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)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 402
- 试验地点
- 2
- 主要终点
- The proportion of participants with a successful outcome at the end of treatment
研究概览
简要总结
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.
详细描述
In 2016, the World Health Organization (WHO) issued guidelines for the use of a shorter treatment regimen (STR) for eligible patients with RR and multidrug-resistant tuberculosis (MDR-TB) which was adopted by the South African National Tuberculosis Program (SANTP) in 2017. The WHO then released guidelines in September 2018 regrouping the medicines for the treatment of MDR/RR-TB into three categories and ranking them based on the latest evidence about the balance of effectiveness to safety. BDQ, LNZ and fluoroquinolones were moved to Category A and should be included in all regimens as core drugs. CFZ and terizidone as Category B drugs, should be added to all regimens.
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Control Strategy
干预措施: Ethambutol Oral Product (Drug)
Study Strategy
干预措施: Bedaquiline Oral Tablet (Drug)
Study Strategy
干预措施: Linezolid Oral Tablet (Drug)
Study Strategy
干预措施: Delamanid in Oral Dosage Form (Drug)
Study Strategy
干预措施: Clofazimine Oral Product (Drug)
Study Strategy
干预措施: Levofloxacin Oral Tablet (Drug)
Control Strategy
干预措施: Bedaquiline Oral Tablet (Drug)
Control Strategy
干预措施: Isoniazid Oral Product (Drug)
Control Strategy
干预措施: Pyrazinamide Oral Product (Drug)
Control Strategy
干预措施: Linezolid Oral Tablet (Drug)
Control Strategy
干预措施: Clofazimine Oral Product (Drug)
Control Strategy
干预措施: Levofloxacin Oral Tablet (Drug)
结局指标
主要结局
The proportion of participants with a successful outcome at the end of treatment
时间窗: 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
时间窗: 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
时间窗: 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
次要结局
- 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 bedaquiline, delamanid, levofloxacin and linezolid exposure(Weeks 4, 12, and 24)
- PK/PD model drug exposures of drugs/metabolites known to cause QT prolongation (clofazimine, bedaquiline M2 metabolite, delamanid DM6705 metabolite, and levofloxacin)(Weeks 4, 12, and 24)
- PK/PD model drug exposures of linezolid(Weeks 4, 12, and 24)
研究者
Francesca Conradie
Deputy Director
Wits Health Consortium (Pty) Ltd