A Novel 4-month Pan-TB Regimen Targeting Both Host and Microbe (panTB-HM)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 352
- 试验地点
- 7
- 主要终点
- The proportion of patients achieving durable (non-relapsing) cure
研究概览
简要总结
This project will develop the first regimen meeting WHO criteria for a pan-TB indication, ie, not requiring knowledge of RIF susceptibility. The regimen will test sutezolid at 2 dose levels, with the approved anti-TB drugs bedaquiline and pretomanid, in a phase 2c trial. It will also test whether the addition of N-acetylcysteine (NAC), a re-purposed host-directed WHO essential medicine, can protect the lung and liver against oxidative damage, preserve lung function, and accelerate the eradication of MTB infection by replenishing glutathione (GSH).
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
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 18 to 65 years
- •Willing and able to provide signed written consent prior to undertaking any trial-related procedures, or, in the case of illiteracy, witnessed oral consent
- •Body weight (in light clothing without shoes) between 30 and 90 kg.
- •Radiographic evidence of pulmonary tuberculosis
- •Positive Xpert TB/RIF (original or Ultra) for MTB
- •RIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmation
- •If sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatment
- •HIV-1 seronegative, or if HIV-1 seropositive, CD4 T cell count ≥100/µl and either receiving ART or willing to start ART during study participation
- •SARS-CoV-2 PCR or antigen test negative, or if positive, either fully vaccinated against Covid-19 or with D-dimer <0.8 ug/ml
- •Willing to adhere to a diet excluding tyramine-rich foods (certain mold-ripened cheeses and cured meats), and to avoid eating grapefruits and pomelos
排除标准
- •Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
- •Current or imminent (within 24 hr) treatment for malaria.
- •Pregnant or nursing
- •Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.
- •TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
- •History of allergy or hypersensitivity to any of the trial therapies or related substances.
- •Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
- •Prior TB treatment in the preceding 6 months
- •Angina pectoris requiring treatment with nitroglycerin or other nitrates
- •Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
- •History of unstable Diabetes Mellitus requiring hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.
- •Use of systemic corticosteroids within the past 28 days.
- •Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors
- •Patients requiring treatment with antidepressants, including MAO inhibitors and SSRIs.
- •Subjects with any of the following abnormal laboratory values:
- •HBsAg positive
- •creatinine >2 mg/dL
- •hemoglobin <8 g/dL
- •platelets <100x109 cells/L
- •serum potassium <3.5 mM/L
- •alanine aminotransferase (ALT) ≥2.0 x ULN
- •alkaline phosphatase (AP) >5.0 x ULN
- •total bilirubin >1.5 mg/dL
- •random blood glucose >200 mg/dL
研究组 & 干预措施
Arm 1 (S1200BP)
Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months
干预措施: Sutezolid (Drug)
Arm 1 (S1200BP)
Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months
干预措施: Pretomanid (Drug)
Arm 1 (S1200BP)
Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months
干预措施: Bedaquiline (Drug)
Arm 2 (S1600BP)
Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months
干预措施: Sutezolid (Drug)
Arm 2 (S1600BP)
Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months
干预措施: Pretomanid (Drug)
Arm 2 (S1600BP)
Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months
干预措施: Bedaquiline (Drug)
Arm 3 (S1600BPN)
Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
干预措施: Sutezolid (Drug)
Arm 3 (S1600BPN)
Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
干预措施: N-acetyl cysteine (Drug)
Arm 3 (S1600BPN)
Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
干预措施: Pretomanid (Drug)
Arm 3 (S1600BPN)
Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
干预措施: Bedaquiline (Drug)
Arm 4 (HRZE)
Rifafour (2HRZE/4HR)
干预措施: Rifafour (Combination Product)
结局指标
主要结局
The proportion of patients achieving durable (non-relapsing) cure
时间窗: Assessed after 1 year of post-treatment follow-up
次要结局
- The proportion of subjects requiring temporary or permanent treatment discontinuation due to safety or tolerability concerns(From day 1 through 4 weeks post end-of-treatment)
- FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment(1, 2, 6, and 18 months after initiation of treatment)
- The proportion of subjects with TE AEs, according to seriousness(From day 1 through 4 weeks post end-of-treatment)
- The proportion of subjects with TE increases in transaminases and bilirubin meeting Hy's criteria for serious liver injury(From day 1 through 4 weeks post end-of-treatment)
- FEV1 and FVC slope during 6 and 18 months after initiation of treatment(6 and 18 months after initiation of treatment)
- The proportion of subjects with sputum cultures showing growth of MTB at 1, 2, 3, and 4 months after initiation of treatment(1, 2, 3, and 4 months after initiation of treatment)
- The hazard ratio for stable culture conversion through the 4th month of treatment(through the 4th month of treatment)
- The proportion of subjects with treatment failure(More than 1 specimen showing growth of MTB during the final 6 weeks of treatment)
- The proportion of subjects with relapse(At week 72 for the control arm and at week 64 for the experimental arms)
- The proportion of subjects with TE ALT increases, graded according to severity(From day 1 through 4 weeks post end-of-treatment)
- The number of TE AEs per treatment arm, according to seriousness(From day 1 through 4 weeks post end-of-treatment)
- FEV1/FVC ratio at 1, 2, 6, and 18 months after initiation of treatment(1, 2, 6, and 18 months after initiation of treatment)