Conditions: Allergic Bronchopulmonary Aspergillosis
Keywords: ABPA Asthma Voriconazole Allergic Bronchopulmonary Aspergillosis
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 58
Healthy volunteers: yes

Brief summary:
The primary safety objectives were:

* Part 1: To determine the safety and tolerability of single doses of ZP-059 in healthy subjects
* Part 2: To determine the safety and tolerability of multiple doses of ZP-059 in subjects with mild stable asthma
* Part 3: To determine the safety and tolerability of single doses of ZP-059 in subjects with mild to moderate stable asthma.

The primary PK objectives were:

* Part 1: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 in healthy subjects
* Part 2: To characterize systemic PK of voriconazole and N-oxide voriconazole after multiple doses of ZP-059 in subjects with mild stable asthma
* Part 3: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 and single doses of oral voriconazole in subjects with mild to moderate stable asthma.

Detailed description:
This was an integrated Phase 1, single centre, multi-part, open-label study in both healthy subjects (Part 1), subjects with mild stable asthma (Part 2) and subjects with mild to moderate stable asthma (Part 3). In all three parts of the study every effort was made to include as close as possible an equal balance between male and female subjects.

This study assessed safety, tolerability and PK of single and multiple ascending doses of ZP-059 capsules administered as dry powder for inhalation in Part 1 to healthy volunteers (single ascending dose; SAD) and in Part 2 to subjects with mild asthma (multiple ascending dose; MAD), respectively.

In Part 3, the bioavailability of ZP-059 in subjects with mild to moderate stable asthma were compared to that of oral voriconazole. Part 3 started only after review of safety data from cohorts 1 to 4 of Part 1 (SAD) have been completed. Parts 2 and 3 of the study also explored voriconazole concentrations in induced sputum samples in asthmatic subjects.

As part of the safety and tolerability assessment, this study investigated the effects of ZP-059 on airway function in both mild and mild to moderate stable asthma subjects.

Arms:
arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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. arm 5: 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. arm 6: 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. arm 7: 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. arm 8: 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. arm 9: 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.

Interventions: intervention 1: Voriconazole inhaled intervention 2: oral voriconazole
Intervention descriptions: intervention 1: 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). intervention 2: 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.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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Page 1 of 115 
 
 
Clinical Study Protocol 
Protocol Title: 
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)  
Protocol Number: Version Final 1.2, 04 June 2020 
Amendment Number: 02 (Non Substantial) 
Compound: ZP-059 (Inhaled voriconazole) 
Study Phase: Phase 1 
Short Title: 
Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 
Sponsor Name: Zambon S.p.A 
Legal Registered Address: Via Lillo del Duca, 10, 20091 Bresso (Milan), Italy 
Regulatory Agency Identifier Number: 
EudraCT:  2019-004031-23 
 
 
 
Approval Date:  04 June 2020 
 
 
 
 
 
THIS DOCUMENT IS ZAMBON'S SOLE PROPERTY AND OWNERSHIP. THIS DOCUMENT, 
AND ALL INFORMATION AND DATA CONTAINED HEREIN HAS TO BE CONSIDERED AND 
TREATED AS STRICTLY CONFIDENTIAL. THIS DOCUMENT SHALL BE USED ONLY FOR 
THE PURPOSE OF THE DISCLOSURE HEREIN PROVIDED. NO DISCLOSURE OR 
PUBLICATION SHALL BE MADE WITHOUT THE PRIOR WRITTEN CONSENT OF ZAMBON.  
 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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Sponsor Approvals: 
Sponsor Signatory: 
 
 
Charlotte Keywood M.D. 
Head of Open R&D, Zambon S.p.A. 
 
Date 
 
 
 
 
4th June 2020


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Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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Medical Monitor’s Name and Contact Information  
Arnd Mueller MD, Clinical Development Physician, Zambon S.p.A. 
Mobile +39 342 617 16.96 
Email: arnd.muller@zambongroup.com  
 
Drug Safety Unit, Zambon S.p.A. 
Tel: +39 02 66524.444 
Fax: +39 02 66524 038 
E-mail: drugsafety@zambongroup.com 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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List of CRO and other Vendors 
CRO:  
 
MEU Solutions Ltd. 
The Langley Building, Southmoor Road, Manchester, 
M23 9QZ, United Kingdom 
 
 
 
 
Monitoring:   
 
MEU Solutions Ltd. 
The Langley Building, Southmoor Road, Manchester, 
M23 9QZ, United Kingdom 
 
 
 
Participating site(s):   
 
Medicines Evaluation Unit 
Ltd. (MEU) 
The Langley Building, Southmoor Road, Manchester, 
M23 9QZ, United Kingdom 
 
 
 
Safety Laboratory testing:   
The 
Doctor’s 
Laboratory 
(TDL) 
The Halo Building, 1 Mabledon Place, London, WC1H 
9AX, United Kingdom 
 
 
 
Pharmacokinetic testing:  
 
Alderley Analytical Ltd. 
 
Alderley Park, Macclesfield, Cheshire, SK10 4TG, 
United Kingdom 
 
 
 
Statistics and Data 
Management:  
 
Syne 
Qua 
Non 
(SQN) 
Clinical 
Gostling House, Diss Business Park, Hopper Way, 
Diss, Norfolk, IP22 4GT, United Kingdom 
 
 
 
 
 




CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
Amendment 02  
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 02 
04 June 2020 
Amendment 01 
14 Feb 2020 
Original Protocol 
13 Dec 2019 
 
Amendment 02, 04 June 2020: 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study. 
 
Overall Rationale for the Amendment: 
The overall rationale for the changes implemented in this protocol amendment is to 
minimize the risk caused by the COVID-19 pandemic to research participants and 
site staff in this trial.  These changes are in line with guidance from the Medicines 
and Healthcare products Regulatory Agency (MHRA) and NHS Health Research 
Authority (HRA) on the conduct of clinical trials during the COVID-19 pandemic and 
focus on assuring the safety of trial participants while maintaining compliance with 
good clinical practice (GCP) and minimizing risks to trial integrity. 
 
 
Section # and Name Description of Change 
Brief Rationale 
Throughout  
Part 3 dosing can occur 
prior to Part 2 dosing.  
Updated to provided clarification that 
dosing in Part 3 can not only be 
performed in parallel to dosing in Part 2 
but also prior to. 
1.1 Synopsis,  
4.1 Overall Design, 
5.3.1 Part 3 
inclusion criteria 13, 
8.11.7 Sputum 
induction 
Minimum of 6 sputum 
producers to be enrolled in 
Part 3 of the study 
Sputum PK is an exploratory endpoint in 
the study, only a minimum of 6 sputum 
producers instead of 16 will be required 
to meet study objective. 
Throughout  
+96hour post dose sputum 
removed from Part 3 
Sputum PK is an exploratory endpoint in 
the study, +96hour sputum sample is not 
necessary from a PK perspective. 
1.2.2. Schedule of 
Activities for Part 2,  
5.2.1 Part 2 
Inclusion criteria 
12.   
Inhaler device training at 
screening to be performed 
as a demonstration only.  
Demonstration 
device 
training 
at 
screening is sufficient for asthmatic 
subjects in Part 2 & 3 as they can be 
considered as being well-trained in 
inhaler usage. 


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Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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Section # and Name Description of Change 
Brief Rationale 
1.1 Synopsis,  
4.1 Overall Design. 
6.1 Administration 
of Investigational 
Products,  
Optional BID dosing in Part 
2 applicable for all cohorts  
Updated to allow BID dosing in all Part 2 
Cohorts and not just in Cohorts 4/5. 
1.1 Synopsis,  
4.1 Overall Design 
For Part 3 minimum 
washout between Treatment 
Periods reduced to 96 
hours. Residential stay 
extended to Day 6. 
Reduced washout based on available 
PK data. Adapted residential stay to 
reduce risk of potential exposure to 
SARS-CoV-2 for both subjects and site 
staff. 
2.3 Benefit/Risk 
Assessment,  
4.1 Overall Design, 
5.2.1 Part 2 
Exclusion criteria 20.
5.3.2 Part 3 
exclusion criteria 20, 
8.1 Screening 
SARS-COV-2 testing 
incorporated in Part 2 and 
Part 3 
Due to the current COVID-19 pandemic 
SARS-COV-2 PCR testing, additional 
body temperature and other measures 
as applicable incorporated to reduce risk 
of potential exposure to SARS-COV-2 
for both subjects and site staff.  
Throughout 
Minor editorial and 
document formatting 
revisions 
Minor, 
therefore 
have 
not 
been 
summarized 
 
 


CONFIDENTIAL 
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Table of Contents 
Sponsor Approvals………………………………………………………………………..2 
Investigator Signature Page……………………………………………………………..5 
Protocol Amendment Summary of Changes Table……………………………………6 
1. 
Protocol Summary ............................................................................................. 12 
1.1. 
Synopsis ................................................................................................................ 12 
1.2. 
Schedule of Activities (SoA) ............................................................................... 22 
1.2.1. 
Schedule of Activities for Part 1 (SAD) ............................................................. 22 
1.2.2. 
Schedule of Activities for Part 2 (MAD – Mild Asthmatics) ............................ 25 
1.2.3. 
Schedule of Activities for Part 3 (Mild to Moderate Asthmatic Subjects) .... 28 
2. 
Introduction ......................................................................................................... 33 
2.1. 
Study Rationale .................................................................................................... 33 
2.2. 
Background ........................................................................................................... 35 
2.3. 
Benefit/Risk Assessment .................................................................................... 36 
2.3.1. 
Risk Assessment .................................................................................................. 36 
2.3.2. 
ZP-059 ................................................................................................................... 37 
2.3.3. 
Induced Bronchoconstriction .............................................................................. 37 
2.3.4. 
Oral voriconazole ................................................................................................. 37 
2.3.5. 
Other....................................................................................................................... 38 
2.3.6. 
Benefit Assessment ............................................................................................. 39 
2.3.7. 
Overall Benefit: Risk Conclusion ....................................................................... 39 
3. 
Objectives and Endpoints ............................................................................... 40 
3.1. 
Objectives .............................................................................................................. 40 
3.1.1. 
Primary Safety Objectives .................................................................................. 40 
3.1.2. 
Pharmacokinetic (PK) Objectives ...................................................................... 40 
3.1.3. 
Exploratory Objectives (Parts 2 and 3 only) .................................................... 40 
3.2. 
Endpoints ............................................................................................................... 41 
3.2.1. 
Safety Endpoints (Parts 1, 2 and 3) .................................................................. 41 
3.2.2. 
Pharmacokinetic Endpoints (Parts 1, 2 and 3) ................................................ 41 
4. 
Study Design ....................................................................................................... 42 
4.1. 
Overall Design ...................................................................................................... 42 
4.1.1. 
Part 1 (SAD) .......................................................................................................... 43 
4.1.2. 
Part 2 (MAD) ......................................................................................................... 44 
4.1.3. 
Part 3 (Two-period crossover) ............................................................................ 46 
4.2. 
Scientific Rationale for Study Design ................................................................ 47 
4.3. 
Justification for Dose ........................................................................................... 48 
4.4. 
End of Study Definition ........................................................................................ 48 
5. 
Study Population................................................................................................ 49 
5.1. 
Part 1 Eligibility Criteria ....................................................................................... 49 
5.1.1. 
Part 1 Inclusion Criteria ....................................................................................... 49 
5.1.2. 
Part 1 Exclusion Criteria ...................................................................................... 49 
5.2. 
Part 2 Eligibility Criteria ....................................................................................... 52 
5.2.1. 
Part 2 Inclusion Criteria ....................................................................................... 52 
5.2.2. 
Part 2 Exclusion Criteria ...................................................................................... 52 
5.3. 
Part 3 Eligibility Criteria ....................................................................................... 55 
5.3.1. 
Part 3 Inclusion Criteria ....................................................................................... 55 


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5.3.2. 
Part 3 Exclusion Criteria ...................................................................................... 56 
5.4. 
Lifestyle Considerations ...................................................................................... 59 
5.4.1. 
Meals and Dietary Restrictions .......................................................................... 59 
5.4.2. 
Caffeine and Alcohol ............................................................................................ 59 
5.4.3. 
Activity .................................................................................................................... 59 
5.4.4. 
Additional Study Restrictions .............................................................................. 60 
5.5. 
Screen Failures .................................................................................................... 60 
5.6. 
Subject Re-Screening ......................................................................................... 60 
6. 
Investigational Medicinal Products ............................................................... 61 
6.1. 
Administration of Investigational Products ....................................................... 62 
6.2. 
Preparation/Handling/Storage/Accountability .................................................. 64 
6.3. 
Measures to Minimize Bias: Randomisation and Blinding ............................. 65 
6.3.1. 
Randomisation ...................................................................................................... 65 
6.3.2. 
Subject Numbers .................................................................................................. 65 
6.3.3. 
Blinding .................................................................................................................. 66 
6.4. 
Investigational Product Compliance .................................................................. 66 
6.5. 
Concomitant Therapy .......................................................................................... 66 
6.5.1. 
Prior and Concomitant Medications .................................................................. 66 
6.5.2. 
Permitted Concomitant Medications for Part 1 (SAD) .................................... 66 
6.5.3. 
Permitted Concomitant Medications for Part 2 (MAD) and Part 3 Crossover)
................................................................................................................................. 67 
6.5.4. 
Prohibited Concomitant Medications ................................................................ 68 
6.6. 
Criteria for Dose Escalation ................................................................................ 69 
6.6.1. 
Part 1 (SAD) .......................................................................................................... 69 
6.6.2. 
Part 2 (MAD) ......................................................................................................... 69 
6.6.3. 
Part 1 (SAD) to Part 3 .......................................................................................... 70 
6.6.4. 
Criteria for Safety Advisory Committee............................................................. 70 
6.6.5. 
Stopping Criteria ................................................................................................... 71 
7. 
Discontinuation of Investigational Medicinal Product and Subject 
Discontinuation/Withdrawal ............................................................................ 73 
7.1. 
Discontinuation of Investigational Medicinal Product ..................................... 73 
7.2. 
Subject Replacement .......................................................................................... 74 
7.3. 
Subject Discontinuation/Withdrawal from the Study ....................................... 74 
7.4. 
Lost to Follow up .................................................................................................. 74 
8. 
Study Assessments and Procedures ........................................................... 76 
8.1. 
Screening .............................................................................................................. 76 
8.2. 
Admission and Pre-dose Procedures ............................................................... 76 
8.3. 
Device Training ..................................................................................................... 76 
8.4. 
Blood Volume ....................................................................................................... 76 
8.5. 
Timing of Procedures .......................................................................................... 77 
8.6. 
Discharge from the Clinical Unit ........................................................................ 77 
8.7. 
Return Visits .......................................................................................................... 77 
8.8. 
Medical Supervision ............................................................................................. 78 
8.9. 
Follow-up ............................................................................................................... 78 
8.10. 
Efficacy Assessments ......................................................................................... 78 
8.11. 
Safety Assessments ............................................................................................ 79 
8.11.1. Physical Examinations ........................................................................................ 79 


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Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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8.11.2. Vital Signs .............................................................................................................. 79 
8.11.3. Body, Weight and Height .................................................................................... 79 
8.11.4. Pulse Oximetry ..................................................................................................... 79 
8.11.5. Electrocardiograms .............................................................................................. 79 
8.11.6. Pulmonary Function Tests .................................................................................. 80 
8.11.7. Sputum Induction (Part 2 and Part 3 only) ....................................................... 80 
8.11.8. Procedures In case of Bronchospasm .............................................................. 80 
8.11.9. Part 1 (Healthy Subjects) .................................................................................... 81 
8.11.10. Part 2 and Part 3 (Asthmatic Subjects) ............................................................ 81 
8.11.11. Additional Safety Procedures ............................................................................. 81 
8.11.12. Clinical Safety Laboratory Assessments .......................................................... 81 
8.12. 
Adverse Events and Serious Adverse Events ................................................. 83 
8.12.1. Time Period and Frequency for Collecting AE and SAE Information .......... 83 
8.12.2. Method of Detecting AEs and SAEs ................................................................. 84 
8.12.3. Follow-up of AEs and SAEs ............................................................................... 84 
8.12.4. Regulatory Reporting Requirements for SAEs ................................................ 84 
8.12.5. Pregnancy ............................................................................................................. 85 
8.12.6. Cardiovascular and Death Events ..................................................................... 85 
8.12.7. Adverse Events of Special Interest ................................................................... 85 
8.13. 
Treatment of Overdose ....................................................................................... 86 
8.14. 
Pharmacokinetics ................................................................................................. 86 
8.14.1. Pharmacokinetic Blood Sampling ...................................................................... 86 
8.14.2. Induced Sputum Sampling (Part 2 and Part 3 only) ....................................... 86 
8.15. 
Biomarkers ............................................................................................................ 87 
8.16. 
Medical Resource Utilisation and Health Economics ..................................... 87 
9. 
Statistical Considerations ............................................................................... 88 
9.1. 
Statistical Hypotheses ......................................................................................... 88 
9.2. 
Sample Size Determination ................................................................................ 88 
9.3. 
Populations for Analyses .................................................................................... 88 
9.4. 
Statistical Analyses .............................................................................................. 89 
9.4.1. 
General considerations ....................................................................................... 89 
9.4.2. 
Background and Demographic Characteristics ............................................... 89 
9.4.3. 
Safety Analysis ..................................................................................................... 89 
9.4.4. 
PK Analysis ........................................................................................................... 89 
9.5. 
Interim Analyses ................................................................................................... 91 
9.6. 
Data Monitoring Committee (DMC) ................................................................... 91 
10. 
Supporting Documentation and Operational Considerations ............... 92 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ...... 92 
10.1.1. Regulatory and Ethical Considerations ............................................................ 92 
10.1.2. Financial Disclosure ............................................................................................. 93 
10.1.3. Informed Consent Process ................................................................................. 93 
10.1.4. Data Protection ..................................................................................................... 93 
10.1.5. Committees Structure .......................................................................................... 94 
10.1.6. Dissemination of Clinical Study Data ................................................................ 94 
10.1.7. Data Quality Assurance ...................................................................................... 94 
10.1.8. Source Documents............................................................................................... 95 
10.1.9. Study and Site Start and Closure ...................................................................... 95 


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10.1.10. Publication Policy ................................................................................................. 96 
10.2. 
Appendix 2: Clinical Laboratory Tests .............................................................. 97 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................... 98 
10.3.1. Definition of AE ..................................................................................................... 98 
10.3.2. Definition of SAE .................................................................................................. 99 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................. 100 
10.3.4. Reporting of SAEs .............................................................................................. 102 
10.4. 
Appendix 4: Contraceptive Guidance, Exposure, Sperm Donation and 
Collection of Pregnancy Information ............................................................... 103 
10.4.1. Contraception ...................................................................................................... 103 
10.4.2. Exposure to Partners during the Study ........................................................... 104 
10.4.3. Sperm Donation .................................................................................................. 104 
10.4.4. Collection of Pregnancy Information ............................................................... 104 
10.5. 
Appendix 5: Abbreviations ................................................................................ 107 
10.6. 
Appendix 6: Protocol Amendment History ..................................................... 111 
11. 
References ......................................................................................................... 113 
 


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1. 
Protocol Summary 
1.1. 
Synopsis 
Study number 
Z7240J01 
 
Study title 
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) 
 
Number of 
centres and 
names 
One centre in the UK:  
Medicines Evaluation Unit Ltd. (MEU) 
The Langley Building, Southmoor Road, Manchester, M23 9QZ, United Kingdom 
 
Objectives 
The primary safety objectives of the study are: 
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 pharmacokinetic (PK) objectives of the study are: 
Part 1: 
To characterize systemic PK of voriconazole after single doses of ZP-059 in 
healthy subjects. 
 
