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. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT04062201 |
Recruitment Status :
Active, not recruiting
First Posted : August 20, 2019
Last Update Posted : October 24, 2022
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
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 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 402 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 : | June 2023 |
Estimated Study Completion Date : | June 2023 |
Arm | Intervention/treatment |
---|---|
Experimental: Study Strategy |
Drug: 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
Other Name: Sirturo Drug: 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
Other Name: Zyvox Drug: 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
Other Name: Deltyba Drug: Clofazimine Oral Product Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - >50kg: 100mg daily
Other Name: Lamprene Drug: 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 |
Active Comparator: Control Strategy |
Drug: 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
Other Name: Sirturo Drug: Isoniazid Oral Product Weight Group 16 - 23kg: 300mg daily Weight Group 23.1 - 50kg: 400mg daily Weight Group >50kg: 600mg daily
Other Name: INH Drug: 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 Drug: 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 Drug: 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
Other Name: Zyvox Drug: Clofazimine Oral Product Weight Group 16 - 23kg: 100mg three times a week or 50mg daily Weight Group 23.1 - >50kg: 100mg daily
Other Name: Lamprene Drug: 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 |
- 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.
- 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.
- 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
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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.
Ages Eligible for Study: | 6 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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 (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
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.
- 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)
- 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)
- 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
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
South Africa | |
Jose Pearson TB Hospital | |
Port Elizabeth, Eastern Cape, South Africa, 6003 | |
King DinuZulu Hospital Complex | |
Durban, KwaZulu Natal, South Africa, 4015 |
Principal Investigator: | Francesca M Conradie | Clinical HIV Research Unit t/a Wits Health Consortium |
Publications:
Responsible Party: | Francesca Conradie, Deputy Director, Wits Health Consortium (Pty) Ltd |
ClinicalTrials.gov Identifier: | NCT04062201 |
Other Study ID Numbers: |
BEAT Tuberculosis 72067418CA00006 ( Other Grant/Funding Number: USAID ) |
First Posted: | August 20, 2019 Key Record Dates |
Last Update Posted: | October 24, 2022 |
Last Verified: | October 2022 |
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. |
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 |
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 |
Tuberculosis Tuberculosis, Multidrug-Resistant Extensively Drug-Resistant Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Levofloxacin Ofloxacin Isoniazid Linezolid Pyrazinamide Ethambutol |
Bedaquiline Clofazimine Anti-Infective Agents, Urinary Anti-Infective 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 Antitubercular Agents Fatty Acid Synthesis Inhibitors Hypolipidemic Agents |