Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects
Condition: Allergic Bronchopulmonary Aspergillosis
MeSH terms: Aspergillosis; Pulmonary Aspergillosis; Aspergillosis, Allergic Bronchopulmonary
Intervention: Voriconazole inhaled; oral voriconazole
Intervention description: 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).; 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.
Intervention MeSH terms: Voriconazole
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
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)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: ABPA; Asthma; Voriconazole; Allergic Bronchopulmonary Aspergillosis

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.
    

Eligibility 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.