Part 2: 
To characterize systemic PK of voriconazole after multiple doses of ZP-059 in 
subjects with mild, stable asthma. 
 
Part 3: 
To characterize systemic PK of voriconazole after single doses of ZP-059 and 
single doses of oral voriconazole in subjects with mild to moderate stable asthma. 
 
The exploratory PK objectives of the study (Part 2 and Part 3 only) are: 
Part 2: 


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Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 - 
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To characterize voriconazole concentrations in induced sputum after multiple 
doses of ZP-059 (i.e. on Day 7; both pre-dose and post-dose) in subjects with mild, 
stable asthma. 
 
Part 3: 
To characterize voriconazole concentrations in induced sputum after single doses 
of ZP-059 and after single doses of oral voriconazole in subjects with mild to 
moderate stable asthma. 
 
Summary of 
study design 
 
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.  
 
Part 1 will comprise 4 separate cohorts (each containing 6 subjects) planned to 
receive single doses of ZP-059. The starting dose for Cohort 1 will be 5 mg with 
subsequent doses being determined from review of safety data by the Safety 
Advisory Committee (SAC) from the preceding cohorts. The criteria to be followed 
by the SAC are detailed in Section 6.6.4. The study will have an interleaved design. 
 
Part 2 will comprise 3 separate cohorts (each containing 6 subjects) planned to 
receive daily doses of ZP-059 on Day 1 to 10. Dose levels for Part 2 will be 
determined from review of safety data from Part 1. Part 2 cohort 1 will commence 
after a review of safety data by the SAC from Part 1 cohort 2 confirms that it is safe 
to do so. The criteria to be followed by the SAC are detailed in Section 6.6.4. In 
each cohort, subjects will receive inhaled doses either once daily (QD) for 10 days 
or twice daily (BID) for 9 days and once in the morning of Day 10, as determined 
by the Sponsor based on data obtained in Part 1. 
 
Part 3 is a 2-period, randomised crossover study in 16 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. Part 3 will comprise of 1 cohort 
randomised to receive ZP-059 and 200 mg of oral voriconazole administered 
across 2 treatment periods with a minimum wash-out period of 96 hours. 
 
The dose of ZP-059 for Part 3 will be confirmed after completion of SAD cohorts 1 
to 4 and review of the available safety data. Hence, dosing of Part 3 may occur 
prior to/in parallel with dosing in Part 2. 
 
Subjects will be screened for eligibility to participate in the study within 28 days 
before dosing (Day 1) and will be admitted to the clinic on the evening of Day -1. 
   


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Further details of each study part are described below. 
 
Part 1 (Single Ascending Dose)  
 
Part 1 is a single ascending dose (SAD) study to assess the safety, tolerability and 
PK of single doses of ZP-059 in 4 cohorts of healthy male and female subjects. 
Each cohort will comprise 6 subjects (planned total of 24 subjects). An evaluable 
subject for Part 1 (SAD) of the study is defined as a subject who has received a 
dose of ZP-059 and has sufficient data to evaluate either the safety or PK 
objectives. An additional cohort of 6 subjects (Cohort 5) may be enrolled if it is 
deemed appropriate to repeat a dose level, assess an interim dose level or assess 
a dose level higher than planned (see Interim Data Reviews section). A repeat 
dose level or higher dose level will only be assessed provided no dose escalation 
or study stopping criteria have been met. Eligible subjects will receive a single dose 
of ZP-059 administered via dry powder inhaler (DPI) on the morning of Day 1. 
Subjects will be required to fast (water permitted) for at least 1 hour prior to each 
dose and 1 hour post each dose. 
 
For the first 2 subjects in each cohort, there will be a minimum interval of 20 minutes 
between dosing. After the second subject is dosed there will be at least a 30 
minutes observation period before the remaining 4 subjects are dosed. The 
remaining subjects will be dosed if the first two subjects show no clinically 
significant safety or tolerability concerns (including vital signs measurements, 
spirometry, physical examinations (symptom directed if required) and review of any 
adverse events [AEs] including any acute side effects e.g. excessive coughing) at 
the discretion of the investigator. Any clinically significant findings from the first two 
subjects in the opinion of the investigator will be discussed with the Sponsor prior 
to dosing of the remaining 4 subjects. The dosing interval between dosing subjects 
in the remainder of the cohort will be at the discretion of the investigator (in 
consultation with the sponsor if required) i.e. this could be increased or decreased 
as appropriate. 
 
The fixed starting dose for SAD Cohort 1 is 5 mg (1 x 5 mg capsule*) ZP-059 single 
dose administered via DPI (RS01 monodose device) on Day 1. *Capsule delivers 
5 mg of voriconazole. Subsequent doses in the following cohorts will be determined 
from review of safety data from the preceding cohorts. 
 
Single doses will not exceed 40 mg of ZP-059 based on safety margins calculated 
following non-clinical studies. For each dose escalation, the dose increase will not 
be more than 3-fold. Details of ZP-059 (investigational medicinal product) are 
provided in the Investigational Medicinal Products section of the protocol. 
 
Subjects will undergo safety, tolerability and PK evaluations at specified time points 
during the study. They will remain resident in the clinic until Day 2 after completion 
of safety assessments at 24 hours post-dose and providing there are no safety 
concerns, they will be discharged from the unit. A safety telephone call will be 
performed on Day 3 to check the status of unresolved AEs and to record any new 
AEs that have occurred after the last visit as well as any changes to concomitant 


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medications. Subjects will return to the clinic on Day 5 for safety evaluations to be 
performed. A safety follow-up call will be performed 8 to 12 days post dose to check 
the status of unresolved AEs and to record any new AEs that have occurred after 
the last visit as well as any changes to concomitant medications. 
 
Part 2 (Multiple Ascending Dose) 
 
Part 2 is a multiple ascending dose (MAD) study to assess the safety, tolerability 
and PK of multiple doses of ZP-059 in 3 cohorts of male and female subjects with 
a physician confirmed documented diagnosis of mild stable asthma. Each cohort 
will comprise 6 subjects (planned total of 18 subjects). Up to 2 optional additional 
cohorts of 6 subjects (Cohort 4 and Cohort 5) may be enrolled in Part 2 if it is 
deemed appropriate to repeat a dose level, assess an additional dose level or 
assess a different dosing regimen, however, the dose will not exceed the highest 
dose studied in Part 1 (see Interim Data Reviews section). If a selected dose does 
not provide the required data to meet the objectives of the study, a previously 
tested dose may be used in a subsequent cohort. However, if the dose level met 
the dose escalation or study stopping criteria, neither that dose level nor a higher 
dose will be repeated. 
 
The planned starting dose of ZP-059 to be administered in MAD cohort 1 will be 
confirmed during an interim review of safety data from completed SAD cohorts and 
will not exceed a previously administered single dose. Dose administration for MAD 
cohort 1 will only commence after completion of review of safety data up to a 
minimum of 24 hours post-dose for the second dose level of Part 1 (SAD cohort 2). 
 
Dose levels for Part 2 will be determined from review of safety data from Part 1. 
 
Details of ZP-059 (investigational medicinal product) are provided in the 
Investigational Medicinal Products section of this synopsis. 
 
In each cohort, subjects will receive inhaled doses either once daily (QD) for 10 
days or twice daily (BID) for 9 days and once in the morning of Day 10, as 
determined by the Sponsor based on data obtained in previous Part 1. In the event 
of QD dosing subjects will receive QD doses of ZP-059 (at Hour 0) on Days 1 to 
10. In the event of BID dosing, ZP-059 will be administered at Hours 0 and 12 on 
Days 1 to 9 and once in the morning of Day 10 (i.e. 19 doses in total). Subjects will 
be required to fast (water permitted) for at least 1 hour prior to each dose and 1 
hour post each dose; in the event of BID dosing this will be for both the 0 hour and 
the 12 hour doses. Following the first dose, subsequent doses will be administered 
within +/- 1 hour of the scheduled dosing time. If any of the additional cohorts (i.e. 
Cohorts 4 and 5) are required, subjects will receive either QD or BID doses, as may 
be appropriate. 
 
For the first 2 subjects in each cohort, there will be a minimum interval of 20 minutes 
between dosing (Day 1; Hour 0). After the second subject is dosed there will be at 
least a 30 minutes observation period before the remaining 4 subjects are dosed 
(Day 1; Hour 0). The remaining subjects will be dosed if the first two subjects show 


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no clinically significant safety or tolerability concerns (including vital signs 
measurements, spirometry, physical examinations (symptom directed if required) 
and review of any adverse events [AEs] including any acute side effects e.g. 
excessive coughing) at the discretion of the investigator. Any clinically significant 
findings from the first two subjects in the opinion of the investigator will be 
discussed with the Sponsor prior to dosing of the remaining 4 subjects. The dosing 
interval between dosing subjects in the remainder of the cohort will be at the 
discretion of the investigator (in consultation with the sponsor, if required) i.e. this 
could be increased or decreased as appropriate. 
 
Subjects will undergo safety, tolerability and PK (serum and sputum) evaluations 
at specified time points during the study (a full serum PK profile will be collected on 
Days 1 and 10). They will remain resident in the clinic until the morning of Day 4 
after completion of dosing and safety assessments and providing there are no 
safety concerns. 
 
The subjects will then return to the clinical unit daily from Day 5 through to Day 9 
for pre-dose study procedures and to receive their scheduled dose (Hour 0) of 
study medication. On Day 7 the visit will also include induced sputum sampling pre-
dose and post-dose. The subject will be discharged after dosing or sputum 
sampling as applicable, providing there are no safety concerns. In the event of BID 
dosing; on Days 4 to 9 the subjects will be required to attend the unit for the evening 
dose (i.e. return in the evening on Day 4 and attend twice daily on Days 5 to 9) and 
will be discharged after dosing, providing there are no safety concerns. The 
subjects will then return to the clinical unit on the morning of Day 10 where they 
will then remain resident overnight until Day 11 (24 hours after the last dose). After 
completion of safety assessments, they will be discharged providing there are no 
safety concerns. They will return to the clinic on Days 14 and 17 for collection of 
PK blood samples (Day 14 only) and safety evaluations. A safety follow-up 
telephone call will be performed 11 to 17 days after the last dose to check the 
status of unresolved AEs and to record any new AEs that have occurred after the 
last visit as well as any changes to concomitant medications. 
 
Part 3 (Crossover) 
 
Part 3 is a 2-period, randomised, crossover study to assess the safety, tolerability 
and PK of single doses of ZP-059 compared to single doses of oral voriconazole 
in 16 male and female subjects with physician confirmed documented diagnosis of 
mild to moderate stable asthma. 
 
The dose of ZP-059 will be confirmed after completion of SAD cohorts 1 to 4 and 
review of the available safety data. Hence, dosing of Part 3 may occur prior to/ in 
parallel with dosing in Part 2. 
 
Eligible subjects will be randomised to receive a single dose of ZP-059 via DPI or 
a single oral dose of voriconazole in Period 1. Each subject then will receive the 
alternative treatment in Period 2 such that on completion of the study, all subjects 
will have received a single dose of ZP-059 via DPI and a single oral dose of 200 


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mg voriconazole (VFEND®). The actual dose of ZP-059 will be determined at the 
safety review performed after completion of cohorts 1 to 4 (SAD) and will not 
exceed the highest dose used in Part 1. 
 
Dosing intervals between subjects in Part 3 are not deemed necessary, however 
may be implemented at the discretion of the investigator (in consultation with the 
sponsor, if required). Subjects should be dosed at approximately the same time of 
day in each study period. 
 
Subjects will be required to fast (water permitted) for at least 1 hour prior to each 
dose and 1 hour post each dose. The washout period between doses in each 
treatment period (TP), (i.e. TP1 Day 1 dose to TP2 Day 1 dose) will be a minimum 
of 96 hours. 
 
Subjects will undergo safety, tolerability and PK evaluations at specified time points 
during the study. They will remain resident in the clinic until Day 6. They will be 
discharged from the unit after completion of Treatment Period 2 assessments up 
to 24 hours post-dose and providing there are no safety concerns,. Subjects will 
return to the clinic on Days 7 and 9 for collection of 48 hour and 96 hour post  dose 
(Treatment Period 2) PK blood and induced sputum samples (Day 7 only), and for 
safety evaluations to be completed. A safety follow-up telephone call will be 
performed 8 to 12 days after last dose (Period 2) to check the status of unresolved 
AEs and to record any new AEs that have occurred after the last visit as well as 
any changes to concomitant medications. 
 
Sputum producer stratum (minimum of 6 subjects):  
It is planned that a minimum of 6 out of the 16 subjects to be randomised in Part 3 
will provide sufficient sputum samples at screening as per inclusion criteria 13. All 
subjects in Part 3 will however attempt to provide a sputum sample at the indicated 
timepoints as detailed in the study schedule of activities (SOA) in Section 1.2.3 
(Part 3), regardless of whether they produce an adequate sample at screening. 
Number of 
subjects 
Part 1 (SAD): 24 healthy subjects (4 cohorts of 6 subjects) and an optional 
additional cohort of 6 subjects. 
 
Part 2 (MAD): 18 subjects with mild stable asthma (3 cohorts of 6 subjects) and up 
to 2 optional additional cohorts of 6 subjects. 
 
Part 3 (Crossover): 16 subjects with mild to moderate stable asthma. 
 
Subjects who discontinue the study may be replaced at the discretion of the 
Sponsor. 
Duration of the 
study 
Part 1 (SAD, healthy subjects): Subjects will receive a single dose of ZP-059 on 1 
occasion. The estimated time from screening to the end of the study for each 
subject is approximately 6 weeks. 
 
Part 2 (MAD, mild, stable asthma subjects): Subjects will either receive a single 
dose of ZP-059 on Days 1 to 10 (total of 10 doses) or will receive twice daily doses 
of ZP-059 on Days 1 to 9 and one dose of ZP-059 on the morning of Day 10 (total 


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19 doses). The estimated time from screening to the end of the study for each 
subject is approximately 8 weeks. 
 
Part 3 (Crossover, mild to moderate, stable asthma subjects): Subjects will receive 
a single dose of IMP on 2 occasions. The estimated time from screening to the end 
of the study for each subject is approximately 7 weeks. 
 
Interim data 
reviews 
The data reviews will be conducted by the safety advisory committee (SAC), which 
will comprise the Principal Investigator (or delegate) and the sponsor’s medical 
monitor as a minimum. Additional data available at the time of each scheduled 
meeting may also be reviewed. 
 
Part 1 (SAD) 
There will be an interim data review before each dose escalation to the next dose 
level to determine safety and tolerability. The time between cohorts will be sufficient 
to allow this review. Interim reviews will be based on safety data from a minimum 
of 4 dosed subjects who have completed up to a minimum of 24 hours post-dose 
for each dose level. Progression to the next dose level will only occur after a review 
of safety data from the previous dose level confirms that it is safe to do so. The 
interim decision meeting following SAD cohort 2 will also determine the dose to be 
administered in Part 2 MAD cohort 1. Based on the observed data, it may be 
necessary or desirable to administer a previously administered dose, a reduced 
dose or a dose level higher than planned (as an additional cohort of 6 subjects) in 
order to determine the safe starting dose for Part 2. A repeat dose level or higher 
dose level will only be assessed provided no dose escalation or study stopping 
criteria have been met. Single doses will not exceed 40 mg of ZP-059 based on 
safety margins calculated following non-clinical studies. For each dose escalation, 
the dose increase will not be more than 3-fold. 
 
