A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Sanfetrinem Cilexetil Administered Orally to 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
- 54
- 试验地点
- 1
- 主要终点
- Rate of change in mycobacterium tuberculosis (Mtb) load in sputum from pre-treatment to Day 14 on-treatment, based on colony forming unit (CFU) count on solid culture media (7H11 agar plates)
研究概览
简要总结
To evaluate the 2-week bactericidal activity, pharmacokinetics, safety and tolerability of sanfetrinem cilexetil in participants with rifampicin-susceptible pulmonary tuberculosis.
详细描述
A single-centre, open-label, clinical trial in two stages. Stage 1 will recruit 20 participants followed by a recruitment pause and an interim analysis to determine if sanfetrinem cilexetil has early bactericidal activity (EBA). Should EBA be demonstrated, stage 2 will focus on optimising sanfetrinem cilexetil.
All treatments will be administered orally (PO) on days 1-14. The treatments are:
Stage 1:
- Sanfetrinem cilexetil 1.6 g PO 12-hourly
- Rifampicin 35 mg/kg PO once daily (OD)*
An interim analysis is planned after stage 1 to review the pharmacokinetics (PK), safety, tolerability and EBA of sanfetrinem cilexetil. Results of stage 1 will determine whether stage 2 should proceed and if any modifications in dose, duration or combinations are required for Stage 2. If deemed possible, a PK-EBA model will be derived using only stage 1 from which clinical trial simulations will be conducted to inform the design of stage 2. If EBA is not demonstrated, the study will be stopped after stage 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Laboratory personnel are blinded to treatment arm
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
- •Participants are required to meet all of the following criteria in order to be randomized.
- •Provide written, informed consent prior to all trial-related procedures.
- •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 taken at screening 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) or GeneXpert cycle threshold of medium or high.
- •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:
- •Female participant/ female sexual partner - bilateral oophorectomy
- •bilateral tubal ligation
- •hysterectomy
- •postmenopausal with no menses for at least 12 consecutive months Male participant/ male sexual partner - vasectomy
- •bilateral orchidectomy more than three months prior to screening
- •Effective birth control methods:
- •Participant is not heterosexually active or practicing sexual abstinence
- •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.
排除标准
- •Participants will be excluded from participation if they fulfil any of the following criteria.
- •Evidence of clinically significant conditions or findings, other than TB, 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.
- •Clinically significant evidence of extrathoracic TB, 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.
- •Alcohol or drug abuse, that in the opinion of the investigator, is sufficient to compromise the safety or cooperation of the participant.
- •HIV positive ONLY IF:
- •CD4 < 250cells/mm3
- •Participation in other clinical studies with investigational agents within 8 weeks prior to trial start (with the exception of COVID-19 vaccines).
- •Female participant who is pregnant, breast-feeding, or planning to conceive a child within the anticipated period of trial participation. Male participant planning to conceive a child within the anticipated period of participating in the trial.
- •Treatment received with any drug active against M.tb (including but not limited to isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides), or with immunosuppressive medications such as TNF-alpha inhibitors within 2 weeks prior to screening, or systemic corticosteroids for more than 7 days within 2 weeks prior to screening.
- •Participants with the following toxicities at screening as defined by the enhanced CTCEA toxicity table
- •creatinine >1.5 times upper limit of normal [ULN];
- •haemoglobin <8.0 g/dL;
- •platelets <50x109 cells/L;
- •serum potassium <3.0 mmol/L;
- •aspartate aminotransferase (AST) ≥3.0 x ULN;
- •alanine aminotransferase (ALT) ≥3.0 x ULN;
- •Total white cell count <1.5 cells/L
- •For participants undergoing PET/CT, the following are excluded:
- •Participants with diabetes (Type 1 or 2) with point of care HbA1c above 6.5, or random glucose over 11.1 mmol/L.
研究组 & 干预措施
Sanfetrinem cilexetil 1.6 gram 12 hourly
Sanfetrinem cilexetil 1.6g will be given orally 12 hourly for 14 consecutive days.
干预措施: Sanfetrinem Cilexetil (Drug)
Rifampicin 35 mg/kg once daily
Rifampicin 35 mg/kg will be given orally once daily for 14 consecutive days.
干预措施: Rifampicin (Drug)
Sanfetrinem cilexetil 2.4 gram once daily
Sanfetrinem cilexetil 2.4 g will be given orally daily for 14 consecutive days.
干预措施: Sanfetrinem Cilexetil (Drug)
结局指标
主要结局
Rate of change in mycobacterium tuberculosis (Mtb) load in sputum from pre-treatment to Day 14 on-treatment, based on colony forming unit (CFU) count on solid culture media (7H11 agar plates)
时间窗: 14 days
Early bactericidal activity (EBA) will be determined, per treatment arm, as the rate of change in log10 CFU count per ml sputum over the treatment period day 0 to day 14, and described using linear, bi-linear or non-linear regression of log10CFU count over time and relation to drug exposure.
次要结局
- Rate of change in mycobacterium tuberculosis (Mtb) load in sputum from pre-treatment to Day 14 on-treatment, based on time to positive (TTP) culture in the BACTEC MGIT 960 liquid culture system(14 days)
- Number of patients with abnormal safety and tolerability findings following the study regimens, administered for 14 days(14 days)