Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects
- Conditions
- Allergic Bronchopulmonary Aspergillosis
- Interventions
- Registration Number
- NCT04229303
- Lead Sponsor
- Zambon SpA
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 58
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Part 1 - ZP-059 5mg Voriconazole inhaled 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. Part 1 - ZP-059 10mg Voriconazole inhaled 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. Part 1 - ZP-059 20mg Voriconazole inhaled 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. Part 1 - ZP-059 40mg Voriconazole inhaled 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. Part 2 - ZP-059 10mg bid Voriconazole inhaled 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. Part 2 - ZP-059 20mg bid Voriconazole inhaled 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. Part 2 - ZP-059 40mg qd Voriconazole inhaled 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. Part 3 - ZP-059 / Oral Voriconazole Voriconazole inhaled 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. Part 3 - Oral Voriconazole / ZP-059 Voriconazole inhaled 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. Part 3 - ZP-059 / Oral Voriconazole 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. Part 3 - Oral Voriconazole / ZP-059 oral voriconazole 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.
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment-Emergent Adverse Events (TEAE) 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.
- Secondary Outcome Measures
Name Time Method 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). Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
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) Peak trough fluctuation in serum concentrations within one dosing interval at steady state. Fluctuation - Over the Dosing Interval - is expressed as percentage concentration.
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). Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
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) AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-24 for Part 2) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
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). AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-12 for Part 1) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
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). Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system.
It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.MR Cmax for N-oxide Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters.
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.Vz/F for Voriconazole - Part 1 Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). Vz/F=Apparent volume of distribution during terminal phase.
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). MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters.
Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)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) Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
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) Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system.
It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.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) Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
Bioavailability of Voriconazole - Cmax On Day 1 in Parts 1-3 and on Day 10 in Part 2 The Cmax estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole.
The Cmax was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations.
In Part 1 and 3, Cmax was estimated only on Day1. In Part 2, Cmax was estimated on Day 10.CL/F for Voriconazole - Part 1 Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
MR Cmax for N-oxide Voriconazole - Part 1 Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters.
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.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) Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
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) Area under the serum concentration time curve for the dosing interval
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) Accumulation ratio. The drug accumulation ratio (Rac) is the ratio of accumulation of a drug under steady state conditions as compared to a single dose. The higher the value, the more the drug accumulates in the body. An Rac of 1 means no accumulation.
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) Rlinear means linearity ratio for Area Under the Serum Concentration-Time Curve from time zero to infinity.
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 = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters.
Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters.
Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)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) Swing for voriconazole and N-oxide voriconazole = \[(Cmax - Cmin) / Cmin\]\*100%
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) MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters.
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-96 for Part 3) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
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) Css,av or Css(ave): Average drug concentration at steady state; Steady-state concentration (Css) occurs when the amount of a drug being absorbed is the same amount that's being cleared from the body when the drug is given continuously or repeatedly
Cmax for Voriconazole and N-oxide Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
Vz/F for Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 Vz/F=Apparent volume of distribution during terminal phase.
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) Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
CL/F for Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
Kel for Voriconazole and N-oxide Voriconazole - Part 3 Day 1 of the respective treatment period 1 or 2 Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system.
It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.Bioavailability of Voriconazole - AUC-inf On Day 1 in Parts 1-3 and on Day 10 in Part 2 The AUC0-inf estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole.
The AUC0-inf was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations.
In Part 1 and 3, AUC0-inf was estimated on Day 1. In part 2, AUC0-in f was estimated on Day 10.
Trial Locations
- Locations (1)
Medicines Evaluation Unit Ltd. (MEU)
🇬🇧Manchester, United Kingdom