Part 2 (MAD) 
 
There will be an interim data review before each dose escalation to the next dose 
level to determine safety and tolerability. The time between cohorts will be sufficient 
to allow this review. There will be an interim data review after completion of MAD 
cohort 1 and SAD cohort 3 to confirm the dose level to be administered in MAD 
cohort 2 and after completion of MAD cohort 2 and SAD cohort 4 to confirm the 
dose level to be administered in MAD cohort 3.  
The dose to be administered in MAD cohort 2 and in MAD cohort 3 will not exceed 
the highest dose investigated in the previous SAD cohorts. The interim review will 
be based on safety data from a minimum of 4 dosed subjects who have completed 
up to a minimum of 24 hours after dosing on Day 10 from MAD cohort 1 and MAD 
cohort 2 respectively and up to a minimum of 24 hours post-dose from SAD cohort 
3 and SAD cohort 4 respectively. Progression to MAD cohort 2 and MAD cohort 3 
respectively will only occur after a review of safety data confirms that it is safe to 
do so.   
 


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Up to 2 optional additional cohorts of 6 subjects (Cohort 4 and Cohort 5) may be 
enrolled in Part 2 if it is deemed appropriate to repeat a dose level, assess an 
additional dose level than planned or assess a different dosing regimen, however, 
the dose will not exceed the highest dose studied in Part 1. 
Pharmacokinetic 
Assessments 
 
For each study part, the serum concentration data for voriconazole and N-oxide 
voriconazole will be analysed using PKNCA (version 0.8.1 or higher) with R 
(version 3.2.2 or higher). 
 
The following non-compartmental PK parameters of voriconazole and N-oxide 
voriconazole will be calculated to obtain estimates of the following single dose PK 
parameters (where possible and appropriate): 
 
Parts 1, 2 and 3 (in Part 3, Day 1 of TP1 and Day 1 of TP2): AUC0-t, AUC0-inf, 
AUCtau, Cmax, tmax, Kel, t1/2, CL/F and Vz/F, where AUC0-t is:  
• AUC0-12 for Part 1, AUC0-24 for Part 2 and AUC0-96 for Part 3 
 
AUC0-t, AUC0-inf and Cmax for Part 3 will also be derived based on the Part 1 PK and 
separately the Part 2 PK time points, so that a like-for-like comparison between 
Part 3 and Part 1 and between Part 3 and Part 2 can be performed for these PK 
parameters. 
 
Part 2 (Day 10): AUC0-tau, Cmax,ss, tmax,ss, Cmin, Ctrough, Css,av, %fluctuation and 
%swing (as appropriate and when applicable). PK parameters will be derived in 
addition to those detailed for Day 1.  
 
Accumulation ratios will be calculated from Day 1 and Day 10 AUC0-tau and Cmax 
values, and the linearity ratios will be calculated from the ratio of the Day 10 AUCtau 
and Day 1 AUC0-inf. 
 
Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. 
Additional PK parameters may be calculated if deemed appropriate. 
 
Investigational 
medicinal 
product, dose 
and mode of 
administration 
 
Test IMP: Dry powder for oral inhalation with a formulation comprising voriconazole 
as the active ingredient; Edry-Voriconazole 5 mg capsule ZP-059 
 
Reference IMP (Part 3): VFEND® oral film-coated tablet (200mg); a currently 
marketed oral voriconazole formulation by Pfizer Limited, UK 
 
Dry Powder Inhaler for administration of voriconazole capsules: RS01 inhaler 
(RS01 Monodose inhaler, product code 239700004AA)  
 
Table 1 Investigational Medicinal Products 
Study 
Part 
Cohort 
IMP 
Dose and Route of Administration 


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1 
SAD 1  
ZP-059 
5 mg (1 x 5 mg capsule) ZP-059 a     
Administered via DPI on Day 1 
SAD 2 
ZP-059 
 ZP-059 (Dose TBD) 
Administered via DPI on Day 1 
SAD 3 
ZP-059 
 ZP-059  (Dose TBD)  
 Administered via DPI on Day 1 
SAD 4 
ZP-059 
ZP-059 (Dose TBD) 
 Administered via DPI on Day 1 
2 
MAD 1 
ZP-059 
 ZP-059 (Dose TBD) 
Administered via DPI once daily on  
Days 1 to 10 or twice daily on Days 1 to 9 
and once on Day 10 
MAD 2 
 ZP-059 
ZP-059 (Dose TBD) 
Administered via DPI once daily on  
Days 1 to 10 or twice daily on Days 1 to 9 
and once on Day 10 
MAD 3 
 ZP-059 
ZP-059 (Dose TBD) 
Administered via DPI once daily on  
Days 1 to 10 or twice daily on Days 1 to 9 
and once on Day 10 
Study 
Part 
Treatment 
Period 
IMP 
Dose and Route of Administration 
3 
1 or 2 
 ZP-059 
 ZP-059 (Dose TBD) 
Administered via DPI on Day 1 of  
Period 1 or Period 2 
Voriconazole 
(VFEND®) 
oral film-
coated tablet  
200 mg Voriconazole (VFEND® - oral film-
coated tablet) on Day 1 of Period 1 or Period 
2 
a Fixed starting dose 
DPI; dry powder inhaler 
TBD; to be determined 
Each capsule delivers 5 mg of voriconazole 
Safety 
assessments 
Adverse events 
Clinical chemistry, haematology and urinalysis 
SARS-COV-2 testing 
Vital signs (blood pressure, pulse rate, respiratory rate, temperature) 
Electrocardiogram 
Pulse oximetry 
Spirometry  
Physical examination 
Statistical 
methodology 
 
No formal statistical analysis will be performed for safety data. 
 
For PK data: 
Part 1 and Part 2: 


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Formal statistical analysis will be performed on the PK parameters AUC(0-t), , 
AUC(0-inf) and Cmax to assess dose proportionality using a power model approach, 
where t is 12 hours for Part 1 and 24 hours for Part 2. 
 
This analysis will be performed for the following: 
Part 1 (SAD): Day 1  
Part 2 (MAD): Day 1 and Day 10 separately (assuming 3 or more dose levels are 
used). 
 
Part 3: 
Formal statistical analysis will be performed on the above PK parameters to assess 
relative bioavailability of ZP-059 to voriconazole. The PK parameters will undergo 
a natural logarithmic (loge) transformation and will be analysed using a mixed 
effects ANOVA. The mixed effects ANOVA model will include fixed effect terms for 
treatment, period, sequence and sex and a random effect term for subject (nested 
within sequence). Adjusted geometric mean ratio (GMR) and 90% confidence 
intervals (CIs) for the adjusted GMR for the comparison between test ZP-059 and 
reference oral voriconazole tablets will be provided, where the ratio is defined as 
test/reference. 
 
In addition, the above PK parameters will be compared between asthma subjects 
in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 
2 to assess relative bioavailability of the ZP-059 dose taken in Part 3 in these 
populations. An ANOVA model will be fitted to the loge transformed PK parameter 
including terms for the population group (i.e., healthy subjects or asthma subjects) 
and sex. The adjusted GMR and 90% CI for the adjusted GMR for the comparison 
between the two populations for the relevant dose will be provided, where the ratio 
is defined as either Part 3 subjects/Part 1 subjects or Part 3 subjects/Part 2 
subjects, depending on the comparison. 
 
Sample size 
calculation: 
 
Part 1 (SAD - Healthy Subjects) and Part 2 (MAD – Mild, Stable Asthma Subjects): 
This study is not powered for any formal hypothesis test. The sample size of up to 
30 subjects (24 subjects plus an additional 6 subjects in 1 optional cohort) in Part 1 
and up to 30 subjects (18 subjects plus an additional 6 subjects in 2 optional 
cohorts i.e. an additional 12 subjects in total) in Part 2 was chosen to minimise 
exposure to ZP-059 while allowing an adequate assessment of safety at each dose 
in order to support dose escalation and an adequate number of subjects to assess 
mean PK parameters. A minimum of 4 evaluable subjects will be required for each 
cohort for both dose escalation decisions and assessment of mean PK parameters. 
 
Part 3 (Mild to Moderate, Stable Asthma Subjects): 
This study is not powered for any formal hypothesis test. A sample size of up to 16 
subjects was chosen to minimise exposure to IMP, while allowing an adequate 
assessment of safety and drug concentration in sputum. No replacements are 
foreseen. However, should the drop-out rate for non-safety reasons be high, which 
may compromise the reliability of the study results, additional subjects could be 
randomised.  
 


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1.2. 
Schedule of Activities (SoA) 
1.2.1. 
Schedule of Activities for Part 1 (SAD) 
Study Day 
-28 to 
-1 
-1 
1 
2 
3 
5  
8 to 12 days 
after dosing  
Early 
Discontinuation 
Visit (EDV) 
 
 
 
 
 
Times After Dosing (hours) 
 
Phone 
Call  
Return 
Visit a 
Follow-up 
Phone Call 
 
Study Procedures b 
Screen Adm Pre-
dose 
0 
0.25 
0.5 
0.75 1.5 
2 
3 
4 
6 8 12 16 24 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including 
demographics)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and Height c 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
(including Cotinine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test d 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Inhaler Device Training 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from the 
Clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X e 
 
 
 
 
Physical Examination f 
X 
X 
X 
 
 
 
X 
 
X 
Safety Labs g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Serology 
(HIV/Hepatitis screen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Day 
-28 to 
-1 
-1 
1 
2 
3 
5  
8 to 12 days 
after dosing  
Early 
Discontinuation 
Visit (EDV) 
 
 
 
 
 
Times After Dosing (hours) 
 
Phone 
Call  
Return 
Visit a 
Follow-up 
Phone Call 
 
Study Procedures b 
Screen Adm Pre-
dose 
0 
0.25 
0.5 
0.75 1.5 
2 
3 
4 
6 8 12 16 24 
 
 
 
 
FSH (postmenopausal 
females only; if required) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram h 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
Vital Signs i 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X X 
 
X 
 
X 
 
X 
Pulse Oximetry 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X X 
 
X 
 
X 
 
X 
Spirometry 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Adverse Events 
 
Concomitant Medication 
 
Blood Samples for PK 
assessments 
 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Part 1 Footnotes 
      ADM - admission    
      EDV – Early Discontinuation Visit 
a. Subjects will return on Day 5 for safety evaluations. 
b. Screening procedures (including informed consent) can be performed over more than 1 day. Repeat of study procedures is permitted on 
the day and/or on another day (as appropriate) at the discretion of the investigator.  
c. Height and Weight at screening. Weight only on Day 1 (pre-dose). 
d. All female subjects. 
e. Discharge from clinic after completion of 24 hour post-dose assessments. 
f. 
Full physical examination at screening, Day 5 and EDV. Symptom directed examination; if required at any other visits or times at the 
discretion of the investigator. 
g. Clinical safety laboratory samples (clinical chemistry, haematology and urinalysis) must be performed within 7 days of Day 1; if this interval 
is exceeded, sampling must be repeated. Samples for clinical chemistry will be obtained following a fast of at least 8 hours (water permitted). 
h. Performed in triplicate. For assessment of time windows, the time of the first ECG of the triplicate will be used. 
i. 
Systolic and diastolic blood pressure, pulse rate and respiratory rate. Tympanic temperature measured at screening and pre-dose only. 
 


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24 
 
Permitted windows for all relevant procedures and dosing will be provided in the Study Reference Manual. Where the protocol requires more than 
one procedure to be completed at the same time point, all efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Any other procedures scheduled at the same time point will be performed either before or after the PK, as appropriate. 
 
 


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25 
1.2.2. 
Schedule of Activities for Part 2 (MAD – Mild Asthmatics) 
Study Day 
-28 to -1 
-4/-
3bb 
-1 
Treatment Period 
 
Return 
Visits a  
 
Follow-up  
Phone Call  
 
EDV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
14 
17 
11 to 17 days 
after last dose 
 
Study Procedures b 
Screening 
 
Adm 
Pre-
dose 0 Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Residential Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History (including 
demographics) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and Height c 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
(including Cotinine) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test d 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Inhaler Device Training 
Xcc 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from the Clinic e 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Physical Examination f 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety Labs g 
X 
 
 
 
 
 
Xh 
 
 
 
 
Xi 
 
 
 
Xj 
 
X 
 
X 
Serology (HIV/Hepatitis screen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal females 
only; if required)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Testaa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram k 
X 
 
 
X 
 
Xl 
Xh 
 
 
Xi 
 
 
 
 
Xm 
 
 
X 
 
X 
Vital Signs n 
X 
 
 
X 
 
X o 
Xh 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xp 
Xj 
X 
X 
 
X 
Tympanic Body Temperature 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pulse Oximetry 
X 
 
 
X 
 
Xo 
Xh 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xp 
Xj 
 
X 
 
X 
Spirometry q 
X 
 
 
X 
 
Xr 
Xh 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xs 
Xj 
X 
X 
 
X 
Adverse Events 
 
Concomitant Medications 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
26 
Study Day 
-28 to -1 
-4/-
3bb 
-1 
Treatment Period 
 
Return 
Visits a  
 
Follow-up  
Phone Call  
 
EDV 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
14 
17 
11 to 17 days 
after last dose 
 
Study Procedures b 
Screening 
 
Adm 
Pre-
dose 0 Post-
dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration t 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Blood Samples for PK assessments 
 
 
 
X 
 
Xu 
Xv 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi X w 
Xj 
X 
 
 
X y 
Induced Sputum Samples for PK 
assessments 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X z 
      ADM - admission 
Part 2 Footnotes 
 
EDV – Early Discontinuation Visit 
a. Subjects will return on Day 14 and Day 17 for PK sample collection (Day 14 only) and safety evaluations. 
b. Screening procedures (including informed consent) can be performed over more than 1 day. Repeat of study procedures is permitted on 
the day and/or on another day (as appropriate) at the discretion of the investigator. In the event of BID dosing; assessments will be performed 
relative to the 0-hour dose only. 
c. Height and Weight at screening. Weight only on Day 1 (pre 0-hour dose). 
d. All female subjects. 
e. Residential Periods: Discharge from clinic after completion of Day 4 and Day 11 assessments as applicable. 
f. 
Full physical examination at screening, Day 17 and EDV. Symptom directed examination; if required at any other visits or times at the 
discretion of the investigator. 
g. Clinical safety laboratory samples (clinical chemistry, haematology and urinalysis) must be performed within 7 days of Day 1; if this interval 
is exceeded, sampling must be repeated. Samples for clinical chemistry will be obtained following a fast of at least 8 hours (water permitted). 
h. 24 hours post 0-hour dose Day 1 and prior to Day 2, 0-hour dose administration.   
i. 
Prior to 0-hour dosing. 
j. 
24 hours post the 0-hour dose on Day 10. 
k. Performed in triplicate. For assessment of time windows, the time of the first ECG of the triplicate will be used. 
l. 
Performed at 2 and 4 hours post 0-hour dose.   
m. Pre-dose (0-hour) and post 0-hour dose at 2 and 4 hours.  
n. Systolic and diastolic blood pressure, pulse rate and respiratory rate.  
o. Performed at 0.5, 2, 4, 8 and 12 hours post 0-hour dose. If dosing is BID, the 12-hour assessment will be performed before the evening 
(i.e. 12-hour) dose. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
27 
p. Pre-dose (0-hour) and post 0-hour dose at 0.5, 2, 4, 8 and 12 hours.  
q. Pre- and post-bronchodilator (salbutamol) reversibility testing at screening. At all other visits and time-points, spirometry may be performed 
pre- or post-bronchodilator; i.e. there are no requirements for bronchodilator restrictions after the screening visit. 
r. 
Performed at 0.5, 2, 4 and 8 hours post 0-hour dose. 
s. Pre-dose (0-hour) and post 0-hour dose at 0.5, 2, 4 and 8 hours. 
t. 
On Days 4 to 9 the subjects will be required to attend the unit for the evening for their 12-hour dose (i.e. return in the evening on Day 4 and 
attend twice daily on Days 5 to 9) if dosing is BID.  
u. PK blood samples: at 1.5, 2, 3, 4 and 12 hours post 0-hour dose. If dosing is BID, the 12-hour sample will be collected before the evening 
(i.e. 12-hour) dose.  
v. PK blood sample: at 24 hours post 0-hour dose Day 1 and prior to Day 2, 0-hour dose administration.  If dosing is BID, the 24 hour sample 
can be taken anytime pre-dose on Day 2. 
w. PK blood samples: Pre-dose (0 hour) and post 0-hour dose at 1.5, 2, 3, 4 and 12 hours.  
x. Induced Sputum Samples for PK assessments: Pre-dose (0 hour) and post 0-hour dose at 3 hours and 6 hours.   
y. PK blood sample:  Only required if EDV is performed up to and including Day 14. 
z. Induced Sputum Samples for PK assessments:  Only required if EDV is performed up to and including Day 7. 
aa. Subjects will undergo a SARS-COV-2 RT-PCR test. Subjects testing negative may proceed to enrol in the study, provided other eligibility 
criteria are met; Subjects who test positive should be withdrawn from screening for the study and undergo or be referred for appropriate 
medical care as determined by local policy for managing a positive result. SARS-COV-2 RT-PCR test may be conducted at any time between 
Day -4 and Day -3 at the discretion of the site. Additional RT-PCR testing may be performed throughout the study if deemed necessary by 
the investigator. 
bb. Day -4/-3 procedures may be performed on the same day as the screening procedures if screening is performed within 3 or 4 days of dosing.  
cc. Inhaler device training at screening is to be a demonstration only. 
 
Permitted windows for all relevant procedures and dosing will be provided in the Study Reference Manual. Where the protocol requires more than 
one procedure to be completed at the same time point, all efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Any other procedures scheduled at the same time point will be performed either before or after the PK, as appropriate. 
 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
28 
1.2.3. 
 Schedule of Activities for Part 3 (Mild to Moderate Asthmatics) 
1.2.3.1 Part 3 Schedule of activities: Screening to Day 4 
 
 
 
 Treatment Period 1 a 
 
Study Day 
-28 to -1 
-1 
1 
2  
3 
4 
 
Treatment Days 
 
 
Day 1 
Day 2  
Day3  
Day 4 
 
 
 
 
 
Times After Dosing (hours) 
 
Study Procedures 
b 
Screen 
Adm 
Pre-
dose 
0 
0.25 0.5 
0.75 
1.5 
2 
3 
4 
6 
8 
12 
16 
23 
24 
48 
72 
 
Residential Period 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including 
demographics) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and Height c 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
(including Cotinine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test d 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaler Device 
Training 
Xn 
 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination f 
X 
 
X 
 
X 
X 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
29 
 
 
 
 Treatment Period 1 a 
 
Study Day 
-28 to -1 
-1 
1 
2  
3 
4 
 
Treatment Days 
 
 
Day 1 
Day 2  
Day3  
Day 4 
 
 
 
 
 
Times After Dosing (hours) 
 
Study Procedures 
b 
Screen 
Adm 
Pre-
dose 
0 
0.25 0.5 
0.75 
1.5 
2 
3 
4 
6 
8 
12 
16 
23 
24 
48 
72 
 
Residential Period 
 
 
Safety Labs g 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serology (HIV/ 
Hepatitis screen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
females only; if 
required)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Test 
m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram   
h 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Vital Signs i 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Tympanic Body 
Temperature 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Pulse Oximetry 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Spirometry j 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Concomitant 
Medication 
 
Adverse Events 
 
Blood Samples for 
PK assessments 
 
 
X 
 
X 
 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Induced Sputum 
Samples for PK 
assessmentsl 
X l 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
30 
 
Part 3 Footnotes 
      ADM - admission 
a. 
Washout interval of a minimum of 96 hours between doses in each treatment period i.e. Day 1 dosing to Day 1 of the next treatment period.  
Example of minimum washout period: Period 1, Day 1 Monday the earliest Period 2, Day 1 of the next treatment period is the following 
Friday. 
b. 
Screening procedures (including informed consent) can be performed over more than 1 day. Repeat of study procedures is permitted on the 
day and/or on another day (as appropriate) at the discretion of the investigator. 
c. 
Height and Weight at screening. Weight only on Day 1 (pre-dose) of each treatment period. 
d. 
All female subjects. 
e. 
Of the relevant treatment period only, training will be performed pre-dose on Day 1. 
f. 
Full physical examination at screening Study Day 5 and Study Day 9. Symptom directed examination; if required at any other visits or times 
at the discretion of the investigator. 
g. 
Clinical safety laboratory samples (clinical chemistry, haematology and urinalysis) must be performed within 7 days of Day 1, Period 1; if 
this interval is exceeded, sampling must be repeated. There is no requirement for Day 1 pre-dose laboratory assessment results to be 
available before dosing in either Period 1 or Period 2. Samples for clinical chemistry will be obtained following a fast of at least 8 hours 
(water permitted). 
h. 
Performed in triplicate. For assessment of time windows, the time of the first ECG of the triplicate will be used. 
i. 
Systolic and diastolic blood pressure, pulse rate and respiratory rate.  
j. 
Pre and post bronchodilator (salbutamol) reversibility testing at screening. At all other visits and time-points spirometry may be performed 
pre or post bronchodilator; i.e. there are no requirements for bronchodilator restrictions after the screening visit.  
k. 
Screening sputum samples will be collected for assessment of eligibility only and will not be analysed. 
l. 
A minimum of 6 out of the 16 subjects to be randomised in Part 3 must provide a sufficient sputum sample at screening as per inclusion 
criteria 13.  
m. Subjects will undergo a SARS-COV-2 RT-PCR test prior to sputum induction at screening. Subjects testing negative may proceed to enrol 
in the study, provided other eligibility criteria are met; Subjects who test positive should be withdrawn from screening for the study and 
undergo or be referred for appropriate medical care as determined by local policy for managing a positive result. SARS-COV-2 RT-PCR 
test must be performed within 14 days of Day 1, Period 1. If this interval is exceeded, sampling must be repeated. Additional RT-PCR 
testing may be performed throughout the study if deemed necessary by the investigator.  
n. Inhaler device training at screening is to be a demonstration only. 
 
Permitted windows for all relevant procedures and dosing will be provided in the Study Reference Manual. Where the protocol requires more than 
one procedure to be completed at the same time point, all efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
Any other procedures scheduled at the same time point will be performed either before or after the PK, as appropriate. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
31 
1.2.3.2 Part 3 Schedule of activities: Day 5 to EDV 
 
End of Treatment Period 1 / Treatment Period 2a 
Follow-Up Phone 
Callb 
 
EDVd 
Study Day 
5 
6c 
7e 
9e 
8 to 12 
days after last dose 
 
Treatment Day 
TP1 Day 5 
/pre dose 
TP2  
TP 2  - Day 1 
Day 2 
Day 3 Day 5 
 
 
 
Times After Dosing (hours) 
 
 
Study Procedures  
96hr / 
Pre-dose j 
0 
0.25 
0.5 
0.75 
1.5 
2 
3 
4 
6 
8 
12 
16 
23 
24 
48 
96 
 
 
Residential Periodc 
 
 
 
 
 
Weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
IMP Administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination g 
X 
 
X 
 
X 
Safety Labsm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X  
 
X 
Electrocardiogram h 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
Vital Signs i 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
Tympanic Body 
Temperature 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Pulse Oximetry 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
Inhaler Device Training 
X k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
Concomitant 
Medication 
 
Adverse Events 
 
Blood Samples for PK 
assessments 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Induced Sputum 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version Final 1.2; 04 June 2020- 
Amendment 02 
 
 
32 
 
 
Part 3 Footnotes 
a. Washout interval of a minimum of 96 hours between doses in each treatment period i.e. Day 1 dosing to Day 1 of the next treatment 
period.  Example of minimum washout period: Period 1, Day 1 Monday the earliest Period 2, Day 1 of the next treatment period 
is the following Friday. 
b. Follow-up Phone Call 8 to 12 days after last dose in Period 2, or in the event of early discontinuation to be performed after last dose 
in Period 1. 
c. Discharge from clinic after completion of treatment period 2, 24-hour post-dose assessments. 
d. The EDV is only to be performed for subjects who discontinue during a treatment period (prior to Study Day 5 or Study Day 9) i.e. 
is not required if discontinue during the washout period.  
e. Subjects will return on Day 7 and Day 9 for collection of PK blood sample, induced sputum sample (Day 7 only) and safety 
evaluations. 
f. 
All female subjects. 
g. Full physical examination at screening, Study Day 5 and Study Day 9. Symptom directed examination; if required at any other visits 
or times at the discretion of the investigator. 
h. Performed in triplicate. For assessment of time windows, the time of the first ECG of the triplicate will be used. 
i. 
Systolic and diastolic blood pressure, pulse rate and respiratory rate.  
j. 
All +96-hour procedures for Treatment Period 1 are to be performed prior to Treatment Period 2 dosing and can also be considered 
as Treatment Period 2 pre dose assessments.   
k. Of the relevant treatment period only, training will be performed pre-dose on Day 1. 
l. 
 A minimum of 6 out of the 16 subjects to be randomised in Part 3 must provide a sufficient sputum sample at screening as per 
inclusion criteria 13.  
m. Clinical safety laboratory samples (clinical chemistry, haematology and urinalysis), Samples for clinical chemistry will be obtained 
following a fast of at least 8 hours (water permitted). 
Samples for PK 
assessments l 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           33 
2. 
Introduction 
Asthma is a chronic condition which occurs as a result of immune response in the 
bronchial airways, causing intermittent inflammation and airway swelling. Many factors, 
including infection as well as different allergens can irritate and inflame the airways, 
leading to worsening of asthma symptoms. 
 
The frequency of Aspergillus sensitisation in asthmatic subjects varies, with a range from 
16% to 38% being reported in different geographical regions [1]. Some asthmatics with 
sensitisation to Aspergillus present with allergic bronchopulmonary aspergillosis (ABPA), 
a progressive fungal allergic lung disease, which can be a cause of poorly controlled 
asthma. While ABPA is often under-diagnosed due to the complexity and relative lack of 
standardisation of diagnostic criteria, prevalence of ABPA in asthmatics of up to 12.9% 
has been reported [2, 3].  
 
The link between asthma severity and fungal allergy is well established. Indeed, 
sensitisation to fungal allergens and ABPA are associated with the risk of severe asthma 
exacerbations requiring multiple hospital and intensive care admission [4, 5] and 
management with prolonged courses of systemic corticosteroids and azoles [6], which 
are associated with significant adverse effects.  
  
In this setting, there is a need for development of new, effective and well tolerated 
therapies to control fungus-associated inflammation of the airways. Inhaled 
administration of antifungals like voriconazole could potentially be an effective alternative 
treatment option for ABPA and may improve asthma control and reduce its severity and 
frequency of exacerbations. 
 
2.1. 
Study Rationale 
There is a growing evidence linking asthma severity with fungal allergy. Sensitisation to 
fungi and long-term or uncontrolled fungal infection are associated with poor control of 
asthma.  
 
Several studies of antifungal treatments in asthmatic patients with ABPA showed 
improvement in patient quality of life, reduction in the frequency of exacerbations and 
corticosteroid requirements [7, 8]. Anti-fungal treatment of ABPA is based on various 
agents from the azole class, like itraconazole, voriconazole or posaconazole [9]. These 
medications have shown to be beneficial against Aspergillus spp. colonisation of the 
airways.  
 
Randomised controlled trials reported that treatment with oral itraconazole for 4 months 
improved both clinical outcomes and reduce inflammation in asthmatics with ABPA [10, 
11, 12]. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           34 
 
The major problem with the use of itraconazole is the high failure rate and frequent 
adverse events (AEs). The most common side effects include nausea and vomiting, 
diarrhea and flatulence, constipation, hyperlipidemia, hypokalemia, liver enzyme 
elevations, peripheral edema, and peripheral neuropathy. Perhaps most importantly, 
adrenal suppression, especially when combined with some inhaled corticosteroids (ICS), 
can occur in many patients. Occasionally, itraconazole has been associated with heart 
failure [13]. 
 
Oral itraconazole is also associated with variable pharmacokinetics (PK). The oral 
bioavailability of itraconazole in healthy volunteers can be low and dependent on food 
intake, and may be further reduced in patients with poor digestive function [14]. 
 
Newer oral triazoles with excellent anti-Aspergillus activity (voriconazole and 
posaconazole) have also been reported as beneficial in the treatment of ABPA [14]. 
Chishimba et al [15] reported high clinical response rates to both voriconazole and 
posaconazole in patients who discontinued treatment with itraconazole either due to lack 
of efficacy or adverse events. Clinical responses were associated with a marked reduction 
in oral corticosteroids and short-acting beta-agonist use, health-care utilization due to 
asthma, and improvement in overall health status. 
 
Voriconazole has a similar in vitro minimum inhibitory concentration against A. fumigatus 
as itraconazole and posaconazole, and an improved safety and PK profile, with good 
penetration into the lung tissue and epithelial lining fluid [16].  
 
However, despite promising efficacy in ABPA patients and the improved PK profile, 
systemic, prolonged use of voriconazole is still associated with a significant number of 
adverse events and treatment discontinuations, with visual toxicity being one of the main 
reasons for poor patient tolerability [17]. Development of an inhaled formulation of 
voriconazole could offer an attractive therapeutic alternative, deprived of the side effects 
associated with systemic exposure. 
 
ZP-059 (inhaled voriconazole) is an anti-fungal product being developed as a therapeutic 
for the treatment of ABPA in patients with asthma and cystic fibrosis (CF). 
 
This study will evaluate the 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 will 
be compared to that of oral voriconazole. Part 3 will only start after review of safety data 
from cohorts 1 to 4 of Part 1 (SAD) have been completed. 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           35 
Parts 2 and 3 of the study will also explore voriconazole concentrations in induced sputum 
samples in asthmatic subjects. 
 
As part of the safety and tolerability assessment, this study will investigate the effects of 
ZP-059 on airway function in both mild and mild to moderate stable asthma subjects. 
 
Population rationale: 
 
ABPA affects both men and women; therefore, a target population of both male and non-
pregnant, non-lactating female subjects of childbearing potential (providing they agree to 
use highly effective contraception) or women of non-childbearing potential between 18 
and 60 years will be suitable for all parts of the study (i.e. Parts 1, 2 and 3). As PK of 
voriconazole has been shown to differ between males and females, 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. 
  
Japanese and Chinese subjects will not be included in this study as voriconazole 
exposures in these populations could be influenced by poor metabolism due to CYP2C19 
genotype [18]. 
 
2.2. 
Background 
Aspergillus fumigatus is a mould that can cause invasive, life threatening infections, 
predominantly in immunocompromised patients. At the same time, airway colonization 
with A. fumigatus in patients with chronic lung disease such as asthma and CF may lead 
to an allergic immune response without tissue invasion, resulting in a complex 
manifestation of clinical symptoms and radiological and laboratory test abnormalities. 
 
The immunological response to fungal antigens in the airway that leads to the 
development of ABPA results in T-helper type 2 (Th2) cell activation and inflammatory 
cell recruitment to the airways, the most significant of which are eosinophils. Expression 
of interleukin-4 and interleukin-5 (IL-4 and IL-5) is central to these processes. IL-4 
stimulates the upregulation of adhesion molecules involved in eosinophil recruitment and 
the production of IgE by B cells, which in turn leads to mast cell activation. IL-5 produced 
by both Th2 cells and mast cells is a key mediator of eosinophil activation. Activation of 
both mast cells and eosinophils results in the release of mediators that induce 
bronchoconstriction [19, 20].  
 
The main symptoms of ABPA are those of poor controlled asthma with wheeze, dyspnea, 
mucus production, bronchoconstriction and productive cough. Repeated episodes of 
mucus production, bronchial obstruction and inflammation can lead to the development 
of bronchiectasis that may progress to fibrosis if untreated. The clinical symptomatology 
is associated with increased levels of total and Aspergillus-specific IgE, positive 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           36 
immediate hypersensitivity skin test for Aspergillus, peripheral eosinophilia, serum 
precipitins or Aspergillus-specific IgG, and radiographic pulmonary opacities, either 
transient (consolidation, nodules, or finger-in-glove) or permanent (bronchiectasis or 
fibrosis) [20, 21]. 
 
Hence, recognition and proper management of ABPA is very important in order to prevent 
permanent lung damage in patients with severe, difficult to control asthma. Long-term 
treatment of ABPA aims to control inflammation and prevent further injury to the lungs. 
Use of oral corticosteroids and antifungals are the main stay of treatment to reduce the 
number of exacerbations. However, new treatment modalities are required to improve 
tolerability of therapy and also to reduce the need for systemic steroids. 
2.3. 
Benefit/Risk Assessment 
Allergic bronchopulmonary aspergillosis (ABPA) is a rare disease that affects patients 
with asthma and cystic fibrosis (CF). There is currently no specific therapy for treatment 
of ABPA in asthmatics and this debilitating condition has led researchers to find new 
avenues of treatments, including new ways of administering antifungals. Oral antifungals 
like voriconazole are useful for ABPA along with steroids as they have shown to improve 
clinical symptoms and lung function, reduce frequency of exacerbations, and to provide 
steroid-sparing effect. However, the confidence in the beneficial effects of oral 
voriconazole is limited by poor PK and adverse events in high concentrations. Hence, an 
inhaled formulation of voriconazole by using Edry technology, can overcome these 
limitations with efficient lung deposition, resulting in a lower systemic exposure and 
subsequently minimizing toxic effects. 
Given the dynamic, ongoing global health crisis related to COVID-19, the risk to subjects 
must be assessed and addressed on an ongoing basis. Risk mitigation elements include 
a reverse transcription polymerase chain reaction (RT-PCR) test for SARS-CoV-2 that 
will be conducted at Day -4/-3 for Part 2 and prior to screening sputum induction for Part 
3. While subjects are resident in the clinic, the clinic staff will follow locally established 
risk mitigation processes to minimize exposure to SARS-COV-2 for subjects and staff. 
Any subjects testing positive for SARS-COV-2 during the study will receive the 
appropriate medical care, and precautions, according to local requirement, will be taken 
to ensure the safety of other subjects and research staff. Any additional policies or 
information will be assessed on an ongoing basis and integrated into study conduct, as 
appropriate. 
 
 
2.3.1. 
Risk Assessment 
In the population selected for this study, ZP-059 and all study related procedures do not 
pose any significant risks because pre-clinical studies have shown that systemic 
exposure of ZP-059 is low (IB section 5.3.1) and all staff are competent in the study 
related procedures. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
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VFEND® 
is 
a 
licensed 
broad-spectrum, 
antifungal 
agent 
(Ref: 
https://bnf.nice.org.uk/drug/voriconazole.html,  
https://www.medicines.org.uk/emc/product/7383/smpc 
Generally, asthmatics are considered vulnerable when compared to a healthy population, 
However, the asthmatic population included in part 2 and part 3 of the study are mild (Part 
2) or mild to moderate (Part 3) and stable with no other significant co-morbidities. 
 
2.3.2. 
ZP-059 
ZP-059 is an antifungal product, being developed using Edry technology as an inhaled 
therapy, for the treatment of ABPA in patients with asthma. It has been developed such 
that there is efficient lung deposition, compared to other inhalative treatments, avoiding 
extra pulmonary deposition, and causing a low systemic exposure level, as well regarding 
effects on plasma concentration of contraceptives. 
 
The overall summary of toxicology data for ZP-059 is provided in the Investigator’s 
Brochure (IB). There was no evidence of systemic toxicity in the preclinical studies. All 
the repeat doses were tolerated well apart from a single episode of vomiting and reduction 
in food consumption in dog at 35.7mg/kg/day. Based on animal data the no-observed-
adverse-affect-level (NOAEL) was  49.3mg/kg/day in rats and 21mg/kg/day in dogs and 
in our study the starting dose is considerably lower. 
 
 
2.3.3. 
Induced Bronchoconstriction 
Bronchoconstriction is an expected adverse reaction with any inhaled therapy and is a 
theoretical risk for ZP-059. Subjects will be monitored for AEs and for bronchoconstriction 
(through scheduled spirometry assessments) throughout the study and treated with 
bronchodilators e.g. salbutamol and other appropriate therapies as deemed necessary 
by the Investigator, if required for symptomatic bronchoconstriction. 
2.3.4. 
Oral voriconazole 
VFEND®, is a licensed broad-spectrum, triazole antifungal agent which is indicated in 
adults and children aged 2 years and above for the treatment of invasive aspergillosis, 
candidemia in non-neutropenic patients etc. It is available as a lyophilized powder for 
solution for intravenous infusion, film-coated tablets for oral administration, and as a 
powder for oral suspension. 
 
Repeat dose toxicity studies of oral voriconazole indicated hepatoxicity occurs at plasma 
exposures similar to those obtained at therapeutic doses in humans. Animal data has 
also shown minimal adrenal changes. Regular safety assessments, including laboratory 


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tests, vital signs, physical examination, ECGs as per the schedule of activities will be 
performed throughout the study.  
 
Voriconazole has shown teratogenic effects in rats and embryotoxic effects in rabbits with 
no observed impairment of male or female fertility in rats. Overall, there was no special 
hazard seen for humans. Contraceptive measures will be followed as per protocol. Due 
to being substrates for CYP3A4, the plasma concentration of hormonal contraceptives 
may increase by concomitant administration of voriconazole. However, the inhaled dose 
has low systemic exposure and there is only a single oral dose of voriconazole 
administered in part 3, with no increased risk to women of childbearing potential on 
hormonal contraceptives. Strong CYP3A4 inhibitors and inducers as concomitant 
medication will not be permitted for the duration of the study. 
 
2.3.5. 
Other 
During cannulation, more than one attempt may be needed to insert the cannula in a vein 
of a subject and it is possible that bruising and/or inflammation may be experienced at 
the site of cannulation. More rarely fainting, a local clot developing or local infection can 
occur. At times when a cannula is not required, blood samples will be taken via 
venepuncture. This can also result in discomfort, bruising or a haematoma at the site of 
puncture. 
Electrocardiogram stickers on the subjects' chests and limbs may cause some local 
irritation and may be uncomfortable to remove but subjects will be closely monitored to 
ensure any local irritation does not persist.  
Sputum induction is a relatively non-invasive method to obtain sputum for analysis in 
clinical practice and in research. It is performed using an aerosol of normal and hypertonic 
saline generated by an ultrasonic nebuliser. Subjects will be pre-treated with a 
bronchodilator, e.g. 200 to 400 µg of salbutamol will be administered via a spacer device 
as required to mitigate against aerosol induced bronchoconstriction. Subjects will be 
monitored during the procedure (by performing regular lung function), which will be 
stopped if the subject develops symptoms suggestive of bronchoconstriction or a 
significant fall (i.e. ≥ 20%) in forced expiratory volume in 1 sec (FEV1), and treated with a 
bronchodilator as appropriate. Site-specific standard operating procedures (SOPs) for 
sputum induction will be followed. 
All other investigations such as measurements of blood pressure and pulse rate are well 
established methods which do not present a risk to the subjects. 
 


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2.3.6. Benefit Assessment 
There is no benefit to the subjects from taking part in this study. The development of a 
product to improve the treatment of ABPA in patients with severe asthma or CF will be of 
benefit to the wider community/patients with this condition.  
 
2.3.7. Overall Benefit: Risk Conclusion 
The administered doses will be gradually escalated following defined procedures to 
guarantee the included participant`s appropriate safety. Hence, the overall benefit risk 
assessment is considered to be acceptable for the proposed trial based on the available 
pharmacological data from IB. 
 
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments) current ICH E6 Good Clinical Practices and all other applicable local laws 
and regulations [24]. 


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3. 
Objectives and Endpoints 
3.1. 
Objectives 
3.1.1. 
Primary Safety Objectives 
 
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. 
3.1.2. 
Pharmacokinetic (PK) Objectives 
 
Part 1: 
To characterize systemic PK of voriconazole after single doses of ZP-059 in healthy 
subjects. 
 
Part 2: 
To characterize systemic PK of voriconazole after multiple doses of ZP-059 in subjects 
with mild, stable asthma. 
 
Part 3: 
To characterize systemic PK of voriconazole after single doses of ZP-059 and single 
doses of oral voriconazole in subjects with mild to moderate stable asthma. 
3.1.3. 
Exploratory Objectives (Parts 2 and 3 only) 
 
Part 2: 
To characterize voriconazole concentrations in induced sputum after multiple doses of 
ZP-059 (i.e. on Day 7; both pre-dose and post-dose) in subjects with mild, stable asthma. 
 
Part 3: 
To characterize voriconazole concentrations in induced sputum after single doses of 
ZP-059 and after single doses of oral voriconazole in subjects with mild to moderate 
stable asthma. 


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3.2. 
Endpoints 
3.2.1. 
Safety Endpoints (Parts 1, 2 and 3) 
Safety and tolerability, as assessed by monitoring of AEs, physical examinations, 
changes in vital signs, clinical laboratory parameters, electrocardiogram (ECG), pulse 
oximetry and spirometry assessments (FEV1, forced vital capacity [FVC], peak expiratory 
flow rate [PEFR] and FEV1/FVC). 
3.2.2. 
Pharmacokinetic Endpoints (Parts 1, 2 and 3) 
For each study part, the serum concentration data for voriconazole and N-oxide 
voriconazole will be analysed using PKNCA (version 0.8.1 or higher) with R (version 3.2.2 
or higher). 
 
For Parts 2 and 3, sputum concentration of voriconazole will be analysed. 
 
Pharmacokinetic parameters: 
The following non-compartmental PK parameters of voriconazole and N-oxide 
voriconazole will be calculated: 
 
Parts 1, 2 and 3 (in Part 3, Day 1 of TP1 and Day 1 of TP2): AUC0-t, AUC0-inf, AUCtau, 
Cmax, tmax, Kel, t1/2, CL/F and Vz/F, where AUC0-t is:  
• AUC0-12 for Part 1, AUC0-24 for Part 2 and AUC0-96 for Part 3   
 
AUC0--t, AUC0-inf and Cmax for Part 3 will also be derived based on the Part 1 PK and 
separately the Part 2 PK time points, so that a like-for-like comparison between Part 3 
and Part 1 and between Part 3 and Part 2 can be performed for these PK parameters. 
 
Part 2 (Day 10): AUC0-tau, Cmax,ss, tmax,ss, Cmin, Ctrough, Css,av, %fluctuation and %swing (as 
appropriate and when applicable). PK parameters will be derived in addition to those 
detailed for Day 1.  
 
Accumulation ratios will be calculated from Day 1 and Day 10 AUC0-tau and Cmax values, 
and the linearity ratios will be calculated from the ratio of the Day 10 AUCtau and Day 1 
AUC0-inf. 
 
Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. 
Additional PK parameters may be calculated if deemed appropriate. 


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4. 
Study Design 
4.1. 
Overall Design 
 
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).  
 
Part 1 will comprise 4 separate cohorts (each containing 6 subjects) planned to receive 
single doses of ZP-059. The starting dose for Cohort 1 will be 5 mg with subsequent 
doses being determined from review of safety data by the SAC from the preceding 
cohorts. The criteria to be followed by the SAC are detailed in Section 6.6.4. The study 
will have an interleaved design.  
 
Part 2 will comprise 3 separate cohorts (each containing 6 subjects) planned to receive 
daily doses of ZP-059 on Day 1 to 10. Dose levels for Part 2 will be determined from 
review of safety data by the SAC from Part 1. Part 2 cohort 1 will commence after a review 
of safety data from Part 1 cohort 2 confirms that it is safe to do so. The criteria to be 
followed by the SAC are detailed in Section 6.6.4 
 
Part 3 is a 2-period, randomised crossover study in 16 subjects to assess the safety, 
tolerability and PK of single doses of ZP-059 and single doses of oral voriconazole. Part 
3 will comprise of 1 cohort randomised to receive ZP-059 and 200 mg oral voriconazole; 
across 2 treatment periods with a minimum wash-out period of 96 hours.  
 
The dose of ZP-059 for Part 3 will be confirmed after completion of SAD cohorts 1 to 4 
and review of the available safety data. Hence, dosing of Part 3 may occur prior to/in 
parallel with dosing in Part 2. 
 
Subjects will be screened for eligibility to participate in the study within 28 days before 
dosing (Day 1) For Part 2 subjects who completed the initial Screening Visit will attend 
the clinic on Day -4 or Day -3, for a SARS-COV-2 RT-PCR test. This may be performed 
on the same day as screening if screening is performed within 3 or 4 days of dosing. 
Subjects will then be admitted to the clinic on the evening of Day -1. 
 
Further details of each study part are described in Sections 4.1.1 to 4.1.3. 
 


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4.1.1. 
Part 1 (SAD) 
Part 1 is a single ascending dose (SAD) study to assess the safety, tolerability and PK of 
single doses of ZP-059 in 4 cohorts of healthy male and female subjects. Each cohort will 
comprise 6 subjects (planned total of 24 subjects). An evaluable subject for Part 1 (SAD) 
of the study is defined as a subject who has received a dose of ZP-059 and has sufficient 
data for evaluation of the safety and PK objectives as outlined in Section 3.1.1 and 
Section 3.1.2 – 3.1.3, respectively.  
 
An additional cohort of 6 subjects (Cohort 5) may be enrolled if it is deemed appropriate 
to repeat a dose level, assess an interim dose level or assess a dose level higher than 
planned (Section 6.6.1). Single doses will not exceed 40 mg of ZP-059 based on safety 
margins calculated following non-clinical studies (Section 4.3). For each dose escalation, 
the dose increase will not be more than 3-fold. A repeat dose level or higher dose level 
will only be assessed provided no dose escalation or study stopping criteria have been 
met.  
 
Eligible subjects will receive a single dose of ZP-059 on the morning of Day 1. Subjects 
will be required to fast (water permitted) for at least 1 hour prior to each dose and 1 hour 
post each dose. 
 
ZP-059 is a first in human IMP and therefore an additional safety precaution has been 
considered for dosing in each cohort and dose level for Parts 1 and 2. For the first 2 
subjects in each cohort, there will be a minimum interval of 20 minutes between dosing. 
After the second subject is dosed there will be at least a 30 minutes observation period 
before the remaining 4 subjects are dosed. The remaining subjects will be dosed if the 
first two subjects show no clinically significant safety or tolerability concerns (including 
vital signs measurements, spirometry, physical examinations (symptom directed if 
required) and review of any adverse events [AEs] including any acute side effects e.g. 
excessive coughing) at the discretion of the investigator. Any clinically significant findings 
from the first two subjects in the opinion of the investigator will be discussed with the 
Sponsor prior to dosing of the remaining 4 subjects. The dosing interval between dosing 
subjects in the remainder of the cohort will be at the discretion of the investigator (in 
consultation with the sponsor if required) i.e. this could be increased or decreased as 
appropriate. 
 
The fixed starting dose for SAD Cohort 1 is 5 mg (1 x 5 mg capsule*) ZP-059 single dose 
administered via DPI (RS01 monodose device) on Day 1. *Capsule delivers 5 mg of 
voriconazole. Subsequent doses in the following cohorts will be determined from review 
of safety data from the preceding cohorts. 
There will be an interim data review before each dose escalation to the next dose level to 
determine safety and tolerability. The time between cohorts will be sufficient to allow this 
review. Interim reviews will be based on safety data up to a minimum of 24 hours post-


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dose for each dose level. Progression to the next dose level will only occur after a review 
of safety data from the previous dose level confirms that it is safe to do so. The interim 
decision meeting following SAD cohort 2 will also determine the dose to be administered 
in Part 2 MAD cohort 1. The data reviews will be conducted by the safety advisory 
committee (SAC), which will always comprise the Principal Investigator (or delegate) and 
the sponsor’s medical monitor as a minimum (Section 6.6). Full details of interim data 
reviews, including dose escalation criteria, are provided in Sections 6.6.1 to 6.6.4.  
Subjects will undergo safety, tolerability and PK evaluations at specified time points 
during the study (see Section 1.2). They will remain resident in the clinic until Day 2 after 
completion of safety assessments at 24 hours post-dose and providing there are no safety 
concerns, they will be discharged from the unit. A safety telephone call will be performed 
on Day 3 to check the status of unresolved AEs and to record any new AEs that have 
occurred after the last visit as well as any changes to concomitant medications. They will 
return to the clinic on Day 5 for safety evaluations to be performed. A safety follow-up call 
will be performed 8 to 12 days post dose to check the status of unresolved AEs and to 
record any new AEs that have occurred after the last visit as well as any changes to 
concomitant medications. 
 
4.1.2. 
Part 2 (MAD) 
Part 2 is a multiple ascending dose (MAD) study to assess the safety, tolerability and PK 
of multiple doses of ZP-059 in 3 cohorts of male and female subjects with a physician 
confirmed documented diagnosis of mild stable asthma. Each cohort will comprise 6 
subjects (planned total of 18 subjects). An evaluable subject for Part 2 (MAD) of the study 
is defined as a subject who has received 10 days of dosing with ZP-059 and has sufficient 
data for evaluation of the objectives of the study. 
 
Up to 2 optional additional cohorts of 6 subjects (Cohort 4 and Cohort 5) may be enrolled 
in Part 2 if it is deemed appropriate to repeat a dose level, assess an additional dose level 
or assess a different dosing regimen (), however, the dose will not exceed the highest 
dose studied in Part 1 (Section 6.6.2). If a selected dose does not provide the required 
data to meet the objectives of the study, a previously tested dose may be used in a 
subsequent cohort. However, if the dose level met the dose escalation or study stopping 
criteria, neither that dose level nor a higher dose will be repeated. 
 
In each cohort, subjects will receive inhaled doses either once daily (QD) for 10 days or 
twice daily (BID) for 9 days and once in the morning of Day 10, as determined by the 
Sponsor based on data obtained in previous Part 1. In the event of QD dosing eligible 
subjects will receive QD doses of ZP-059 (at Hour 0) on Days 1 to 10. In the event of BID 
dosing, ZP-059 will be administered at Hours 0 and 12 on Days 1 to 9 and once in the 
morning of Day 10 (i.e. 19 doses in total). Subjects will be required to fast (water 
permitted) for at least 1 hour prior to each dose and 1 hour post each dose; in the event 


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of BID dosing this will be for both the 0 hour and the 12 hour doses. Following the first 
dose, subsequent doses will be administered within +/- 1 hour of the scheduled dosing 
time. If any of the additional cohorts (i.e. Cohorts 4 and 5) are required, subjects will 
receive either QD or BID doses, as may be appropriate. 
 
For the first 2 subjects in each cohort, there will be a minimum interval of 20 minutes 
between dosing (Day 1; Hour 0). After the second subject is dosed there will be at least 
a 30 minutes observation period before the remaining 4 subjects are dosed (Day 1; Hour 
0). The remaining subjects will be dosed if the first two subjects show no clinically 
significant safety or tolerability concerns (including vital signs measurements, spirometry, 
physical examinations (symptom directed if required) and review of any adverse events 
[AEs] including any acute side effects e.g. excessive coughing) at the discretion of the 
investigator. Any clinically significant findings from the first two subjects in the opinion of 
the investigator will be discussed with the Sponsor prior to dosing of the remaining 4 
subjects. The dosing interval between dosing subjects in the remainder of the cohort will 
be at the discretion of the investigator (in consultation with the sponsor, if required) i.e. 
this could be increased or decreased as appropriate. 
 
The planned starting dose of ZP-059 to be administered in MAD cohort 1 will be confirmed 
during an interim review of safety data from completed SAD cohorts and will not exceed 
a previously administered single dose. Dose administration for MAD cohort 1 will only 
commence after completion of review of safety data up to a minimum of 24 hours 
post-dose for the second dose level of Part 1 (SAD cohort 2).  
 
There will be an interim data review before each dose escalation to the next dose level to 
determine safety and tolerability. The time between cohorts will be sufficient to allow this 
review. There will be an interim data review after completion of MAD cohort 1 and SAD 
cohort 3 to confirm the dose level to be administered in MAD cohort 2 and after completion 
of MAD cohort 2 and SAD cohort 4 to confirm the dose level to be administered in MAD 
cohort 3.  
 
The data reviews described above will be conducted by the SAC, which will always 
comprise the Principal Investigator (or delegate) and the sponsor’s medical monitor as a 
minimum. Full details of interim data reviews, including dose escalation criteria, are 
provided in Sections 6.6.1 to 6.6.4. 
 
In the event of QD dosing subjects will receive QD doses of ZP-059 (at Hour 0) on Days 
1 to 10.  In the event of BID dosing, ZP-059 will be administered at Hours 0 and 12 on 
Days 1 to 9 and once in the morning of Day 10 (i.e. 19 doses in total). If any of the 
additional cohorts (i.e. Cohorts 4 and 5) are required, subjects will receive either QD or 
BID doses, as may be appropriate. 
 
Details of ZP-059 are provided in the Investigational Medicinal Product Section of the 


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protocol. 
 
