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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
Last Update Posted : September 25, 2020
Sponsor:
Information provided by (Responsible Party):
Zambon SpA

Tracking Information
First Submitted Date  ICMJE December 6, 2019
First Posted Date  ICMJE January 18, 2020
Last Update Posted Date September 25, 2020
Actual Study Start Date  ICMJE February 11, 2020
Actual Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 10, 2020)
  • Number of participants with treatment-related Adverse Events as assessed by CTCAE v4.0 [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    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
  • Twelve lead electrocardiography (ECG) [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Scheduled 12-lead ECGs (e.g. PR, QRS, QTc, QTcF and RR Interval in msec) will be measured in triplicate after the subject has been in the supine position for a minimum of 5 minutes. ECGs will be performed within a time window of 5 minutes, with minimum of 1 minute between subsequent ECGs. Repeats are permitted on the day and/or on another day (as appropriate) at the discretion of the investigator.
  • Pulse oximetry [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Oxygen saturation via pulse oximetry will be measured in %
  • Blood pressure [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Base line systolic and diastolic blood pressure will be measured in mmHg. Repeat tests are permitted on the day and/or on another day (as appropriate) at the discretion of the investigator. Blood pressure will be measured by automated equipment. Measurements will be collected after the subject had rested in the supine position for at least 5 minutes
  • Pulse rate [ Time Frame: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Base line pulse rate will be measured in beats per minute (bpm). Repeat tests are permitted on the day and/or on another day (as appropriate) at the discretion of the investigator. Pulse rate will be measured by automated equipment. Measurements will be collected after the subject had rested in the supine position for at least 5 minutes
  • Respiratory rate [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Base line respiratory rate will be measured in breaths per minute (bpm). Respiratory rate will be measured by automated equipment. Measurements will be collected after the subject had rested in the supine position for at least 5 minutes
  • Tympanic temperature [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Tympanic temperature (in °C) will be measured at screening and pre-dose
  • Physical examination [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    A full physical examination will involve assessment of the following: general appearance; head, neck and thyroid; ears, nose and throat; cardiovascular; respiratory; lymph nodes; abdomen; skin; musculoskeletal and nervous system. A symptom directed physical examination will involve any body system deemed necessary at the investigator's discretion due to on-going AEs at the time of assessment. Any clinically significant changes will be recorded as AEs
  • Hematology [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Any clinically significant abnormality, including changes from baseline, must be reported as an AE. Haematology: Basophils, Eosinophils, Haematocrit, (Packed Cell Volume- PCV), Haemoglobin, Lymphocytes, Mean Cell Haemoglobin (MCH), Mean Cell Haemoglobin Concentration (MCHC), Mean Cell Volume (MCV), Monocytes, Neutrophils, Platelet Count, Red Blood Cell (RBC) Count, White Blood Cell (WBC) Count
  • Clinical Chemistry [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Any clinically significant abnormality, including changes from baseline, must be reported as an AE. Scheduled blood samples for clinical chemistry will be taken following at least an 8 hour fast (water is permitted). Clinical chemistry: Alanine Aminotransferase (ALT), Albumin, Alkaline Phosphatase, Aspartate Aminotransferase (AST), Bicarbonate, Bilirubin (Total), Bilirubin (Direct) (only if Total is elevated), Calcium, Chloride, Creatine Kinase (CK), Creatinine, Follicle Stimulating Hormone, (FSH; may be performed for post-menopausal female subjects to confirm post menopausal status at discretion of investigator), Beta-hCG (all female subjects), Gamma Glutamyl Transferase (GGT), Glucose, Glucose (Fasting), Lactate dehydrogenase (LDH), Potassium, Phosphate (Inorganic), Protein (Total), Sodium, Urea
  • Urinalysis [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Any clinically significant abnormality, including changes from baseline, must be reported as an AE. Urinalysis : Bilirubin, Blood, Glucose, hCG (all female subjects), Ketones, Leukocytes, Nitrites, pH, Protein, Specific gravity, Urobilinogen. If urinalysis is positive for protein, blood, nitrite and/or leukocytes, a microscopic examination (for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed
  • Spirometry assessments [ Time Frame: Part 1: From 2 to 6 weeks, Part 2 and 3: From 3 to 8 weeks ]
    Pulmonary function tests will be performed to determine parameters as detailed below. The following lung function tests will be performed using a standard calibrated spirometer: forced expiratory volume in 1 sec (FEV1 in L), forced vital capacity (FVC in L), peak expiratory flow rate (PEFR in L/min), FEV1/FVC (%).Predicted values will be calculated according to GLI-2012 Quanjer and adjusted for age, gender and race. Age at the time of each spirometry assessment will be used for assessment of predicted values. For Part 2 and Part 3, reversibility at screening will be assessed by performing pre-bronchodilator spirometry after withholding SABA for at least 6 hours and LABA for at least 12 hours or at least 24 hours for Ultra-long acting LABA. Subsequent to pre-bronchodilator spirometry, 400 μg salbutamol will be administered via a spacer. Post-bronchodilator spirometry will be performed with first maneuver commencing within 15 to 30 minutes of salbutamol administration
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects
Official Title  ICMJE A Phase 1, Three-Part, Open-Label Study to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of Inhaled Voriconazole (ZP-059) in Healthy Subjects (Part 1), Multiple Doses of ZP-059 in Mild Stable Asthma Subjects (Part 2) and in a Two Period Crossover Study of Single Doses of ZP-059 and Single Doses of Oral Voriconazole in Mild to Moderate Stable Asthma Subjects (Part 3)
Brief Summary

This is 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 parts of the study (i.e. Parts 1, 2 and 3) every effort will be made to include as close as possible an equal balance between male and female subjects; in Part 1 and Part 2 this will be in each of the individual cohorts.

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE 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
Condition  ICMJE Allergic Bronchopulmonary Aspergillosis
Intervention  ICMJE
  • Drug: Voriconazole inhaled (ZP-059)
    Part 1 is a single ascending dose (SAD) study; Part 2 is a multiple ascending dose (MAD) study.
  • Drug: Cross-over with VFEND
    Part 3 is a 2-period, randomised, crossover study of single doses of ZP-059 compared to single doses of VFEND
Study Arms  ICMJE
  • Experimental: Active Voriconazole inhaled (ZP-059)
    Part 1 - 4 separate cohorts planned to receive single doses of ZP-059 Part 2 - 3 separate cohorts planned to receive daily doses of ZP-059 on Day 1 to 10.
    Intervention: Drug: Voriconazole inhaled (ZP-059)
  • Active Comparator: Cross-over with VFEND
    Part 3 - 1 cohort randomised to receive VFEND (Cross-over with ZP-059).
    Interventions:
    • Drug: Voriconazole inhaled (ZP-059)
    • Drug: Cross-over with VFEND
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 24, 2020)
58
Original Estimated Enrollment  ICMJE
 (submitted: January 10, 2020)
76
Actual Study Completion Date  ICMJE August 31, 2020
Actual Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04229303
Other Study ID Numbers  ICMJE Z7240J01
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Zambon SpA
Study Sponsor  ICMJE Zambon SpA
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Zambon SpA
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP