A Phase I Bioavailability Study of Selected Oral Prototype Granule Formulations of OZ439 in Healthy Subjects, to Evaluate the Pharmacokinetics of OZ439 When Co-Administered With Piperaquine Phosphate Tablets in the Fasted State
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Piperaquine Cmax
研究概览
简要总结
This is a single-centre, 2-part, randomised, single-dose parallel group study in healthy male subjects and female subjects of non-childbearing potential.
详细描述
Parts 1 and 2 will be randomised with 8 subjects receiving each regimen:
Part 1:
- Regimen A: Reference: 800 mg OZ439 + α-Tocopherol polyethylene glycol 1000 succinate (TPGS) granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
- Regimen B: Prototype 1: 800 mg OZ439 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
- Regimen C: Prototype 3: 800 mg OZ439 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
There will be an interim decision after Part 1 to determine the formulation prototypes and the oral suspension volume to be administered in Part 2.
Part 2
研究设计
- 研究类型
- 干预性
- 分配方式
- 随机
- 干预模型
- 平行分组
- 主要目的
- 治疗
- 盲法
- 开放（无盲法）
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- Healthy males, or healthy females of non-childbearing potential ie surgically sterilised or post-menopausal
- Body mass index of 18.0 to 30.0 kg/m2 inclusive. Total body weight >50 kg at screening.
- Must agree to use an adequate method of contraception.
- Normal laboratory tests as judged by the Investigator.
- Must have QTcF ≤450 ms, QTcB ≤450 ms for male subjects, QTcF ≤470 ms, QTcB ≤470 ms for female subjects and PR interval ≤200 ms for screening and pre-dose ECG measurements.
排除标准
- Male subjects who have currently pregnant partners or who have partners planning to be pregnant.
- Evidence or history of clinically significant disease, or current infection.3.
- Clinically relevant abnormalities in the ECG.
- Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.
- History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia, heart rate ≤39 bpm.
- Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.
- History of any drug or alcohol abuse in the past 2 years prior to screening.
- Receipt of an investigational drug or participation in another clinical research study within 90 days prior to drug administration.
- Use of any prescription or non-prescription medications, vitamins, herbal supplements or dietary supplements, including protein supplements, within 14 days prior to the first dose of study drug.
- Positive hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus results.
- Clinically significant abnormal biochemistry, haematology or urinalysis.
- Positive urine drug screen result.
- History of intolerance or hypersensitivity to PQP or any 4-aminoquinoline, or ascertained or presumptive hypersensitivity to the active principle and/or formulation ingredients; history of anaphylaxis to drugs or allergic reactions in general, that the investigator considers may affect the outcome of the study.
- Presence or history of allergy requiring treatment; hayfever is allowed unless it is active.
- Donation or loss of >400 mL of blood within 90 days prior to drug administration.
研究组 & 干预措施
Regimen A: OZ439 + TPGS and PQP
800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: OZ439 + TPGS (Drug)
Regimen B: OZ439 Prototype 1 and PQP - 110mL
800 mg OZ439 Prototype 1 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: OZ439 Prototype 1 (Drug)
Regimen C: OZ439 Prototype 3 and PQP - 110mL
800 mg OZ439 Prototype 3 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: OZ439 Prototype 3 (Drug)
Regimen D: OZ439 + TPGS and PQP
800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: OZ439 + TPGS (Drug)
Regimen E: OZ439 Prototype 1 or 3 and PQP - XmL
800 mg OZ439 Prototype 1 or 3 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets
干预措施: OZ439 Prototype 1 (Drug)
Regimen F: OZ439 Prototype 1 or 3 and PQP - XmL
800 mg OZ439 Prototype 1 or 3 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets
干预措施: OZ439 Prototype 3 (Drug)
Regimen C: OZ439 Prototype 3 and PQP - 110mL
800 mg OZ439 Prototype 3 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: PQP (Drug)
Regimen D: OZ439 + TPGS and PQP
800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: PQP (Drug)
Regimen B: OZ439 Prototype 1 and PQP - 110mL
800 mg OZ439 Prototype 1 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: PQP (Drug)
