A Phase II, Multi-centre, Open-label, Randomised Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Oral Sitamaquine Compared With Amphotericin B in the Treatment of Visceral Leishmaniasis Caused by L. Donovani in Endemic Areas.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 3
- 主要终点
- Area under the concentration-time curve over the dosing interval AUC(0-tau) for sitamaquine
研究概览
简要总结
Sitamaquine is an 8-aminoquinoline which is being developed as an oral treatment for visceral leishmaniasis (VL). Pre-clinical and subsequent clinical investigations have demonstrated oral efficacy against Leishmania donovani. The purposes of this study are to characterise the pharmacokinetic profile of sitamaquine, administered orally, and to determine if the pharmacokinetic profile is affected by administration with food. The study is also designed to further characterise the safety and tolerability of sitamaquine compared with amphotericin B, particularly in reference to renal, hepatic and cardiac adverse events, prior to initiation of phase III studies. Finally the study will investigate the efficacy of a 21 day treatment course. Previous studies have used 28 days dosing, but parasitological evidence from one study suggests that shorter courses may be effective.
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
- 16 Years 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical diagnosis of visceral leishmaniasis; symptoms and signs compatible with VL and diagnosis confirmed by visualisation of amastigotes in splenic aspirate or bone marrow.
- •Written informed consent or witnessed oral consent.
- •Willing to comply with the study visits and procedures.
- •For female subjects, a negative urine pregnancy test at screening and before dosing and the subject agrees to use an established method of birth control (including abstinence).
排除标准
- •Past history of renal disease or impaired renal function at screening.
- •History of any significant hepatic or biliary disease, or the following abnormal laboratory values at screening; hepatic dysfunction (AST or ALT 2.5 times upper limit of normal).
- •Subjects with the following abnormal laboratory values; haemoglobin 6.5 g/dl, neutrophils <750/ mm3, platelets <50,000 / mm3, any clinically relevant abnormality identified on screening examination or clinical laboratories which would preclude the subject's safe participation in the study.
- •History of cardiac disease, arrhythmias, conduction abnormalities or any clinically relevant abnormality identified on 12-lead ECG at screening.
- •Subjects suffering from a concomitant infection, blood disorder or any other serious underlying disease which would preclude evaluation of the subject's response to the study medication.
- •Methaemoglobin levels >5% at screening. G6PD deficiency.
- •Positive HIV antibody, hepatitis B surface antigen or hepatitis C antibody at screening.
- •Pregnant or nursing women; women of childbearing potential who are unwilling or unable to use an appropriate form of contraception, from prior to study medication administration until 2 weeks following the last dose of investigational product.
- •Any contraindication to splenic aspirate (or bone marrow aspirate), including but not limited to PT prolonged >3 seconds longer than control or platelets <50,000 / mm
- •Subjects with a known hypersensitivity reaction to 8-aminoquinolines (e.g. primaquine) or any of the investigational product excipients.
- •Treatment with an established antileishmanial chemotherapeutic agent within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
- •Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
结局指标
主要结局
Area under the concentration-time curve over the dosing interval AUC(0-tau) for sitamaquine
时间窗: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose
AUC is defined as the area under the concentration-time curve from 0 to last quantifiable concentration (AUC 0-tau). AUC is a measure of exposure. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21. Only those participants with data available at the specified time points were analyzed.
Maximum plasma concentration (Cmax) for sitamaquine
时间窗: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose.
Cmax was defined as the maximum concentration of sitamaquine. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21.
Time to maximum observed plasma concentration (tmax) for sitamaquine
时间窗: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose.
Tmax is defined as the time to peak concentration from initiation of sitamaquine dosing. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21.
Accumulation ratio for sitamaquine
时间窗: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose
Point estimate was the ratio of adjusted geometric means between repeat dosing days (Day 21 or Day 10) and single dose day (Day 1). An evaluation on the accumulation rate was based upon the comparison of AUC(0-24) values after repeated dosing to the values from the first dose on day 1. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21. Individual observed accumulation ratios on Day 10 were calculated by dividing AUC (0-tau) on Day 10 by AUC (0-tau) on Day 1. A similar formula was applied to the accumulation ratio on Day 21.
次要结局
- Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 180(Baseline (Day 1 pre-dose) and Day 180)
- Change from Baseline in heart rate(Baseline (Day 1 pre-dose) and Day 180)
- Change from Baseline in body temperature(Baseline (Day 1 pre-dose) and Day 180)
- Change from Baseline in body weight(Baseline (Day 1 pre-dose) and Day 49 for Sitamaquine and Day 58 for Amphotericin B)
- Number of participants with adverse events(AEs) and serious adverse events(SAEs)(Up to 180 days)
- Number of participants with abnormal 12-lead Electrocardiogram (ECG) values(At Day 22 for Sitamaquine and Day 31 for Amphotericin B)
- Number of participants with abnormal echocardiography results(Up to Day 22 and 49 (sitamaquine only) and Day 31 and 58 (amphotericin B only))
- Number of participants with abnormal hematology values at the end of study (Day 180)(Day 180)
- Number of participants with abnormal clinical chemistry values at the end of study (Day 180)(Day 180)
- Number of participants with Initial parasitological cure (28 days)(Up to 28 days)
- Number of participants with Final parasitological cure (6 months)(Up to 180 days)
- Terminal elimination half-life (t1/2) for sitamaquine(At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose)