: Pyrazinamide Oral Product
Weight Group 30-33kg: 1000mg daily for 40 weeks; Weight Group 33-50kg: 1500mg daily for 40 weeks; Weight Group more than 50kg: 2000mg daily for 40 weeks

Drug: Linezolid Oral Tablet
Weight Group 30-33kg: 300mg daily for 8 weeks; Weight Group more than 33kg: 600mg daily for 8 weeks;
Other Name: Zyvox

Drug: Clofazimine Oral Product
100mg for 40 weeks
Other Name: Lamprene

Drug: Levofloxacin Oral Tablet
Weight Group 30-33kg: 15mg/kg daily for 40 weeks; Weight Group 33-50kg: 750mg daily for 40 weeks; Weight Group more than 50kg: 1000mg daily for 40 weeks




Primary Outcome Measures :
  1. The proportion of participants with a successful outcome at the end of treatment [ Time Frame: From 24 weeks to 76 weeks depending on assigned strategy and type of TB ]

    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.


  2. The proportion of participants with a successful outcome at the end of follow up at 76 weeks post treatment initiation [ Time Frame: 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.


  3. The proportion of participants who experience grade 3 or greater adverse events during treatment and up to 30 days following the end of treatment [ Time Frame: From treatment initiation 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


Secondary Outcome Measures :
  1. The proportion of participants with a successful composite outcome at 76 weeks post treatment initiation [ Time Frame: At the end of follow up at 76 weeks post treatment initiation ]
    A successful composite outcome is defined as a successful end of follow up outcome at 76 weeks post treatment initiation and no grade 3 or higher adverse events during treatment. A successful end of follow up outcome is either Cured or Culture negative when last seen.

  2. PK/PD model of clofazimine exposure [ Time Frame: Week 4 ]
    To link PK/PD measure of Maximum Plasma Concentration (Cmax) to time to culture conversion (efficacy ) clofazimine

  3. PK/PD model of clofazimine exposure [ Time Frame: Week 4 ]
    To link PK/PD measure of Area Under the Plasma Concentration-time to the time to sputum culture (efficacy) conversion for clofazimine

  4. PK/PD model of clofazimine exposure [ Time Frame: Week 4 ]
    To link PK/PD measure of Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to sputum culture (efficacy ) conversion for clofazimine

  5. PK/PD model of clofazimine exposure [ Time Frame: Week 4 ]
    To link PK/PD measure of Elimination Half-life (t1/2) to the time to sputum culture (efficacy ) conversion for clofazimine

  6. PK/PD model of bedaquiline, delamanid, levofloxacin and linezolid exposure [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Maximum Plasma Concentration (Cmax), to culture conversion(efficacy) for bedaquiline, delamanid, levofloxacin, linezolid

  7. PK/PD model of bedaquiline, delamanid, levofloxacin and linezolid exposure [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Time to Reach Minimum Plasma Concentration (Cmin) to the time to sputum culture (efficacy) conversion for bedaquiline, delamanid, levofloxacin, linezolid

  8. PK/PD model of bedaquiline, delamanid, levofloxacin and linezolid exposure [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to sputum culture (efficacy) conversion for bedaquiline, delamanid, levofloxacin, linezolid

  9. PK/PD model of bedaquiline, delamanid, levofloxacin and linezolid exposure [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of the Elimination Half-life (t1/2) to the time to sputum culture (efficacy) conversion for bedaquiline, delamanid, levofloxacin, linezolid

  10. PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin) [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Maximum Plasma Concentration (Cmax) to the time to toxicity of increased QTcF prolongation for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

  11. PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin) [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Time to Reach Maximum Plasma Concentration (Tmax),increased QTcF for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

  12. PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin) [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Minimum Plasma Concentration (Cmin) to the time to toxicity of increased QTcF for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

  13. PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin) [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of the Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to toxicity of increased QTcF conversion for clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin

  14. PK/PD model drug exposures of linezolid [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measures of Maximum Plasma Concentration (Cmax) to the time to toxicity of bone marrow toxicity and neuropathy

  15. PK/PD model drug exposures of linezolid [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Time to Reach Maximum Plasma Concentration (Tmax) to the time to toxicity of bone marrow toxicity and neuropathy

  16. PK/PD model drug exposures of linezolid [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of Plasma Concentration (Cmin) to the time to toxicity of bone marrow toxicity and neuropathy

  17. PK/PD model drug exposures of linezolid [ Time Frame: Weeks 4, 12, and 24 ]
    To link PK/PD measure of the Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 24 Hours (AUCtime-h) to the time to toxicity of bone marrow toxicity and neuropathy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 (12-17 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 12 years or older
  • Weigh more than or equal to 30kg
  • 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 child bearing 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

Exclusion Criteria:

  • 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.

  • Is pregnant or breastfeeding
  • 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 450 ms. Please note: If the QTcF interval is greater than 450 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. Hemoglobin 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04062201


Contacts
Layout table for location contacts
Contact: Katerina A Selibas +27112768800 kselibas@witshealth.co.za
Contact: Jeannine du Bois +27414922490 jdubois@witshealth.co.za

Locations
Layout table for location information
South Africa
Empilweni TB Hospital Recruiting
Port Elizabeth, Eastern Cape, South Africa, 6200
Contact: Nicola Wattrus    +27414922490    nwattrus@witshealth.co.za   
Sponsors and Collaborators
Wits Health Consortium (Pty) Ltd
Regents of the University of California
University of Cape Town
Perinatal HIV Research Unit of the University of the Witswatersrand
Investigators
Layout table for investigator information
Principal Investigator: Francesca M Conradie Clinical HIV Research Unit t/a Wits Health Consortium

Additional Information:
Publications:

Layout table for additonal information
Responsible Party: Francesca Conradie, Deputy Director, Wits Health Consortium (Pty) Ltd
ClinicalTrials.gov Identifier: NCT04062201     History of Changes
Other Study ID Numbers: BEAT Tuberculosis
72067418CA00006 ( Other Grant/Funding Number: USAID )
First Posted: August 20, 2019    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: We plan to share the de-identified individual participant data set to national and international policy makers, including the World Health Organization.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Francesca Conradie, Wits Health Consortium (Pty) Ltd:
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Tuberculosis
Tuberculosis, Multidrug-Resistant
Extensively Drug-Resistant Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Levofloxacin
Ofloxacin
Rifampin
Isoniazid
Linezolid
Pyrazinamide
Ethambutol
Bedaquiline
Diarylquinolines
Clofazimine
Fluoroquinolones
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antibiotics, Antitubercular