Regimen A: OZ439 + TPGS and PQP
800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets
干预措施: PQP (Drug)
Regimen E: OZ439 Prototype 1 or 3 and PQP - XmL
800 mg OZ439 Prototype 1 or 3 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets
干预措施: PQP (Drug)
Regimen F: OZ439 Prototype 1 or 3 and PQP - XmL
800 mg OZ439 Prototype 1 or 3 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets
干预措施: PQP (Drug)
方案终点
主要结局
Piperaquine Cmax
时间窗: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose
Piperaquine Maximum observed concentration
Piperaquine AUC(0-168 h)
时间窗: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose
PQP Area under the plasma concentration versus time curve
OZ439 Cmax
时间窗: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose
OZ439 Maximum observed concentration
OZ439 AUC(0-168 h)
时间窗: pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose
OZ439 Area under the plasma concentration (AUC) versus time curve
次要结局
未报告次要终点
试验结果
结果已于 2016-01-14 在 ClinicalTrials.gov 公示。 在 ClinicalTrials.gov 查看
受试者流程
入组 48 人 · 完成 47 人
主要终点
OZ439 Cmax
ng/mL · Geometric Coefficient of Variation · 时间窗: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose
| Regimen A: OZ439 + TPGS and PQP （n=7） | Regimen B: OZ439 Prototype 1 and PQP - 110mL （n=8） | Regimen C: OZ439 Prototype 3 and PQP - 110mL （n=8） | Regimen D: OZ439 + TPGS and PQP （n=6） | Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） | Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） |
|---|---|---|---|---|---|
| 1600 (36.6) | 824 (38.3) | 616 (49.4) | 1530 (13.2) | 999 (40.8) | 730 (35.7) |
The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
OZ439 AUC(0-168 h)
ng*h/mL · Geometric Coefficient of Variation · 时间窗: pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose
| Regimen A: OZ439 + TPGS and PQP （n=7） | Regimen B: OZ439 Prototype 1 and PQP - 110mL （n=8） | Regimen C: OZ439 Prototype 3 and PQP - 110mL （n=8） | Regimen D: OZ439 + TPGS and PQP （n=6） | Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） | Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） |
|---|---|---|---|---|---|
| 15300 (26.1) | 7920 (26.4) | 5610 (38.1) | 14000 (29.6) | 9550 (57.5) | 7100 (45.7) |
The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
Piperaquine Cmax
ng/mL · Geometric Coefficient of Variation · 时间窗: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose
| Regimen A: OZ439 + TPGS and PQP （n=7） | Regimen B: OZ439 Prototype 1 and PQP - 110mL （n=8） | Regimen C: OZ439 Prototype 3 and PQP - 110mL （n=8） | Regimen D: OZ439 + TPGS and PQP （n=6） | Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） | Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） |
|---|---|---|---|---|---|
| 183 (124.9) | 62.1 (154.4) | 100 (80.7) | 119 (52.1) | 91.8 (108.2) | 95.7 (81.5) |
The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
Piperaquine AUC(0-168 h)
ng*h/mL · Geometric Coefficient of Variation · 时间窗: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose
| Regimen A: OZ439 + TPGS and PQP （n=7） | Regimen B: OZ439 Prototype 1 and PQP - 110mL （n=8） | Regimen C: OZ439 Prototype 3 and PQP - 110mL （n=8） | Regimen D: OZ439 + TPGS and PQP （n=6） | Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） | Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL （n=8） |
|---|---|---|---|---|---|
| 3740 (61.2) | 1940 (69.5) | 2980 (47.6) | 2860 (40.2) | 2550 (47.8) | 2470 (60.8) |
The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
安全性
| 组别 | 严重不良事件 | 死亡 |
|---|---|---|
| Regimen A: OZ439 + TPGS and PQP | 0 / 8 | — |
| Regimen B: OZ439 Prototype 1 and PQP - 110mL | 1 / 8 | — |
| Regimen C: OZ439 Prototype 3 and PQP - 110mL | 0 / 8 | — |
| Regimen D: OZ439 + TPGS and PQP | 0 / 8 | — |
| Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | 0 / 8 | — |
| Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL | 0 / 8 | — |
最常见的严重不良事件（人数）
| 事件 | Regimen A: OZ439 + TPGS and PQP | Regimen B: OZ439 Prototype 1 and PQP - 110mL | Regimen C: OZ439 Prototype 3 and PQP - 110mL | Regimen D: OZ439 + TPGS and PQP | Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL |
|---|---|---|---|---|---|---|
| Atrial Fibrillation | 0 / 8 | 1 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
数值为申办方在 ClinicalTrials.gov 公示的原始数据，未经重新计算；括号内为公示的离散度（如 95% 置信区间）。
研究者
研究点 (1)
标识符
- NCT 编号
- NCT02387580
- 其他研究编号
- MMV_OZ439_15_001
日期
- 首次提交
- (11年前)
- 首次发布
- (11年前)
- 主要完成日期
- 研究完成日期
- 最近核实
- 最近更新
- (10年前)
监管与共享
- FDA 监管药物
- 否
- 是否有结果
- 是