Phase 2 Trial to Evaluate the Early EBA, Safety and Tolerability of Amoxicillin/Clavulanate With or Without Meropenem, Ertapenem or Rifampicin in Adults With Newly Diagnosed, Smear-Positive Rifampicin-Susceptible Pulmonary Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 134
- 试验地点
- 1
- 主要终点
- Early bactericidal activity by change in logCFU over 14 days
研究概览
简要总结
The goal of this single-center, open-labelled, clinical trial in two groups aims to proof that a specific group of antibiotics (carbapenems) can be used to treat pulmonary tuberculosis if it is combined with another antibiotic (amoxicillin/clavulanate). A total of 113 male or female participants (8 groups and 9 treatment regimens as group 8 was split into 2 groups of 4 participants receiving Rifafour e-275), aged between 18 and 65 years (inclusive), with newly diagnosed, smear-positive, pulmonary TB.
详细描述
The overall objective of this study is to evaluate the 2-week bactericidal activity and pharmacokinetics of the following beta-lactam containing combinations with the aim to select the most active and implementable solution to be incorporated into a drug-resistant TB combination regimen:
- Once or twice daily meropenem administered intravenously in combination with once or twice daily oral amoxicillin/clavulanic acid;
- Once daily ertapenem administered intravenously and intramuscularly in combination with twice daily oral amoxicillin/clavulanic acid;
- Twice daily oral amoxicillin/clavulanic acid;
- Once daily rifampicin administered orally at highest currently established dosage of 35mg/kg in combination with twice daily oral amoxicillin/clavulanic acid.
A single-center, open-labeled, clinical trial in two groups. The treatments are:
Group 1:
- Meropenem 6g intravenously once daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally 12-hourly on days 1-14.
- Ertapenem 1g intramuscularly once daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally 12-hourly on days 1-14.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 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
- •Provide written, informed consent prior to all trial-related procedures including HIV testing.
- •Male or female, aged between 18 and 65 years, inclusive.
- •Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
- •Newly diagnosed, previously untreated, rifampicin-susceptible pulmonary TB.
- •A chest X-ray picture which in the opinion of the Investigator is consistent with TB.
- •Sputum positive on direct microscopy for acid-fast bacilli on at least one sputum sample (at least 1+ on the IUATLD/WHO scale).
- •Ability to produce an adequate volume of sputum as estimated from an overnight sputum collection sample (estimated 10 ml or more).
- •Be of non-childbearing potential or using effective methods of birth control, as defined below:
- •Non-childbearing potential:
- •Participant - not heterosexually active or practicing sexual abstinence; or
- •Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or
- •Male participant/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three month prior to screening;
- •Effective birth control methods:
- •Double barrier method which can include a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or
- •Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner; and are willing to continue practicing birth control methods throughout participation in the study until Visit 19 (day 28).
- •(Note: hormone-based contraception alone may not be reliable when taking IP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).
排除标准
- •Evidence of clinically significant conditions or findings, other than the indication being studied, particularly epilepsy, that might compromise safety or the interpretation of trial endpoints, per discretion of the Investigator.
- •Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
- •A history of TB less than 3 years ago.
- •Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
- •History of allergy to any of the trial IP/s or related substances i.e. β-lactams and penicillin, as confirmed by the clinical judgement of the Investigator.
- •Known or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.
- •HIV infected participants.
- •Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.
- •Female participant who is pregnant, breast-feeding, or planning to conceive a child within the anticipated period of participating in the trial. Male participant planning to conceive a child within the anticipated period of participating in the trial.
- •Subjects with diabetes (Type 1 or 2), point of care HbA1c above 6.5, or random glucose over 11.1 mmol/L.
- •Hypersensitivity to local anaesthesia of amide type.
- •Treatment received with any drug active against MTB (including but not limited to isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole), or with immunosuppressive medications such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within 2 weeks prior to screening
- •Participants with the following toxicities at screening as defined by the enhanced CTCEA toxicity table
- •creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);
- •haemoglobin <7.5 g/dL;
- •platelets grade 2 or greater (under 50x109 cells/L);
- •serum potassium grade 2 or greater (<3.0 mEq/L);
- •aspartate aminotransferase (AST) grade 3 (≥3.0 x ULN) to be excluded;
- •alanine aminotransferase (ALT) grade 3 (≥3.0 x ULN) to be excluded;
- •APTT grade 3
- •INR grade 3
- •Total white cell count grade 3
研究组 & 干预措施
Group 1 Arm 1
Meropenem 6g IV over 6 hours plus amoxicillin/CA
干预措施: Meropenem 6g IV over 6 hours (Drug)
Group 1 Arm 1
Meropenem 6g IV over 6 hours plus amoxicillin/CA
干预措施: Amoxicillin/CA twice daily (Drug)
Group 1 Arm 2
Ertapenem 1g IM plus amoxicillin/CA
干预措施: Ertapenem 1g IM (Drug)
Group 1 Arm 2
Ertapenem 1g IM plus amoxicillin/CA
干预措施: Amoxicillin/CA twice daily (Drug)
Group 2 Arm 1
Meropenem 3g over 1 hour twice daily plus amoxicillin/CA
干预措施: Meropenem 3g IV (Drug)
Group 2 Arm 1
Meropenem 3g over 1 hour twice daily plus amoxicillin/CA
干预措施: Amoxicillin/CA twice daily (Drug)
Group 2 Arm 2
Ertapenem 1g IV plus amoxicillin/CA
干预措施: Ertapenem 1g IV (Drug)
Group 2 Arm 2
Ertapenem 1g IV plus amoxicillin/CA
干预措施: Amoxicillin/CA twice daily (Drug)
Group 2 Arm 3
Amoxicillin; CA
干预措施: Amoxicillin/CA twice daily (Drug)
Group 2 Arm 4
Rifampicin 35mg/kg plus amoxicillin/CA
干预措施: Amoxicillin/CA twice daily (Drug)
Group 2 Arm 4
Rifampicin 35mg/kg plus amoxicillin/CA
干预措施: Rifampicin 35 mg/kg (Drug)
Group 2 Arm 5
Meropenem 6g or 4g IV over 60 minutes plus amoxicillin/CA
干预措施: Meropenem 6g IV over 60 minutes (Drug)
Group 2 Arm 5
Meropenem 6g or 4g IV over 60 minutes plus amoxicillin/CA
干预措施: Meropenem 4g IV (Drug)
Group 2 Arm 5
Meropenem 6g or 4g IV over 60 minutes plus amoxicillin/CA
干预措施: Amoxicillin/CA once daily (Drug)
Group 1
Rifafour e-275
干预措施: Rifafour e-275 (Drug)
结局指标
主要结局
Early bactericidal activity by change in logCFU over 14 days
时间窗: 14 days
The EBACFU(0-14) as determined by the rate of change in logCFU (colony forming units) per ml sputum over the period Day 0 to Day 14 which will be summarised and described with a statistical model as an estimated average decrease per day for patients in each group.
Early bactericidal activity by change in time-to-positivity over 14 days
时间窗: 14 days
The EBATTP(0-14) as determined by the percentage rate of change in TTP (time to positivity) per ml sputum over the period Day 0 to Day 14, which will be summarised and described with a statistical model as an estimated average increase per day for patients in each group.
次要结局
- Early bactericidal activity by change in logCFU and TTP per ml over 0-2 days, 0-7 days, and 2-14 days(0-2 days, 0-7 days, 2-14 days)