Subjects will undergo safety, tolerability and PK (serum and sputum) evaluations at 
specified time points during the study (a full serum PK profile will be collected on Days 1 
and 10). They will remain resident in the clinic until the morning of Day 4 after completion 
of dosing and safety assessments and providing there are no safety concerns.  
 
The subjects will then return to the clinical unit daily from Day 5 through to Day 9 for pre-
dose study procedures and to receive their scheduled dose (Hour 0) of study medication.  
On Day 7 the visit will also include induced sputum sampling pre-dose and post-dose.  
The subject will be discharged after dosing or sputum sampling as applicable, providing 
there are no safety concerns. In the event of BID dosing; on Days 4 to 9 the subjects will 
be required to attend the unit for the evening dose (i.e. return in the evening on Day 4 
and attend twice daily on Days 5 to 9) and will be discharged after dosing providing there 
are no safety concerns. The subjects will then return to the clinical unit on the morning of 
Day 10 where they will then remain resident overnight until Day 11 (24 hours after the last 
dose). After completion of safety assessments, they will be discharged providing there 
are no safety concerns. They will return to the clinic on Days 14 and 17 for collection of 
PK blood samples (Day 14 only) and safety evaluations. A safety follow-up telephone call 
will be performed 11 to 17 days after the last dose (Day 24, +/- 3 Days) to check the status 
of unresolved AEs and to record any new AEs that have occurred after the last visit as 
well as any changes to concomitant medications.  
 
 
4.1.3. 
Part 3 (Two-period crossover)  
Part 3 is a 2-period, randomised, crossover study to assess the safety, tolerability and PK 
of single doses of ZP-059 compared to single doses of oral voriconazole in 16 male and 
female subjects with a physician confirmed documented diagnosis of mild to moderate 
stable asthma.  
 
An evaluable subject for Part 3 of the study is defined as a subject who has been dosed 
in each treatment period and has sufficient data for evaluation of the objectives of the 
study. 
 
The dose of ZP-059 will be confirmed after completion of SAD cohorts 1 to 4 and review 
of the available safety data. Hence, dosing of Part 3 may occur prior to/ in parallel with 
dosing in Part 2. The data review will be conducted by the SAC, which will comprise as a 
minimum the Principal Investigator (or delegate) and the sponsor’s medical monitor (see 
Sections 6.6.1 to 6.6.4). 
 
Eligible subjects will be randomised to receive a single dose of ZP-059 or a single oral 
dose of voriconazole in Period 1. Each subject then will receive the alternative treatment 
in Period 2 such that on completion of the study, all subjects will have received a single 


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dose of ZP-059 and a single oral dose of 200 mg voriconazole. The actual dose of ZP-
059 will be determined at the safety review performed after completion of cohorts 1 to 4 
(SAD) and will not exceed the highest dose used in Part 1. 
 
Dosing intervals between subjects in Part 3 are not deemed necessary, however may be 
implemented at the discretion of the investigator (in consultation with the sponsor, if 
required). Subjects should be dosed at approximately the same time of day in each study 
period. 
Subjects will be required to fast (water permitted) for at least 1 hour prior to each dose 
and 1 hour post each dose. The washout period between doses in each treatment period 
will be a minimum of 96 hours. 
 
Subjects will undergo safety, tolerability and PK evaluations at specified time points 
during the study. They will remain resident in the clinic until Day 6. They will be discharged 
from the unit after completion of Treatment Period 2 assessments up to 24 hours post 
dose and providing there are no safety concerns . Subjects will return to the clinic on Days 
7 and 9 for collection of 48 hour and 96 hour post dose (Treatment Period 2)  PK blood 
and induced sputum samples (Day 7 only), and for safety evaluations to be completed. A 
safety follow-up telephone call will be performed 8 to 12 days after last dose to check the 
status of unresolved AEs and to record any new AEs that have occurred after the last visit 
as well as any changes to concomitant medications. 
 
Sputum producer stratum (minimum of 6 subjects):  
It is planned that a minimum of 6 out of the 16 subjects to be randomised in Part 3 will 
provide sufficient sputum samples at screening as per inclusion criteria 13. All subjects in 
Part 3 will however attempt to provide a sputum sample at the indicated timepoints as 
detailed in the study schedule of activities (SOA) in Section 1.2.3 (Part 3), regardless of 
whether they produce an adequate sample at screening. 
 
 
4.2. 
Scientific Rationale for Study Design 
This is a Phase 1, first in human (FIH) study which is aimed to test an inhaled formulation 
of voriconazole in healthy individuals and mild to moderate asthmatic subjects. Using an 
interleaved study design would allow us to switch between different interventions and give 
an opportunity to receive assessment data about the PK/PD profile for this new 
compound, safety and tolerability in both populations which would aim to develop a new 
approach or mode of treatment for ABPA in asthmatics in the future. 
 


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4.3. 
Justification for Dose 
Oral Voriconazole (VFEND®): is licensed as one of the antifungals for the treatment of 
invasive aspergillosis at a dose of 200mg, twice daily for 3 months. Therefore, a single 
oral dose of 200mg in Part 3 of the study is considered safe and enough to achieve the 
anticipated endpoints. 
ZP-059: Toxicology studies were performed to assess the maximum tolerated dose when 
administered to 2 beagle dogs for 12 days at increasing doses every three days at 5,10, 
20 and 30mg/kg/day. Escalated doses of ZP-059, up to 21.3mg/kg/day were well 
tolerated. Additionally, 2 beagle dogs were administered the inhaled formulation for 14 
days at a dose of 20mg/kg/day. A constant dose of 21mg/kg/day was well tolerated by 
both dogs throughout the 14 days. A single incidence of vomiting and reduction in food 
consumption during dosing was observed with 35.7mg/kg/day (Investigator’s Brochure 
section 5.3.1). 
Based on the NOAELs of the 4-week repeat-dose toxicology studies, a dose of 5mg ZP-
059 was selected, which provides a conservative approach (at least 10 times lower) with 
adequate safety margins for the proposed human dose.  
The safety margins were calculated considering the deposited dose in humans equal to 
the 100% of the delivered dose, further decreasing the risk and indicating that the adopted 
strategy can be considered satisfactory. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed treatment 
to the end of their assigned cohort and their final safety follow up telephone call has been 
performed or early discontinuation visit (if applicable) i.e. last contact with the site.  
The end of the study is defined as the date of the last visit or telephone contact with the 
last subject in the study.  
 


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5. 
Study Population 
This protocol contains healthy subjects (Part 1), subjects with mild stable asthma (Part 2) 
and subjects with mild to moderate stable asthma (Part 3). 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known 
as protocol waivers or exemptions is not permitted. 
5.1. 
Part 1 Eligibility Criteria 
 
5.1.1. 
Part 1 Inclusion Criteria 
Subjects are eligible to be included in the study only if all the following criteria apply: 
1. Subject’s written informed consent obtained prior to any study-related procedure. 
2. Healthy male and female subjects (aged ≥ 18 and ≤ 60 years at the time of 
informed consent. 
3. Female subjects must be either of non-childbearing potential or if of childbearing 
potential use a highly effective birth control method (see Section 10.4.1). 
4. 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) (see Section 10.4.1). 
5. Subject must agree not to donate semen or ova/oocytes during the study and for 
14 days after the last dose of IMP. 
6. Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening. 
7. Are willing and able to comply with all aspects of the protocol. 
8. FEV1 ≥80% of the predicted value (calculated according to the Global Lung 
Function Initiative [GLI-2012 Quanjer [25]) and FEV1/FVC ratio > 0.70; at 
screening. 
9. Able to demonstrate the correct inhalation technique for use of delivery device 
during the study at screening and pre-dose Day 1. 
 
5.1.2. 
Part 1 Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
1. Subjects who are Chinese or Japanese. 
2. Subjects who have received any IMP in a clinical research study within the 
previous 3 months prior to Day 1. 
3. Participation in other interventional studies for the duration of the study. 
4. Subjects who are study site employees or immediate family members of a study 
site or sponsor employee. 
5. History of any drug or alcohol abuse in the past 2 years prior to screening. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           50 
6. 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). 
7. Current tobacco or marijuana smokers and those who have smoked within the last 
12 months prior to screening or prior to Day 1. 
8. A confirmed positive urine cotinine test at screening or Day -1. 
9. 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. 
10. Smoking history of >5 pack years at screening. 
11. 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). 
12. Female subject with a positive pregnancy test at screening or pre-dose on Day 1.  
13. Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening. 
14. 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. 
15. Positive urine drugs of abuse test or alcohol breath test result at screening or Day 
-1.  
16. History of or currently infected with/carrier of human immunodeficiency virus (HIV). 
17. 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. 
18. 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. 
19. Subjects with congestive heart failure or a history of congestive heart failure. 
20. 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. 
21. History of severe cough or bronchospasm upon inhalation of any inhalation 
product. 
22. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients. 
23. Have had allergies to or hypersensitivity reactions after administration of 
voriconazole or other antifungal azoles. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           51 
24. 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.  
25. Major trauma or surgery within the last 3 months prior to screening or prior to Day 
1. 
26. Planned or elective surgery or hospitalisations for the duration of the study that 
may interfere with study logistics or safety. 
27. Donation or loss of more than 400 mL of blood within the previous 3 months prior 
to screening. 
28. 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.  
29. Subjects who are taking or have taken any herbal remedies or CYP3A4 or 
CYP2C19 inducers in the 28 days prior to Day 1. 
30. Any use of voriconazole in the 3 months prior to Day 1. 
31. Subjects who have received a live or killed/inactive vaccine in the 14 days prior to 
Day 1. 
32. Subjects who are taking, or have taken medications that are known to prolong QTc 
interval in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 (Excluded 
medications are stated in the Study Reference Manual). 
33. 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. 
34. 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. 
35. 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. 
36. Failure to satisfy the investigator of fitness to participate for any reason. 
 
 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           52 
5.2. 
Part 2 Eligibility Criteria 
 
5.2.1. 
Part 2 Inclusion Criteria 
Subjects are eligible to be included in the study only if all the following criteria apply: 
1. Subject’s written informed consent obtained prior to any study-related procedure. 
2. Male and female subjects aged ≥ 18 and ≤ 60 years at the time of informed 
consent. 
3. Subjects with mild stable asthma with a documented physician confirmed 
diagnosis of asthma for at least 3 months prior to screening. 
4. Asthma assessed by investigator as being stable for at least 4 weeks prior to 
screening and prior to Day 1. 
5. Female subjects must be either of non-childbearing potential or if of childbearing 
potential use a highly effective birth control method (see Section 10.4.1). 
6. 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) (see Section 10.4.1). 
7. Subject must agree not to donate semen or ova/oocytes during the study and for 
14 days after the last dose of IMP. 
8. Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening. 
9. Are willing and able to comply with all aspects of the protocol. 
10. Subject is being treated with short acting beta-agonists alone or in conjunction with 
low to medium doses of inhaled corticosteroids (ICS). (The ICS doses allowed are 
stated in the Study Reference Manual). 
11. Pre-bronchodilator FEV1 ≥70% of the predicted value (calculated according to the 
Global Lung Function Initiative [GLI-2012 Quanjer [25]); at screening. 
12. Able to understand at screening and demonstrate at pre-dose Day 1 the correct 
inhalation technique for use of delivery device during the study. 
 
5.2.2. 
Part 2 Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
1. Subjects who are Chinese or Japanese. 
2. Subjects who have received any IMP in a clinical research study within the 
previous 3 months prior to Day 1. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           53 
3. Participation in other interventional studies for the duration of the study. 
4. Subjects who are study site employees, or immediate family members of a study 
site or sponsor employee. 
5. Subjects who have previously received IMP in this study. 
6. History of any drug or alcohol abuse in the past 2 years prior to screening. 
7. 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).  
8. Current tobacco or marijuana smokers and those who have smoked within the last 
12 months prior to screening or prior to Day 1. 
9. A confirmed positive urine cotinine test at screening or Day -1. 
10. 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.  
11. Smoking history of >5 pack years at screening. 
12. 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). 
13. Female subject with a positive pregnancy test at screening or pre-dose Day 1. 
14. Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening. 
15. 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. 
16. 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). 
17. Positive alcohol breath test at screening or Day -1. 
18. History of or currently infected with/carrier of HIV.  
19. 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. 
20. Subjects who tests positive for active SARS-COV-2. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           54 
21. Evidence or history of clinically significant cardiovascular, renal, hepatic, 
dermatologic, ophthalmologic or gastrointestinal disease, neurological or 
psychiatric disorder, as judged by the investigator. 
22. 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. 
23. Current diagnosis of any chronic airways disease other than asthma such as 
Chronic Obstructive Pulmonary Disease, pulmonary fibrosis, CF, Churg-Strauss 
syndrome, bronchiectasis. 
24. Evidence of ventricular dysfunction such as congestive cardiac failure (CCF) or a 
history of CCF assessed at screening and pre-dose Day 1.  
25. 12-lead ECG demonstrating a mean QTcF interval >450 msec for males or >470 
msec for females at screening or pre-dose Day 1. 
26. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients. 
27. Have had allergies to or hypersensitivity reactions after administration of 
voriconazole or other antifungal azoles. 
28. Presence or history of clinically significant allergy, including drug allergies, as 
judged by the investigator. Hay fever is allowed unless it is active. 
29. Major trauma or surgery within the last 3 months prior to screening or prior to Day 
1. 
30. Planned or elective surgery, hospitalisations for the duration of the study that may 
interfere with study logistics or safety. 
31. Donation or loss of more than 400 mL of blood within the previous 3 months prior 
to screening. 
32. 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. 
33. Subjects who are taking or have taken any herbal remedies or CYP3A4 or 
CYP2C19 inducers in the 28 days prior to Day 1.  
34. Subjects who have received a live or killed/inactive vaccine in the 14 days prior to 
Day 1. 
35. Presence of hoarseness or oropharyngeal candidiasis at screening or prior to 
dosing on Day 1. 
36. Any use of voriconazole in the 3 months prior to Day 1. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           55 
37. Subjects who are taking, or have taken medications that are known to prolong QTc 
interval in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 (Excluded 
medications are stated in the Study Reference Manual). 
38. 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. 
39. 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. 
40. Occurrence of asthma exacerbations or respiratory tract infections within 4 weeks 
prior to screening or prior to Day 1. 
41. 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. 
42. 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. 
43. Failure to satisfy the investigator of fitness to participate for any reason. 
 
5.3. 
Part 3 Eligibility Criteria 
 
5.3.1. 
Part 3 Inclusion Criteria 
Subjects are eligible to be included in the study only if all the following criteria apply: 
1. Subject’s written informed consent obtained prior to any study-related procedure. 
2. Male and female subjects aged ≥ 18 and ≤ 60 years at the time of informed 
consent. 
3. Subjects with mild to moderate stable asthma with a documented physician 
confirmed diagnosis of asthma for at least 3 months prior to screening. 
4. Asthma assessed by investigator as being stable for at least 4 weeks prior to 
screening and prior to randomisation. 
5. Female subjects must be either of non-childbearing potential or if of childbearing 
potential use a highly effective birth control method (see Section 10.4.1). 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           56 
6. 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) (see Section 10.4.1). 
7. Subject must agree not to donate semen or ova/oocytes during the study and for 
14 days after the last dose of IMP. 
8. Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening. 
9. Are willing and able to comply with all aspects of the protocol. 
10. Subject is being treated with low to medium doses of inhaled corticosteroids (ICS) 
with or without long-acting beta-agonists. (The ICS doses allowed are stated in the 
Study Reference Manual). 
11. Pre-bronchodilator FEV1 ≥70% of the predicted value (calculated according to the 
Global Lung Function Initiative [GLI-2012 Quanjer [25]); at screening. 
12. Able to understand  the correct inhalation technique for use of delivery device 
during the study at screening.  
13. Sputum producer stratum only (minimum of 6 of the 16 planned subjects): Able to 
produce a sputum sample with a minimum weight of 50 mg at screening. 
 
