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Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04229303
Recruitment Status : Completed
First Posted : January 18, 2020
Results First Posted : November 15, 2021
Last Update Posted : November 15, 2021
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Allergic Bronchopulmonary Aspergillosis Drug: Voriconazole inhaled Drug: oral voriconazole Phase 1

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 58 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Safety, tolerability and PK will be assessed following either single ascending (SAD) or multiple ascending (MAD) dosing of ZP-059; Part 1 and Part 2, respectively. Part 1 will comprise 4 separate cohorts planned to receive single doses of ZP-059; part 2 will comprise 3 separate cohorts planned to receive daily doses of ZP-059 on Day 1 to 10; part 3 is a 2-period, randomised crossover study in subjects with mild to moderate stable asthma to assess the safety, tolerability and PK of single doses of ZP-059 and single doses of oral voriconazole.
Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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)
Actual Study Start Date : February 11, 2020
Actual Primary Completion Date : August 31, 2020
Actual Study Completion Date : August 31, 2020


Arm Intervention/treatment
Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.

Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Experimental: 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.
Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Drug: oral voriconazole
Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study.
Other Name: Vfend

Experimental: 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.
Drug: Voriconazole inhaled

Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.

Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.

Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.

ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).

Other Name: ZP-059

Drug: oral voriconazole
Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study.
Other Name: Vfend




Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (TEAE) [ Time Frame: 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 :
  1. AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 [ Time Frame: 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

  2. Cmax for Voriconazole and N-oxide Voriconazole - Part 1 [ Time Frame: 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;

  3. Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 [ Time Frame: 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.

  4. Kel for Voriconazole and N-oxide Voriconazole - Part 1 [ Time Frame: 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.


  5. CL/F for Voriconazole - Part 1 [ Time Frame: 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.

  6. Vz/F for Voriconazole - Part 1 [ Time Frame: 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.

  7. MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 [ Time Frame: 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)


  8. MR Cmax for N-oxide Voriconazole - Part 1 [ Time Frame: 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.


  9. AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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

  10. Cmax for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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;

  11. Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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.

  12. Kel for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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.


  13. CL/F for Voriconazole - Part 2 [ Time Frame: 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.

  14. Swing for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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%

  15. AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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

  16. Css,av for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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

  17. Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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.

  18. Rac for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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.

  19. Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 [ Time Frame: 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.

  20. MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 [ Time Frame: 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)


  21. MR Cmax N-oxide Voriconazole - Part 2 [ Time Frame: 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.


  22. Cmax for Voriconazole and N-oxide Voriconazole - Part 3 [ Time Frame: 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;

  23. Vz/F for Voriconazole - Part 3 [ Time Frame: Only at Day 10 ]
    Vz/F=Apparent volume of distribution during terminal phase.

  24. AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 [ Time Frame: 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

  25. Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 [ Time Frame: 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.

  26. CL/F for Voriconazole - Part 3 [ Time Frame: 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.

  27. Kel for Voriconazole and N-oxide Voriconazole - Part 3 [ Time Frame: 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.


  28. Vz/F for Voriconazole - Part 3 [ Time Frame: Day 1 of the respective treatment period 1 or 2 ]
    Vz/F=Apparent volume of distribution during terminal phase.

  29. MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 [ Time Frame: 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)


  30. MR Cmax for N-oxide Voriconazole - Part 3 [ Time Frame: 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.


  31. Bioavailability of Voriconazole - Cmax [ Time Frame: 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.


  32. Bioavailability of Voriconazole - AUC-inf [ Time Frame: 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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria (part 1):

  • Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
  • Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s)
  • Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
  • BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
  • Are willing and able to comply with all aspects of the protocol.
  • FEV1 ≥80% of the predicted value and FEV1/FVC ratio > 0.70; at screening.
  • Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1.

Inclusion Criteria (part 2):

  • Subjects with mild stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening.
  • Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to Day 1.
  • Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
  • Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s).
  • Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
  • Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
  • Are willing and able to comply with all aspects of the protocol.
  • Subject is being treated with short acting beta-agonists alone or in conjunction with low to medium doses of ICS.
  • Pre-bronchodilator FEV1 ≥70% of the predicted value at screening.
  • Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1.

Inclusion Criteria (part 3):

  • Subjects with mild to moderate stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening.
  • Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to randomisation.
  • Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method .
  • Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s)
  • Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
  • BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
  • Are willing and able to comply with all aspects of the protocol.
  • Subject is being treated with low to medium doses of ICS with or without long-acting beta-agonists.
  • Pre-bronchodilator FEV1 ≥70% of the predicted value at screening.
  • Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1, Treatment Period 1.
  • Able to produce a sputum sample with a minimum weight of 50 mg at screening.

Exclusion Criteria (part 1):

