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

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)

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.

Study Overview

• Status: Completed
• Conditions: Allergic Bronchopulmonary Aspergillosis
• Intervention / Treatment: Drug: Voriconazole inhaled; Drug: oral voriconazole

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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M239QZ
    • Medicines Evaluation Unit Ltd. (MEU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Vfend

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAE)	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.	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).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1	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	Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Cmax for Voriconazole and N-oxide Voriconazole - Part 1	Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;	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 1	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.	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	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.	Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
CL/F for Voriconazole - Part 1	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.	Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
Vz/F for Voriconazole - Part 1	Vz/F=Apparent volume of distribution during terminal phase.	Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1	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)	Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).
MR Cmax for N-oxide Voriconazole - Part 1	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.	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	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	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 for Voriconazole and N-oxide Voriconazole - Part 2	Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;	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 and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2	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.	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	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.	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	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.	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 - Part 2	Swing for voriconazole and N-oxide voriconazole = [(Cmax - Cmin) / Cmin]*100%	Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
AUCtau for Voriconazole and N-oxide Voriconazole - Part 2	Area under the serum concentration time curve for the dosing interval	Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Css,av for Voriconazole and N-oxide Voriconazole - Part 2	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	Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)
Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2	Peak trough fluctuation in serum concentrations within one dosing interval at steady state. Fluctuation - Over the Dosing Interval - is expressed as percentage concentration.	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	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.	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	Rlinear means linearity ratio for Area Under the Serum Concentration-Time Curve from time zero to infinity.	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	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)	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 Cmax N-oxide Voriconazole - Part 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.	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 for Voriconazole and N-oxide Voriconazole - Part 3	Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;	Day 1 of the respective treatment period 1 or 2
Vz/F for Voriconazole - Part 3	Vz/F=Apparent volume of distribution during terminal phase.	Only at Day 10
AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3	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	Day 1 of the respective treatment period 1 or 2
Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3	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.	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	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.	Day 1 of the respective treatment period 1 or 2
Kel for Voriconazole and N-oxide Voriconazole - Part 3	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.	Day 1 of the respective treatment period 1 or 2
Vz/F for Voriconazole - Part 3	Vz/F=Apparent volume of distribution during terminal phase.	Day 1 of the respective treatment period 1 or 2
MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3	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)	Day 1 of the respective treatment period 1 or 2
MR Cmax for N-oxide Voriconazole - Part 3	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.	Day 1 of the respective treatment period 1 or 2
Bioavailability of Voriconazole - Cmax	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.	On Day 1 in Parts 1-3 and on Day 10 in Part 2
Bioavailability of Voriconazole - AUC-inf	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.	On Day 1 in Parts 1-3 and on Day 10 in Part 2

Collaborators and Investigators

• Sponsor: Zambon SpA
• Investigators: Study Director: Sukh Dave Singh, Prof, MD,, The Medicine Evaluation Unit (MEU) Ltd, Langley building,

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2020
• Primary Completion (Actual): August 31, 2020
• Study Completion (Actual): August 31, 2020

Study Registration Dates

• First Submitted: December 6, 2019
• First Submitted That Met QC Criteria: January 10, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): November 15, 2021
• Last Update Submitted That Met QC Criteria: November 12, 2021
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Asthma; Voriconazole; ABPA; Allergic Bronchopulmonary Aspergillosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bacterial Infections and Mycoses; Respiratory Hypersensitivity; Hypersensitivity; Mycoses; Lung Diseases, Fungal; Aspergillosis; Pulmonary Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Voriconazole
• Other Study ID Numbers: Z7240J01; 2019-004031-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No