A Phase 2, Partially-blinded, Randomised Trial Assessing the Safety and Efficacy of TBAJ-876 or Bedaquiline, in Combination With Pretomanid and Linezolid in Adult Participants With Newly Diagnosed, Drug-sensitive, Smear-positive Pulmonary Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 309
- 试验地点
- 39
- 主要终点
- Time to stable sputum conversion
研究概览
简要总结
The goal of this clinical trial is to evaluate 3 dose levels of TBAJ876 for 8 weeks in combination with pretomanid and linezolid, compared to 8 weeks of Isoniazid, rifampicin, pyrazinamide and ethambutol (2HRZE), in adult participants with newly diagnosed, smear-positive, pulmonary drug sensitive tuberculosis (DS-TB).
The main questions the trial aims to answer are:
- What is the optimal dose of TBAJ876 to continue further in development.
- What is the bactericidal activity of bedaquiline with pretomanid and linezolid (B-Pa-L) compared to 2HRZE and TBAJ876-Pa-L over 8 weeks
- What is the efficacy and safety of the 26-week B-Pa-L regimen compared with the SOC (2HRZE/4HR) in participants with DS-TB.
Participants will be seen regularly during treatment (up to 26 weeks) and follow-up (52 weeks post treatment) for safety and efficacy assessments, including but not limited to:
- Safety labs, ECGs, vital signs, physical exams, PK sampling, neuropathy assessments and adverse event monitoring
- Sputum collection
详细描述
Participants will be treated up to 26 weeks with either:
- TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
- TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
- TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
- Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks
- Isoniazid (H) + rifampicin (R) + pyrazinamide (Z), ethambutol (E) for 8 weeks followed by HR for 18 weeks (dose based on participant's weight).
TBAJ876 and bedaquiline will be blinded during the first 8 weeks of trial treatment; participants randomised to the TBAJ876 or bedaquiline arms will receive open-label pretomanid and linezolid. Participants randomised to the 2HRZE/4HR arm will receive open-label HRZE.
After receiving 8 weeks of treatment, participants randomised to the TBAJ876-Pa-L treatment arms will receive open-label HR for at least 7 weeks. Treatment completion will be allowed at Week 15 in participants randomised to the TBAJ876-Pa-L arms, if the below criteria are met:
- Week 8 or EOT Make-up Period 1 sputum MGIT culture is negative, and
- The participant has no TB-related symptoms by Week 15. Participants with symptoms that have a more likely alternative explanation are eligible to complete treatment at Week 15.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
TBAJ-876 and the first 8 weeks of bedaquiline will be blinded. Participants randomized to TBAJ-876 or bedaquiline arms will received active TBAJ-876 (and placebo TBAJ876 to blind the dose) and placebo bedaquiline or placebo TBAJ-876 and active bedaquiline
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent
- •DS-TB as defined as sensitive to rifampicin and isoniazid by rapid sputum-based test AND either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB
- •Of non-childbearing potential OR using effective birth control methods
- •Body weight ≥ 35 kg
排除标准
- •Karnofsky score < 60 at screening
- •Any evidence of extrapulmonary TB
- •Cardiovascular or QT prolongation risk factors
- •Pregnant or breast-feeding
- •Any of the following lab toxicities:
- •Platelets <100,000/mm³
- •Creatinine >1.3 x ULN
- •Haemoglobin <9.5 g/dL or <95 g/L
- •Absolute neutrophil count <800/mm³
- •Serum potassium less than the lower limit of normal for the laboratory.
- •ALT and/or AST ≥2.5 x ULN
- •Total bilirubin ≥1.6 x ULN
- •Direct bilirubin >1 x ULN
- •Haemoglobin A1c ≥8.0%
- •Total lipase ≥1.5 x ULN
- •Total amylase ≥1.5 x ULN
- •CPK >3 x ULN (if >3 x ULN, enquire about the participant's recent strenuous activity and consider repeating the test within the screening window)
- •TSH >1 x ULN
- •Positive results at screening for HBsAg, HAV IgM, or hepatitis C antibodies
- •For participants living with HIV only:
- •CD4+ count<200 cells/μL.
- •WHO Clinical Stage 4 HIV disease
- •Participant does not agree to use DTG/TFV/3TC during trial if ARV therapy is indicated, and randomised to the TBAJ876 or the B-Pa-L regimen
- •If initiation of ARV therapy is indicate, participants who are known to be intolerant, non-responsive to DTG/TFV/3TC or have DTG/TFV/3TC as a contraindication.
研究组 & 干预措施
TBAJ876 25 mg
TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: TBAJ-876 (Drug)
TBAJ876 25 mg
TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: Pretomanid (Drug)
TBAJ876 25 mg
TBAJ876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: Linezolid (Drug)
TBAJ876 50 mg
TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: TBAJ-876 (Drug)
TBAJ876 50 mg
TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: Pretomanid (Drug)
TBAJ876 50 mg
TBAJ876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: Linezolid (Drug)
TBAJ876 100 mg
TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: TBAJ-876 (Drug)
TBAJ876 100 mg
TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: Pretomanid (Drug)
TBAJ876 100 mg
TBAJ876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by HR for 7 to 18 weeks
干预措施: Linezolid (Drug)
BPaL
Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks
干预措施: Pretomanid (Drug)
BPaL
Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks
干预措施: Linezolid (Drug)
BPaL
Bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks
干预措施: Bedaquiline (Drug)
结局指标
主要结局
Time to stable sputum conversion
时间窗: Through 8 weeks of treatment
Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment.
次要结局
- Favorable Outcome 26 Weeks after End of Treatment(26 weeks after end of treatment)