5.3.2. 
Part 3 Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
1. Subjects who are Chinese or Japanese. 
2. Subjects who have received any IMP in a clinical research study within the 
previous 3 months prior to randomisation. 
3. Participation in other interventional studies for the duration of the study. 
4. Subjects who are study site employees, or immediate family members of a study 
site or sponsor employee. 
5. Subjects who have previously received IMP in this study. 
6. History of any drug or alcohol abuse in the past 2 years prior to screening. 
7. 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).  
8. Current tobacco or marijuana smokers and those who have smoked within the last 
12 months prior to screening or prior to randomisation. 
9. A confirmed positive urine cotinine test at screening or prior to randomisation. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           57 
10. 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 
randomisation. 
11. Smoking history of >5 pack years at screening. 
12. 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). 
13. Female subject with a positive pregnancy test at screening or prior to 
randomisation. 
14. Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator at screening. 
15. 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. 
16. 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 prior to 
randomisation; unexpected positive results may require discussion with sponsor). 
17. Positive alcohol breath test at screening or prior to randomisation. 
18. History of or currently infected with/carrier of HIV. 
19. 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. 
20. Subjects who tests positive for active SARS-COV-2. 
21. Evidence or history of clinically significant cardiovascular, renal, hepatic, 
dermatologic, ophthalmologic or gastrointestinal disease, neurological or 
psychiatric disorder, as judged by the investigator. 
22. 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. 
23. Current diagnosis of any chronic airways disease other than asthma such as 
Chronic Obstructive Pulmonary Disease, pulmonary fibrosis, CF, Churg-Strauss 
syndrome, bronchiectasis. 
24. Evidence of ventricular dysfunction such as congestive cardiac failure (CCF) or a 
history of CCF assessed at screening and prior to randomisation. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           58 
25. 12-lead ECG demonstrating a mean QTcF interval >450 msec for males or >470 
msec for females at screening or prior to randomisation. 
26. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients. 
27. Have had allergies to or hypersensitivity reactions after administration of 
voriconazole or other antifungal azoles. 
28. Presence or history of clinically significant allergy, including drug allergies, as 
judged by the investigator. Hay fever is allowed unless it is active. 
29. Major trauma or surgery within the last 3 months prior to screening or prior to 
randomisation. 
30. Planned or elective surgery, hospitalisations for the duration of the study that may 
interfere with study logistics or safety. 
31. Donation or loss of more than 400 mL of blood within the previous 3 months prior 
to screening. 
32. 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 randomisation and for the duration of the study. 
33. Subjects who are taking or have taken any herbal remedies or CYP3A4 or 
CYP2C19 inducers in the 28 days prior to randomisation. 
34. Subjects who have received a live or killed/inactive vaccine in the 14 days prior to 
randomisation. 
35. Presence of hoarseness or oropharyngeal candidiasis at screening or prior to 
randomisation. 
36. Any use of voriconazole in the 3 months prior to randomisation. 
37. Subjects who are taking, or have taken medications that are known to prolong QTc 
interval in the 14 days (or 5 half-lives, whichever is longer) prior to randomisation 
(Excluded medications are stated in the Study Reference Manual). 
38. 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. 
39. Hospitalisation (including accident and emergency visits) for the treatment of 
asthma within 3 months prior to screening or prior to randomisation or have been 
hospitalised or have attended the accident and emergency for asthma more than 
twice in the 12 months prior to screening. 
40. Occurrence of asthma exacerbations or respiratory tract infections within 4 weeks 
prior to screening or prior to randomisation. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           59 
41. Recent (within the last 4 weeks prior to randomisation) clinically significant 
bacterial, viral or fungal infection that required systemic (oral or intravenous) 
antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are 
allowed. 
42. 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. 
43. Failure to satisfy the investigator of fitness to participate for any reason. 
 
5.4. 
Lifestyle Considerations 
5.4.1. 
Meals and Dietary Restrictions 
1. Subjects must not drink liquids or eat food containing grapefruit, starfruit or 
cranberry or consume red wine, from 24 hours prior to admission on Day -1 until 
discharge (24 hours post-dose for Parts 1 and 3 (post Treatment Period 2 dose), 
and the morning of Day 11 for Part 2; i.e. through to 24 hours post last dose in a 
treatment period). 
2. Subjects must fast (water permitted) for at least 8 hours prior to clinical chemistry 
safety blood samples. 
3. Subjects must fast (water permitted) for at least 1 hour prior to dosing and 1 hour 
post-dose. In the event of BID dosing in Part 2 this restriction will apply to both the 
0 hour and the 12 hour doses. 
4. When subjects are confined in the clinical unit, meals and snacks will be provided 
at appropriate times, except when subjects are required to fast. When confined in 
the clinical unit, subjects will be required to fast from all food and drink except water 
between meals and snacks. 
 
5.4.2. 
Caffeine and Alcohol 
1. Subjects must abstain from alcohol for 24 hours prior to and during all visits. 
2. Subjects must not drink liquids or eat food containing caffeine or other xanthines 
from 24 hours prior to and during all visits. Decaffeinated beverages are allowed. 
 
5.4.3. 
Activity 
1. Subjects must not take part in any unaccustomed strenuous exercise from the 72 
hours prior to and during all visits. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           60 
 
5.4.4. 
Additional Study Restrictions 
1. It is recommended that all subjects avoid exposure to direct sunlight and use 
measures such as protective clothing and sunscreen with high sun protection 
factor (SPF) from admission on Day -1 until 72 hours post last dose. 
 
5.5. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but 
who do not subsequently receive IMP. A minimal set of data from all subjects who are 
screen failures will be required to be entered into the CRF. 
 
5.6. 
Subject Re-Screening 
Re-screening will be allowed for a subject who has discontinued the study as eligible-but-
not-required (i.e. reserves) or could not be dosed within the permitted screening window 
for any reason, or as a pre-treatment failure (i.e., subject has not been treated); the reason 
for failure must be temporary and expected to resolve. If re-screened, the subject must 
be re-consented. 
Re-screened subjects should be assigned a new screening number at the time of re-
consent. 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           61 
6. 
Investigational Medicinal Products 
ZP-059 inhaled voriconazole is manufactured according to Good Manufacturing Practices 
(GMPs) by MICRO-SPHERE S.A. CH – 6998 Monteggio, packaged and QP released by 
STM PHARMA PRO srl Italy. 
ZP-059 inhaled voriconazole contains Voriconazole as active pharmaceutical ingredient.   
The 
chemical 
name 
for 
Voriconazole 
is: 
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-
fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol. 
ZP-059 
inhaled 
voriconazole 
is 
provided 
in 
clear, 
colourless 
size 
3 
hydroxypropylmethylcellulose (HPMC) hard capsules. The hard capsules are individually 
and manually triggered by breath actuated inhalation device. The capsules are packaged 
in aluminium-aluminium blisters. 
The formulation strength is expressed as delivered dose; the strength, expressed as 
metered dose on unit basis, is voriconazole 5.74 mg inhalation powder.  
The composition of the formulation ZP-059 inhaled voriconazole and the amount of 
ingredients on a unit basis, the function of the components as well as the reference to 
their quality standard is presented in Table  
Table 2  Composition of ZP-059 (inhaled voriconazole capsule) 
Components 
Amount 
mg/capsule % w/w 
Function 
Quality 
Standard* 
Voriconazole 
Corresponding to 
mg/inhalation 
5.74 
5.0 
70.00 
Active Substance 
 
Ph. Eur. 
L-Leucine 
2.378 
29.00 
Disaggregation 
agent 
Ph. Eur. 
Polysorbate 80 
0.082 
1.00 
Dissolution agent 
Ph. Eur. 
Purified Water (1) 
q.s. 
- 
Solvent-process 
agent 
Ph. Eur. 
Ethanol, anhydrous (2) 
q.s. 
- 
Solvent-process 
agent 
Ph. Eur. 
HPMC (3) hard capsules 
size 3  
(1) 
 
Powder container 
In-house 
Total powder weight per 
capsule 
8.20 
100.00 
 
 
1 Removed during processing 
2 Removed during processing 
3 HPMC = hydroxypropyl methylcellulose 
q.s.= quantum satis 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           62 
* current Edition of Ph. Eur. is endorsed 
Polysorbate 80 is a common excipient for inhalation products as its use is widely accepted 
inside liquid and pressurised formulations and it has been incorporated into the 
formulation to allow for rapid dissolution and dispersion of the active component. 
L-leucine is a naturally occurring amino-acid whose purpose in the formulation is to 
facilitate the deagglomeration of the particles during the inhalation. 
In Part 3, VFEND® oral film-coated 200 mg tablet, a currently marketed oral voriconazole 
formulation, will be administered. The dose of VFEND® will be a single dose of 200 mg, 
which is the recommended dose of the marketed product.  
Provision of the ZP-059 5 mg capsules (nominal voriconazole dose strength 5 mg) and 
DPIs will be the responsibility of Zambon. VFEND® 200mg tablets, will be sourced from 
the UK and labelled for clinical use by MEU.  
Test IMP: Dry powder for oral inhalation with a formulation comprising voriconazole as 
the active ingredient; Edry-Voriconazole 5 mg capsule ZP-059 
Reference IMP (Part 3): VFEND® oral film-coated tablet (200 mg); a currently marketed 
oral voriconazole formulation by Pfizer Limited, UK. 
 
Dry Powder Inhaler for administration of voriconazole capsules: RS01 inhaler (RS01 
Monodose inhaler, product code 239700004AA) 
 
The DPI used for inhalation of voriconazole capsules is the RS01 inhaler (RS01 
Monodose inhaler, Model 7 high-resistance, product code 239700004AA), manufactured 
by Plastiape, S.p.A. This device is CE-marked for use in the European Union. The RS01 
is a passive DPI, utilising the subject’s inhalation flow to disperse and deliver the drug 
formulation. The DPI is a reloadable, single capsule device that uses pre-metered, size 3 
HPMC capsules. The DPI will be manufactured and supplied according to Good 
Manufacturing Practices (GMP) for use in the clinical trial. 
 
Details of the IMPs to be used in each study part are provided in Table 3. 
 
All IMPs will be reconciled and destroyed upon approval by the sponsor in accordance 
with site’s SOPs. 
6.1. 
Administration of Investigational Products 
Specific details of IMPs and doses to be administered are provided in Table 2 below. For 
all study parts, subjects will be dosed on each study period/dosing day, as applicable. 


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The exact time of dosing will be decided based on logistics and will be documented in the 
source records. 
 
Subjects in Part 1 will receive a total of 1 administration of ZP-059 on one occasion. 
Subjects in Part 2 will receive a total of 10 administrations of ZP-059 on 10 separate 
occasions (based on the dosing frequency of q.d.) or in the event of BID dosing they will 
receive a total of 19 doses. Subjects in Part 3 will receive a total of 1 administration of 
ZP-059 on one occasion and a total of 1 administration of oral voriconazole (VFEND®) 
on one occasion. 
 
Detailed instructions for dose administration will be provided in a pharmacy manual. The 
start and end time of dosing (i.e. first and last capsule dose times) will be recorded in the 
source data. For the purposes of PK sampling and post-dose procedures, the time of 
inhalation of the first capsule will be the dose time and thus time ‘0’. 
 
For Part 3, the subjects will be required to swallow the VFEND® tablet whole with some 
water.  
 
Table 3 Investigational Medicinal Products 


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Study 
Part 
Cohort 
IMP 
Dose and Route of Administration 
1 
SAD 1  
ZP-059 
5 mg (1 x 5 mg capsule) ZP-059 a     
Administered via DPI on Day 1 
SAD 2 
ZP-059 
ZP-059 (Dose TBD)   
Administered via DPI on Day 1 
SAD 3 
ZP-059 
ZP-059 (Dose TBD)   
 Administered via DPI on Day 1 
SAD 4 
ZP-059 
ZP-059 (Dose TBD)      
 Administered via DPI on Day 1 
2 
MAD 1 
ZP-059 
ZP-059 (Dose TBD) 
Administered via DPI once daily on Days 1 to 10 or 
twice daily on Days 1 to 9 and once on Day 10 
MAD 2 
 ZP-059 
ZP-059 (Dose TBD) 
Administered via DPI once daily on Days 1 to 10 or 
twice daily on Days 1 to 9 and once on Day 10 
MAD 3 
 ZP-059 
ZP-059 (Dose TBD) 
Administered via DPI once daily on Days 1 to 10 or 
twice daily on Days 1 to 9 and once on Day 10 
Study 
Part 
Treatment 
Period 
IMP 
Dose and Route of Administration 
3 
1 or 2 
 ZP-059 
ZP-059 (Dose TBD) 
Administered via DPI on Day 1 of  
Period 1 or Period 2 
Voriconazole 
(VFEND®) oral 
film-coated tablet  
200 mg Voriconazole (VFEND® - oral film-coated 
tablet) on Day 1 of Period 1 or Period 2 
a Fixed starting dose  
DPI; dry powder inhaler 
TBD; to be determined 
Each capsule delivers 5 mg of voriconazole 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all IMPs received and any discrepancies 
are reported and resolved before use of the IMP. 
2. Only subjects who meet eligibility criteria for the study may receive study IMP and 
only authorised site staff may supply or administer IMP. All IMP must be stored in 


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a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the 
investigator and authorised site staff. 
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for IMP accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of used and unused study 
IMP are provided in the Pharmacy Manual. 
 
6.3. 
Measures to Minimize Bias: Randomisation and Blinding 
6.3.1. 
Randomisation 
Parts 1 and 2 are an open-label, non-randomised design, therefore a randomisation 
schedule will not be produced. 
 
Part 3 is a randomised, open-label design; therefore, a randomisation schedule will be 
produced. 
 
The original randomisation schedule for Part 3 and proof of quality control procedures will 
be held by SQN Clinical until the study is archived, at which time the randomisation 
materials will be retained in the Investigator Site File (ISF). Subjects will be randomised 
immediately before administration of the first dose. 
6.3.2. 
Subject Numbers 
In Part 1, subject numbers will be allocated on the morning of dosing according to the 
code 101 to 130 using the lowest number available. In case of subject replacement, the 
subject will be assigned a number from 101R to 130R with the same first three digits as 
the original subjects. In case of a second replacement, the replacement subject will be 
assigned a number from 101S to 130S. In case of third replacement, the replacement 
subject will be assigned a number from 101T to 130T. 
 
In Part 2, subject numbers will be allocated on the morning of dosing on Day 1 according 
to the code 201 to 230 using the lowest number available. In case of subject replacement, 
the subject will be assigned a number from 201R to 230R with the same first three digits 
as the original subjects. In case of a second replacement, the replacement subject will be 
assigned a number from 201S to 230S. In case of third replacement, the replacement 
subject will be assigned a number from 201T to 230T. 
 
In Part 3, subject numbers will be allocated on the morning of dosing during Period 1 
according to the code 301 to 316 using the lowest number available. In case of subject 
replacement, the subject will be assigned a number from 301R to 316R with the same 
first three digits as the original subjects. In case of a second replacement, the 


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replacement subject will be assigned a number from 301S to 316S. In case of third 
replacement, the replacement subject will be assigned a number from 301T to 316T. 
6.3.3. 
Blinding 
This is an open-label study and therefore blinding is not required. 
 
6.4. 
Investigational Product Compliance 
During all clinical phases of the study, subjects will be observed by study staff to assure 
compliance to all study procedures, including dose administration. 
 
For Part 3, mouth and dosing vessel checks will be conducted after dose administration 
of oral voriconazole to ensure the tablet has been swallowed. 
 
For all study parts, the date and time that each subject is dosed will be recorded in the 
subject’s source record. Any violation of compliance will require evaluation by the 
investigator and sponsor to determine if the subject can continue in the study. 
 
6.5. 
Concomitant Therapy 
6.5.1. 
Prior and Concomitant Medications 
Any medications used will be recorded in the source records. Any prior medications taken 
within 28 days prior to screening and all concomitant medications will be recorded in the 
eCRF. 
 
6.5.2. 
Permitted Concomitant Medications for Part 1 (SAD) 
 
No medication will be permitted from 14 days before IMP administration until the follow-
up visit except hormonal contraceptives, hormone replacement therapy (HRT), ≤4 g per 
day paracetamol and those deemed necessary by the investigator to treat AEs. 
Exceptions may apply on a case by case basis, if considered not to interfere with the 
objectives of the study (and are not a prohibited medication), as agreed by the Principal 
Investigator and sponsor’s medical monitor. 
 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the event that they are required, their use will be documented. 
 


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6.5.3. 
Permitted Concomitant Medications for Part 2 (MAD) and Part 3 
Crossover) 
During Part 2 and Part 3 of the study subjects will be permitted to take the following 
medications in addition to IMP during the study. 
 
6.5.3.1. 
Part 2 and Part 3 
• Inhaled corticosteroids (ICS) e.g. beclometasone, budesonide, only if the dose is 
stable from at least 4 weeks prior to screening. On study dosing days, the morning 
dose should be taken prior to pre-dose spirometry. Evening doses should be taken 
as logistics allow. 
• Short-acting beta-agonists (SABA; e.g. salbutamol, terbutaline). At screening, 
SABA should be withheld for at least 6 hours prior to pre-bronchodilator spirometry. 
On study dosing days, SABA should be used as required per subject’s symptoms 
and as required by site-specific SOPs for sputum induction. 
• Paracetamol (≤4 g per day). 
• Hormonal contraception.  
• Hormone replacement therapy (HRT). 
• Any medication taken at a stable dose for at least 4 weeks prior to IMP 
administration that is not specifically prohibited by Section 6.5.4. and is not 
believed to interfere with the study assessments is acceptable e.g. stable 
thyroxine, antihypertensives, metformin etc.  
• Medication deemed necessary by the investigator to treat AEs. 
 
6.5.3.2. 
Part 3 
• Long-acting beta-agonists (LABA) e.g. formoterol, salmeterol. At screening, LABA 
should be with-held for at least 12 hours prior to pre-bronchodilator spirometry. On 
study dosing days, the morning dose should be taken prior to pre-dose spirometry. 
Evening doses should be taken as logistics allow. 
• Ultra-long acting beta-agonist e.g. indacaterol. At screening, ultra-long LABA 
should be with-held for at least 24 hours prior to pre-bronchodilator spirometry. On 
study dosing days, the morning dose should be taken prior to pre-dose spirometry. 
Evening doses should be taken as logistics allow. 
• ICS/LABA combination products (e.g. fluticasone + salmeterol, budesonide + 
formoterol), only if the dose has been stable from at least 4 weeks prior to 
screening. At screening ICS/LABA should be withheld for at least 12 hours prior to 
pre-bronchodilator spirometry. On study dosing days, the morning dose should be 
taken prior to pre-dose spirometry. Evening doses should be taken as logistics 
allow. 


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• ICS/ultra-long acting beta-agonist e.g. fluticasone + vilanterol. At screening 
ICS/ultra-long acting beta- agonist should be withheld for 24 hours prior to pre-
bronchodilator spirometry. On study dosing days, the morning dose should be 
taken prior to pre-dose spirometry. Evening doses should be taken as logistics 
allow. 
If a required inhaled medication with-hold has not been met at the screening visit, the visit 
and/or spirometry assessment may be rescheduled at the discretion of the investigator. 
 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the event that they are required, their use will be documented. 
 