  • Subjects who are Chinese or Japanese.
  • Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1.
  • Participation in other interventional studies for the duration of the study.
  • Subjects who are study site employees or immediate family members of a study site or sponsor employee.
  • History of any drug or alcohol abuse in the past 2 years prior to screening.
  • Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type).
  • Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1.
  • A confirmed positive urine cotinine test at screening or Day -1.
  • Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1.
  • Smoking history of >5 pack years at screening.
  • Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause).
  • Female subject with a positive pregnancy test at screening or pre-dose on Day 1.
  • Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
  • Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required.
  • Positive urine drugs of abuse test or alcohol breath test result at screening or Day -1.
  • History of or currently infected with/carrier of human immunodeficiency virus (HIV).
  • Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
  • Evidence or history of clinically significant cardiovascular, renal, hepatic, endocrine, immunological or autoimmune, dermatological, ophthalmological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
  • Subjects with congestive heart failure or a history of congestive heart failure.
  • 12-lead ECGs demonstrating a mean QTcF interval >450 msec for males or QTcF interval >470 msec for females at screening or pre-dose Day 1.
  • History of severe cough or bronchospasm upon inhalation of any inhalation product.
  • Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
  • Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles.
  • Presence or history of clinically significant allergy, including drug allergies, but excluding untreated, mild seasonal allergies, as judged by the investigator. Hay fever is allowed unless it is active.
  • Major trauma or surgery within the last 3 months prior to screening or prior to Day 1.
  • Planned or elective surgery or hospitalisations for the duration of the study that may interfere with study logistics or safety.
  • Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening.
  • Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than ≤4 g per day of paracetamol, hormonal contraception or hormone replacement therapy), dietary supplements or CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the Principal Investigator and sponsor's medical monitor.
  • Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1.
  • Any use of voriconazole in the 3 months prior to Day 1.
  • Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1.
  • Upper respiratory tract infection (excluding otitis media), fever, acute or chronic cough within 14 days of Day 1, or lower respiratory tract infection within the last 4 weeks prior to Day 1.
  • Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.
  • Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the investigator would make the subject inappropriate for entry into the study.
  • Failure to satisfy the investigator of fitness to participate for any reason.

Exclusion Criteria (part 2 and 3):

  • Subjects who are Chinese or Japanese.
  • Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1.
  • Participation in other interventional studies for the duration of the study.
  • Subjects who are study site employees, or immediate family members of a study site or sponsor employee.
  • Subjects who have previously received IMP in this study.
  • History of any drug or alcohol abuse in the past 2 years prior to screening.
  • Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type).
  • Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1.
  • A confirmed positive urine cotinine test at screening or Day -1.
  • Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1.
  • Smoking history of >5 pack years at screening.
  • Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause).
  • Female subject with a positive pregnancy test at screening or pre-dose Day 1.
  • Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
  • Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required.
  • Positive urine drugs of abuse test result (unless in the opinion of the investigator this can be explained by the subject's current medications) at screening or Day -1; unexpected positive results may require discussion with sponsor).
  • Positive alcohol breath test at screening or Day -1.
  • History of or currently infected with/carrier of HIV.
  • Positive HBsAg, HCV Ab or HIV results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
  • Evidence or history of clinically significant cardiovascular, renal, hepatic, dermatologic, ophthalmologic or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
  • Evidence of history of endocrine, immunological, autoimmune disease that would affect the subject's safety or confound the assessment of study endpoints in the opinion of the investigator.
  • Current diagnosis of any chronic airways disease other than asthma such as Chronic Obstructive Pulmonary Disease, pulmonary fibrosis, CF, Churg-Strauss syndrome, bronchiectasis.
  • Evidence of ventricular dysfunction such as congestive cardiac failure (CCF) or a history of CCF assessed at screening and pre-dose Day 1.
  • 12-lead ECG demonstrating a mean QTcF interval >450 msec for males or >470 msec for females at screening or pre-dose Day 1.
  • Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
  • Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles.
  • Presence or history of clinically significant allergy, including drug allergies, as judged by the investigator. Hay fever is allowed unless it is active.
  • Major trauma or surgery within the last 3 months prior to screening or prior to Day 1.
  • Planned or elective surgery, hospitalisations for the duration of the study that may interfere with study logistics or safety.
  • Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening.
  • Subjects who are taking, or have taken, any prescribed or over-the-counter drugs that are CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study.
  • Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1.
  • Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1.
  • Presence of hoarseness or oropharyngeal candidiasis at screening or prior to dosing on Day 1.
  • Any use of voriconazole in the 3 months prior to Day 1.
  • History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest and/or hypoxic seizures.
  • Hospitalisation (including accident and emergency visits) for the treatment of asthma within 3 months prior to screening or prior to Day 1 or have been hospitalised or have attended the accident and emergency for asthma more than twice in the 12 months prior to screening.
  • Occurrence of asthma exacerbations or respiratory tract infections within 4 weeks prior to screening or prior to Day 1.
  • Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.
  • Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the Investigator would make the subject inappropriate for entry into the study.
  • Failure to satisfy the investigator of fitness to participate for any reason.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04229303


Locations
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United Kingdom
Medicines Evaluation Unit Ltd. (MEU)
Manchester, United Kingdom, M239QZ
Sponsors and Collaborators
Zambon SpA
Investigators
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Study Director: Sukh Dave Singh, Prof, MD, The Medicine Evaluation Unit (MEU) Ltd, Langley building,
  Study Documents (Full-Text)

Documents provided by Zambon SpA:
Study Protocol  [PDF] June 4, 2020
Statistical Analysis Plan  [PDF] October 28, 2020

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Responsible Party: Zambon SpA
ClinicalTrials.gov Identifier: NCT04229303    
Other Study ID Numbers: Z7240J01
2019-004031-23 ( EudraCT Number )
First Posted: January 18, 2020    Key Record Dates
Results First Posted: November 15, 2021
Last Update Posted: November 15, 2021
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Zambon SpA:
ABPA
Asthma
Voriconazole
Allergic Bronchopulmonary Aspergillosis
Additional relevant MeSH terms:
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Aspergillosis
Pulmonary Aspergillosis
Aspergillosis, Allergic Bronchopulmonary
Mycoses
Bacterial Infections and Mycoses
Infections
Lung Diseases, Fungal
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Voriconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors