A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens Versus Standard Treatment for Drug-Sensitive Sputum Smear-Positive Pulmonary Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 157
- 试验地点
- 1
- 主要终点
- Time to Sputum Culture Conversion on Liquid Medium
研究概览
简要总结
Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to first-line tuberculosis (TB) treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic) over 12 weeks of treatment. Funding Source - FDA Office of Orphan Products Development (OOPD)
详细描述
Phase IIB, 12-week, open-label, single-site, randomized clinical trial with three treatment groups. Patients with drug-sensitive TB will all receive once daily isoniazid and pyrazinamide for 8 weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1 participants will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. Arm 2 participants will receive PA-824 200 mg daily and rifabutin 300 mg daily for 12 weeks. Arm 3 participants (control group) will receive rifampin for 12 weeks and ethambutol for 8 weeks. Patients will be screened within 1 week of TB diagnosis, will receive 12 weeks of study treatment and will return for follow-up visits at 4, 12, and 36 weeks after study treatment completion. All patients will be referred to the local TB treatment program after completion of study treatment to finish their 24-week TB treatment course.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated sputum or Gene Xpert positive sputum sample. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrollment.
- •Age > 18 years
- •. Weight ≥ 40 kg and ≤ 80 kg
- •Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs)
- •. Signed informed consent
- •. HIV negative, or positive with CD4 ≥350 cells/cu mm and not currently taking or planning to take combination antiretroviral therapy for HIV during the study.
- •Ability to adhere with study follow-up
- •8 Agrees to adhere to contraceptive requirements
排除标准
- •Pregnant or breast-feeding
- •Known intolerance or allergy to any of the study drugs
- •Concomitant disorders or conditions for which isoniazid, rifampin, rifabutin, pyrazinamide, or ethambutol is contraindicated. These include severe hepatic damage, acute liver disease of any cause, allergy to the drug, and acute uncontrolled gouty arthritis.
- •Current or planned therapy, during the intensive phase of TB therapy with cyclosporine or tacrolimus, which have unacceptable interactions with rifamycins.
- •Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable.
- •Pulmonary silicosis
- •Central nervous system TB
- •ECG at screening with corrected QT interval (QTc) (Fridericia correction) interval >450 ms or any clinically-significant, in the opinion of the investigator, ECG abnormality
- •History and/or presence (or evidence) of neuropathy or epilepsy.
- •History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination with a value of 1.0 or higher on age-related eye disease scale 2 (AREDS2) Clinical Lens Opacity Classification and Grading System scale.
- •Infection with an isolate known to be resistant to a first-line TB drug (for example, patients with Gene Xpert screening through the local TB program with results suggesting resistance to rifampin)
- •Laboratory parameters done at, or 14 days prior to, screening (with results available for review by study personnel) demonstrating any of the following:
- •Serum alanine aminotransferase (ALT) activity > 3 times the upper limit of normal
- •Serum total bilirubin level > 2 times the upper limit of normal
- •Serum creatinine greater than the upper limit of normal
- •Hemoglobin level less than 7.0 g/dL
- •Platelet count less than 100,000/mm3
- •Positive pregnancy test (women of childbearing potential)
- •More than five days of treatment directed against active tuberculosis in the past 6 months -
研究组 & 干预措施
Arm 2
PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Rifabutin (Drug)
Arm 2
PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Pyrazinamide (Drug)
Arm 1
PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: PA-824 (Drug)
Arm 1
PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Rifampin (Drug)
Arm 1
PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Pyrazinamide (Drug)
Arm 1
PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Isoniazid (Drug)
Arm 2
PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: PA-824 (Drug)
Arm 2
PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Isoniazid (Drug)
Arm 3
Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Rifampin (Drug)
Arm 3
Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Pyrazinamide (Drug)
Arm 3
Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Ethambutol (Drug)
Arm 3
Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks
干预措施: Isoniazid (Drug)
结局指标
主要结局
Time to Sputum Culture Conversion on Liquid Medium
时间窗: 12 weeks
The time (days) it takes for the sputum to convert from positive to negative.
Number of Participants With Grade 3 or Higher Adverse Events
时间窗: 12 weeks
Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table
次要结局
- Time to Culture Conversion on Solid Medium(12 weeks)
- Number of Participants With Permanent Discontinuation of Assigned Study Regimen(12 weeks)
- Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment(8 weeks)
- Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks(12 weeks)
- Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin(pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14)
- PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment(pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14)