To Assess Safety, PK of Inhaled Voriconazole (ZP-059) Single Doses in Healthy Subjects (Part 1), ZP-059 Multiple Doses in Stable Asthma (Part 2) and in a Crossover Trial of ZP-059 and Oral Voriconazole Single Doses in Stable Asthma (Part 3)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Zambon SpA
- 入组人数
- 58
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (TEAE)
研究概览
简要总结
The primary safety objectives were:
- Part 1: To determine the safety and tolerability of single doses of ZP-059 in healthy subjects
- Part 2: To determine the safety and tolerability of multiple doses of ZP-059 in subjects with mild stable asthma
- Part 3: To determine the safety and tolerability of single doses of ZP-059 in subjects with mild to moderate stable asthma.
The primary PK objectives were:
- Part 1: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 in healthy subjects
- Part 2: To characterize systemic PK of voriconazole and N-oxide voriconazole after multiple doses of ZP-059 in subjects with mild stable asthma
- Part 3: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 and single doses of oral voriconazole in subjects with mild to moderate stable asthma.
详细描述
This was an integrated Phase 1, single centre, multi-part, open-label study in both healthy subjects (Part 1), subjects with mild stable asthma (Part 2) and subjects with mild to moderate stable asthma (Part 3). In all three parts of the study every effort was made to include as close as possible an equal balance between male and female subjects.
This study assessed safety, tolerability and PK of single and multiple ascending doses of ZP-059 capsules administered as dry powder for inhalation in Part 1 to healthy volunteers (single ascending dose; SAD) and in Part 2 to subjects with mild asthma (multiple ascending dose; MAD), respectively.
In Part 3, the bioavailability of ZP-059 in subjects with mild to moderate stable asthma were compared to that of oral voriconazole. Part 3 started only after review of safety data from cohorts 1 to 4 of Part 1 (SAD) have been completed. Parts 2 and 3 of the study also explored voriconazole concentrations in induced sputum samples in asthmatic subjects.
As part of the safety and tolerability assessment, this study investigated the effects of ZP-059 on airway function in both mild and mild to moderate stable asthma subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part 1 - ZP-059 5mg
Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
干预措施: Voriconazole inhaled (Drug)
Part 1 - ZP-059 10mg
Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
干预措施: Voriconazole inhaled (Drug)
Part 1 - ZP-059 20mg
Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
干预措施: Voriconazole inhaled (Drug)
Part 1 - ZP-059 40mg
Part 1: administration of single ascending doses (SAD) of ZP-059.
Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1.
干预措施: Voriconazole inhaled (Drug)
Part 3 - ZP-059 / Oral Voriconazole
Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours.
干预措施: oral voriconazole (Drug)
Part 2 - ZP-059 10mg bid
Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10.
Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10.
干预措施: Voriconazole inhaled (Drug)
Part 2 - ZP-059 20mg bid
Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10.
Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10.
干预措施: Voriconazole inhaled (Drug)
Part 2 - ZP-059 40mg qd
Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10.
Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) administered via DPI (RS01 monodose device) on Days 1 to 10.
干预措施: Voriconazole inhaled (Drug)
Part 3 - ZP-059 / Oral Voriconazole
Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours.
干预措施: Voriconazole inhaled (Drug)
Part 3 - Oral Voriconazole / ZP-059
Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours.
干预措施: Voriconazole inhaled (Drug)
Part 3 - Oral Voriconazole / ZP-059
Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours.
干预措施: oral voriconazole (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (TEAE)
时间窗: Part 1: screening (Day -28 to -1) to follow-up (8 to 12 days after last dose); part 2: screening (Day -28 to -1) to follow-up (11-17 days after last dose); Part 3: screening (Day -28 to -1) to follow-up (8-12 days after last dose of study drug).
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of IMP, whether or not considered related to the study IMP.
次要结局
- Cmax for Voriconazole and N-oxide Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Vz/F for Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- Kel for Voriconazole and N-oxide Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- MR Cmax for N-oxide Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- Cmax for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Kel for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- CL/F for Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Bioavailability of Voriconazole - Cmax(On Day 1 in Parts 1-3 and on Day 10 in Part 2)
- CL/F for Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- MR Cmax for N-oxide Voriconazole - Part 1(Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).)
- Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- AUCtau for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Rac for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Rlinear for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2(Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- Swing for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- MR Cmax N-oxide Voriconazole - Part 2(Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- Css,av for Voriconazole and N-oxide Voriconazole - Part 2(Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours))
- Cmax for Voriconazole and N-oxide Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- Vz/F for Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2 (Pre-dose, 0.25h, 0.75h 1.5h, 2h ,3h ,4h ,6h ,8h ,12h ,16h , 24h ,48h after dosing))
- CL/F for Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- Kel for Voriconazole and N-oxide Voriconazole - Part 3(Day 1 of the respective treatment period 1 or 2)
- Bioavailability of Voriconazole - AUC-inf(On Day 1 in Parts 1-3 and on Day 10 in Part 2)