A Phase 3 Partially-blinded, Randomized Trial Assessing the Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB), Pre-XDR-TB or Treatment Intolerant or Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 181
- 试验地点
- 11
- 主要终点
- Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment
研究概览
简要总结
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB.
详细描述
A phase 3, multi-center, partially-blinded, randomized clinical trial in 4 parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.
Participants will have a screening period of up to 14 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the 4 regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will utilize a randomization system using stratification with a random element to allocate participants evenly across the arms by HIV status and type of TB.
Each participant will receive 26 weeks of treatment. If participant's week 16 sputum sample is culture positive between the week 16 and week 26 treatment visits and their clinical condition suggests they may have an ongoing TB infection, Investigator may consider extending current treatment to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or considered an isolated positive without clinical significance, available culture results should be used to make this decision. All decisions regarding treatment extension should be discussed with and approved by, in consultation with the Sponsor Medical Monitor before implementation. The treatment may also require modification due to toxicities. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for safety concerns.
Participants will be followed for 78 weeks after end of treatment.
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
- Triple (Participant, Care Provider, Investigator)
盲法说明
Participants, trial investigators and staff, including laboratory staff, will be blinded to dose and scheduled duration of linezolid. Bedaquiline and pretomanid dosing will not be blinded. There will be three unblinded analyses which will contain results by linezolid treatment group in aggregate. The first analysis will be after all participants have completed 26 weeks of treatment and here sites, participants, and Sponsor staff will not be unblinded to individual linezolid treatment information. A limited number of statisticians will have access to individual linezolid treatment assignments. The blind for all individual participants will be broken for the primary endpoint analysis (the second unblinded analysis) once all clinical data and outcome parameters have been captured, no more data queries are pending, and the statistical analysis plan has been finalized. The third analysis will occur when all participants have completed 78 weeks of follow-up after end of treatment.
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged 14 years or older.
- •One of the following with documentation of culture positive or molecular test within 3 months of screening:
- •XDR-TB defined as resistance to rifamycins, a fluoroquinolone AND an injectable OR
- •Pre-XDR-TB with defined as resistance to rifamycins, and to a fluoroquinolone OR an injectable OR
- •MDR-TB with resistance to rifamycins, and either non-responsive or non-tolerant to current treatment.
- •Of non-childbearing potential or willing to practice effective birth control methods.
- •Complete informed consent form.
- •Exclusion criteria:
- •Karnofsky score < 60 at screening.
- •Body mass index (BMI) < 17 kg/m2
- •Participants who are expected to require a surgical procedure (for Pulmonary TB).
- •Any risk factor for QT prolongation
- •Pregnant or breast-feeding
- •Any planned contraindicated medicines or received more than 2 weeks of bedaquiline, linezolid or delamanid prior to first dose of IMP.
- •A peripheral neuropathy of Grade 3 or 4, according to DMID. Or, participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator
- •Any of the following lab toxicities/abnormalities:
- •Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who otherwise qualify for participation);
- •CD4+ count < 100 cells/µL (HIV positive participants);
- •Serum potassium less than the lower limit of normal for the laboratory;
- •Hemoglobin < 9.0 g/dL or 90g/L;
- •Platelets <100,000/mm3 or < 100 x 10^9/L
- •Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10^9/L
- •Aspartate aminotransferase (AST) and Alanini aminotransferase (ALT) Grade 3 or greater (> 3.0 x ULN)
- •Total bilirubin greater than 1.5 x ULN
- •Direct bilirubin greater than ULN
- •Serum creatinine level greater than 1.5 times upper limit of normal
- •Albumin <3.0 g/dl or < 30 g/L
排除标准
- 未提供
研究组 & 干预措施
1200mg L x 26 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Pretomanid (Drug)
1200mg L x 26 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Linezolid (Drug)
1200mg L x 26 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Bedaquiline (Drug)
1200mg L x 26 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Placebo Linezolid (Drug)
1200 mg L x 9 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Pretomanid (Drug)
1200 mg L x 9 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Linezolid (Drug)
1200 mg L x 9 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Bedaquiline (Drug)
1200 mg L x 9 weeks + Pa + B
2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Placebo Linezolid (Drug)
600 mg L x 26 weeks + Pa + B
1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Pretomanid (Drug)
600 mg L x 26 weeks + Pa + B
1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Linezolid (Drug)
600 mg L x 26 weeks + Pa + B
1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Bedaquiline (Drug)
600 mg L x 26 weeks + Pa + B
1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Placebo Linezolid (Drug)
600 mg L x 9 weeks + Pa + B
1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Pretomanid (Drug)
600 mg L x 9 weeks + Pa + B
1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Linezolid (Drug)
600 mg L x 9 weeks + Pa + B
1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Bedaquiline (Drug)
600 mg L x 9 weeks + Pa + B
1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks
干预措施: Placebo Linezolid (Drug)
结局指标
主要结局
Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment
时间窗: 26 weeks
Unfavourable status: 1. Participants not classified as having achieved or maintained culture negative status when last seen 2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture 3. Participants who had a positive culture not followed by at least two negative cultures when last seen 4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide 5. Participants definitely or possibly dying from TB related cause during the follow-up phase 6. Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy 7. Participants who have had surgery and the resected tissue is cultured and is positive for MTB 8. Participants lost to follow up or withdrawn from the study before the end of treatment
次要结局
- Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 78 Weeks After the End of Treatment.(78 weeks)
- Sputum Culture Conversion to Negative Status at End of Treatment for Those Positive at Baseline(End of Treatment, 26 weeks)
- Time to Sputum Culture Conversion to Negative Status Through the Treatment Period(26 weeks)