6.5.4. 
Prohibited Concomitant Medications 
Parts 1, 2 and 3 
• Voriconazole is prohibited for 3 months prior to first IMP administration and 
throughout the study. 
• Specific enzyme inducers of CYP3A4 and CYP2C19 are prohibited for 28 days 
prior to first IMP administration until 14 days after last IMP administration. 
• Specific enzyme inhibitors, substrates of CYP3A4 and CYP2C19 are prohibited for 
14 days (or 5 half-lives, whichever is longer) prior to first IMP administration until 
14 days (or 5 half-lives, whichever is longer) after last IMP administration.    
• Any systemic treatment for infection is prohibited in the 28 days prior to first IMP 
administration e.g. amoxicillin, aciclovir. 
• Live and killed/inactive vaccines are prohibited in the 14 days prior to first IMP 
administration and throughout the study. 
• Medications that are known to prolong QTc interval in the 14 days (or 5 half-lives, 
whichever is longer) prior to first IMP administration and throughout the study 
(Excluded medications are stated in the Study Reference Manual). 
• Long-acting muscarinic antagonists (LAMA) e.g. tiotropium for at least 28 days 
prior to first IMP administration. 
• Short-acting muscarinic antagonists (SAMA); e.g. ipratropium for at least 12 hours 
prior to screening pre-bronchodilator spirometry and throughout the study. 
• Oral corticosteroids for at least 28 days prior to first IMP administration. 
• Omalizumab for at least 28 days prior to first IMP administration. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
 


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6.6. 
Criteria for Dose Escalation 
Dose escalation decisions will be made by the SAC, which will always comprise as a 
minimum the Principal Investigator (or delegate) and the sponsor’s medical monitor. 
Additional data available at the time of each scheduled meeting may also be reviewed. 
For all dose escalation decisions, the critical data will be safety data. The criteria to be 
followed by the SAC are detailed in Section 6.6.4. 
 
Data will be provided to the SAC in accordance with the site’s SOP on dose 
escalation/continuation in clinical trials. The decisions will be documented and signed by 
the Principal Investigator (or delegate) per the current SOP. Evidence of the decision will 
be retained in the ISF and Trial Master File maintained by MEU.  
 
Dose escalation/dose decision procedures for each study part are described below. 
  
6.6.1. 
Part 1 (SAD) 
Dose escalation decisions will be made at an interim data review after dose administration 
for each cohort. Progression to the next dose group will be permitted after review of safety 
data suggests that it is safe to do so. 
  
For dose escalation to proceed, data must be available from a minimum of 4 dosed 
subjects who have completed the planned safety assessments up to a minimum of 24 
hours after dosing. The decision to proceed will only be made if all parties agree and if it 
is clear from the safety data that it is appropriate to proceed with the next cohort. If data 
in fewer than 6 subjects are considered acceptable to proceed, additional subjects will 
not be dosed to increase the number of subjects in the completed cohort for dose 
escalation purposes. 
 
Based on the observed data, it may be necessary or desirable to administer a previously 
administered dose, a reduced dose or a dose level higher than planned in order to 
determine the safe starting dose for Part 2 of the study. An additional cohort of 6 subjects 
may be enrolled to assess this. Single doses will not exceed 40 mg of ZP-059 based on 
safety margins calculated following non-clinical studies.  
 
6.6.2. 
Part 2 (MAD) 
Dose administration in Part 2 may only commence after completion of SAD cohort 2 in 
Part 1 and review of safety data up to a minimum of 24 hours post-dose. 
 
The decision to proceed with Part 2 and dose escalation decisions between MAD cohorts 
will be made at an interim data review after dose administration in each cohort. 


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Progression to the next dose group will be permitted after review of safety data suggests 
that it is safe to do so. 
 
The starting dose for Part 2 MAD will be confirmed during an interim review of safety data 
from the completed SAD cohorts. The dose to be administered in MAD cohort 2 will be 
based on emerging data and will not exceed the highest dose investigated in the SAD 
cohorts. 
 
For dose escalation to proceed in MAD cohort 2, data must be available from a minimum 
of 4 dosed subjects from MAD cohort 1 (defined in Section 4.1.2) who have completed 
the planned safety assessments up to a minimum of 24 hours after dosing on Day 10 and 
up to a minimum of 24 hours post-dose from SAD cohort 3. For dose escalation to 
proceed in MAD cohort 3, data must be available from a minimum of 4 dosed subjects 
from MAD cohort 2 (defined in Section 4.1.2) who have completed the planned safety 
assessments up to a minimum of 24 hours after dosing on Day 10 and up to a minimum 
of 24 hours post-dose from SAD cohort 4.  
 
The decision to proceed will only be made if all parties agree and if it is clear from the 
safety data that it is appropriate to proceed with the next cohort. If data in fewer than 6 
subjects are considered acceptable to proceed, additional subjects will not be dosed to 
increase the number of subjects in the completed cohort for dose escalation purposes. 
 
6.6.3. 
Part 1 (SAD) to Part 3 
The oral dose of voriconazole to be administered in Part 3 is 200 mg. 
   
The inhaled ZP-059 dose to be administered in Part 3 will be confirmed after completion 
of SAD cohorts 1 to 4. Hence, dosing of Part 3 may occur prior to/in parallel with dosing 
in Part 2.  
 
The dose decision will be made at an interim review of available safety data from Part 1 
SAD cohorts (see Section 6.6.1). For dose administration to proceed, data must be 
available from a minimum of 4 dosed subjects in each of SAD cohorts 1, 2, 3 and 4 who 
have completed the planned safety assessments up to a minimum of 24 hours after 
dosing. The decision to proceed will only be made if all parties agree and if it is clear from 
the safety data that it is appropriate to proceed. 
 
6.6.4. 
Criteria for Safety Advisory Committee 
Dose levels for each cohort (Parts 1 and 2) and Part 3 will be decided during the SAC 
meetings. 
 


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The SAC may also agree for additional subjects to be included for an intermediate dose 
level if warranted or may agree to reduce or increase (see Section 4.3) the dose. Any 
decision to investigate an intermediate or reduced dose level will be fully documented. 
 
The decision to proceed to the next higher dose level will be based on safety and 
tolerability data. The following data (minimum of 24 hours post-dose) are required for 
dose escalation decisions: 
 
• Adverse events 
• Vital signs (including systolic and diastolic blood pressure, pulse rate, respiratory 
rate and pulse oximetry) 
• Safety laboratory (including clinical chemistry, haematology and urinalysis) 
• ECG 
• Physical examinations 
• Spirometry assessments (including FEV1, forced vital capacity [FVC], peak 
expiratory flow rate [PEFR] and FEV1/FVC) 
 
If, following review by the SAC it is deemed acceptable to continue dose escalation above 
the maximum dose described in this protocol (40 mg ZP-059), a substantial amendment 
with relevant data will be submitted for approval to the regulatory authorities and ethics 
committee (EC). 
 
Dose escalation will not occur if:  
• One or more subjects in a cohort experiences a serious adverse event (SAE) 
related to IMP. 
or 
• Two or more subjects in a cohort experiences severe non-serious AEs related to 
IMP. 
 
6.6.5. Stopping Criteria 
6.6.5.1. 
Part 1, Part 2 and Part 3 
All parts of the study will be halted, if any of the following criteria are met:   
• The occurrence of an SAE considered related to the IMP administration in 1 
subject. 
• The occurrence of severe, non-serious AEs considered related to the IMP 
administration in 2 subjects at the same dose level (Part 1 and Part 2). 


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• The occurrence of severe, non-serious AEs considered related to the IMP 
administration in 2 subjects receiving the same treatment (i.e. 2 subjects 
receiving ZP-059 or 2 subjects receiving oral voriconazole) in Part 3. 
 
Relatedness will be determined by the investigator (see Section 10.3.3). If the study is 
halted, a temporary halt will be submitted to the Medicines and Healthcare products 
Regulatory Agency (MHRA) and EC in the form of a substantial amendment. The study 
will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC. 
 
 


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7. 
Discontinuation of Investigational Medicinal Product and 
Subject Discontinuation/Withdrawal 
7.1. 
Discontinuation of Investigational Medicinal Product 
Subjects will be withdrawn from IMP for the following reasons: 
• Subjects will be withdrawn from IMP if they exhibit a SAE and/or any AEs that in 
the opinion of the PI may jeopardise their safety.  
• QTcF interval of >500 msec or increase in QTcF interval of >60 msec from 
baseline. 
For the purpose of QTcF withdrawal criteria, baseline will be considered as the 
mean pre-dose Day 1 measurement for Parts 1 and 2, and the mean pre-dose Day 
1 measurement of each treatment period for Part 3 (i.e. baseline for Period 1 is 
pre-dose on Day 1 Period 1; baseline for Period 2 is pre-dose on Day 1 Period 2). 
The withdrawal criterion will be assessed against the mean QTcF of triplicate 
ECGs and confirmed by a repeat triplicate ECG. ECGs will be performed within a 
time window of 5 minutes, with minimum of 1 minute between subsequent ECGs 
• Increase of total bilirubin greater than or equal to 3x the upper level of normal 
• Increase of liver enzyme (AST, ALT) value greater than or equal to 3x the upper 
level of normal. Asymptomatic subjects with a liver enzyme [AST, ALT] greater 
than or equal to 2x the upper level of normal but less than or equal to 3x the upper 
level of normal will be retested, as required. 
• Pregnancy of a female subject or female partner of a male subject 
• Upon the subject’s request (withdrawal of consent) 
• Significant deviation from the protocol that is considered, in the opinion of the 
investigator or sponsor, to jeopardise the subject’s safety  
• Requirement for prohibited medication  
• At the discretion of the investigator  
• Termination of the study for any reason by the sponsor. 
• Parts 1 only: Any drug-induced bronchoconstriction requiring treatment  
• Part 2 and 3 only: Exacerbation of asthma requiring systemic treatment 
 
For a subject who withdraws or is withdrawn every effort will be made to ensure the 
subject completes early discontinuation procedures (if applicable) as soon as possible 
after discontinuation and as detailed in the study schedule of activities (SOA) in Section 
1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). A safety follow-up call will 
also be performed, if possible, if the early discontinuation visit has been performed prior 
to the scheduled follow up period. 


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7.2. 
Subject Replacement 
Subjects who withdraw or are withdrawn from the study may be replaced at the discretion 
of the Sponsor. 
7.3. 
Subject Discontinuation/Withdrawal from the Study 
 
• A subject may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, early discontinuation 
procedures (if applicable) as detailed in the study schedule of activities (SOA) in 
Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3) should be 
performed as soon as possible after discontinuation. A safety follow-up call will 
also be performed, if possible, if the early discontinuation visit has been performed 
prior to the scheduled follow up period. 
• The subject will be permanently discontinued both from the study medication and 
from the study at that time. 
• If the subject withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a subject withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
 
7.4. 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 
• 
Before a subject is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 
telephone calls and, if necessary, a certified letter to the subject’s last known 


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mailing address or local equivalent methods). These contact attempts should be 
documented in the subject’s source data records. 
• 
Should the subject continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of the study are handled as part of Appendix 1. 


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8. 
Study Assessments and Procedures 
Study procedures will be performed as detailed in the study schedule of activities (SOA) 
in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3), and in 
accordance with site SOPs unless otherwise stated in this protocol. 
 
8.1. 
Screening 
Within the 28 days preceding first dose, all subjects will be required to undergo a 
screening visit. Screening procedures will be carried out in accordance with the SoA in 
Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). 
Screening procedures may be performed over more than 1 day. Repeats of study 
procedures are permitted on the day and/or on another day during screening at the 
discretion of the investigator(s). 
For Part 2 subjects who completed the initial Screening Visit will attend the Clinic on Day 
-4 or Day -3, for a SARS-COV-2 RT-PCR test. This may be performed on the same day 
as screening if screening is performed within 3 or 4 days of dosing. 
For Part 3 subjects will undergo a SARS-COV-2 RT-PCR test prior to sputum induction 
at screening. SARS-COV-2 RT-PCR test must be performed within 14 days of Day 1, 
Period 1. If this interval is exceeded, sampling must be repeated. 
 
8.2. 
Admission and Pre-dose Procedures 
For all study parts, the subjects will be admitted to the clinic on the evening of Day -1 and 
the ongoing eligibility of subjects will be re-assessed at admission/pre-dose (as 
applicable), as described in Sections 5.1  to  5.3. 
 
8.3. 
Device Training 
For Parts 1, 2 and the relevant treatment period in Part 3, subjects will undergo inhalation 
training in order to ensure optimal dosing. The subjects will undergo device training to 
achieve a steady, slow and deep inhalation. Device training will be performed using an 
empty RS01 inhaler. Training at screening will be for demonstration purposes only. Full 
details of inhalation training are given in the pharmacy manual. 
The admission and pre-dose procedures for Parts 1, 2 and 3 are presented in Section 
1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3) respectively. 
 
8.4. 
Blood Volume 
The total blood volume for each subject will not exceed 400 mL in a 4-week period. 


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At least the first 1 mL of blood withdrawn via cannula will be discarded; this will be based 
on local SOPs. 
 
8.5. 
Timing of Procedures 
Permitted windows for all relevant procedures and dosing will be provided in the Study 
Reference Manual. Where the protocol requires more than one procedure to be 
completed at the same time point, all efforts will be made to obtain the PK samples at the 
exact nominal time relative to dosing. Any other procedures scheduled at the same time 
point will be performed either before or after the PK, as appropriate. 
ECGs should be taken prior to vital signs when both measurements are scheduled at the 
same time point. Other assessments e.g. spirometry, physical examinations, etc. will be 
performed within the required time windows. Assessments taken in a different order for 
logistical reasons will not be considered protocol deviations provided that the required 
rest times have been respected for ECGs and vital signs. 
All safety assessments will be timed and performed relative to the start of dosing (defined 
as time of first capsule inhalation). 
 
8.6. 
Discharge from the Clinical Unit 
A subject will be allowed to leave the clinical unit following completion of the 24-hour post-
dose study-specific procedures (Day 2 in Part 1, Day 6 in Part 3) and at 24 hours after 
dosing on Day 4 (Part 2) and providing there are no safety concerns. 
 
8.7. 
Return Visits 
Part 1:  
Subjects will be required to return to the clinical unit on Day 5 for completion of safety 
evaluations (see Section 1.2.1).  
 
Part 2: 
Subjects will be required to return to the clinical unit daily from Day 5 through to Day 9 for 
pre-dose study procedures and to receive their scheduled dose (Hour 0) of study 
medication. On Day 7 the visit will also include induced sputum sampling pre-dose and 
post-dose. The subject will be discharged after dosing or sputum sampling as applicable, 
providing there are no safety concerns. In the event of BID dosing; on Days 4 to 9 the 
subjects will be required to attend the unit for the evening dose (i.e. return in the evening 
on Day 4 and attend twice daily on Days 5 to 9) and will be discharged after dosing, 
providing there are no safety concerns. The subjects will then return to the clinical unit on 
the morning of Day 10 where they will then remain resident overnight until Day 11 (24 


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hours after the last dose). After completion of safety assessments, they will be discharged 
providing there are no safety concerns. 
 
Subjects will be required to return to the clinical unit on Day 14 and Day 17 for collection 
of PK samples (Day 14 only) and completion of safety evaluations (see Section 1.2.2 
(Part 2)). 
 
Part 3: 
Subjects will be required to return to the clinical unit on Day 7 (48 hours post treatment 
period 2 dose) and Day 9 (96 hours post treatment period 2 dose) for collection of PK 
blood samples, induced sputum samples (Day 7 only), and completion of safety 
evaluations (see Section 1.2.3).  
 
For all study parts; permitted windows for all relevant procedures (including dosing when 
appropriate) will be provided in the Study Reference Manual. 
 
 
8.8. 
Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available 
at all times during the study. In accordance with the current Association of the British 
Pharmaceutical Industry guidelines [22], each subject will receive a card stating the 
telephone number of the investigator. 
 
8.9. 
Follow-up 
A safety follow-up telephone call will take place in accordance with the SoA in Section 
1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3) to all subjects after their 
last dose to ensure their ongoing wellbeing. In the event of early discontinuation, the 
telephone call will not be required if the early discontinuation visit is performed within the 
scheduled follow up period.  
If a subject reports any AEs that may present a cause for concern, they will be required 
to attend the clinic for a further follow-up assessment (as an unscheduled visit).  
 
8.10. 
Efficacy Assessments 
Not applicable for this Phase I study.  
 


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8.11. 
Safety Assessments 
8.11.1. 
Physical Examinations 
Subjects will undergo a physical examination at screening as detailed in Section 1.2.1 
(Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). 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. 
 
8.11.2. 
Vital Signs 
Blood pressure, pulse rate and respiratory rate will be measured after the subject has 
been in a supine position for a minimum of 5 minutes according to the schedule of 
activities presented in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 
(Part 3). Repeat tests are permitted on the day and/or on another day (as appropriate) at 
the discretion of the investigator. Blood pressure and pulse rate will be measured by 
automated equipment. Temperature will be measured according to the schedule of 
activities presented in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 
(Part 3). 
 
8.11.3. 
Body, Weight and Height 
The subject’s body weight and height will be recorded as detailed in Section 1.2.1 (Part 
1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). Measurements will be taken in normal 
indoor clothing with shoes removed. 
 
8.11.4. 
Pulse Oximetry 
Oxygen saturation via pulse oximetry will be measured as detailed in Section 1.2.1 (Part 
1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). 
 
8.11.5. 
Electrocardiograms 
Scheduled 12-lead ECGs will be measured in triplicate after the subject has been in the 
supine position for a minimum of 5 minutes according to the schedule of activities 
presented in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). 
Repeats are permitted on the day and/or on another day (as appropriate) at the discretion 
of the investigator. ECGs will be performed within a time window of 5 minutes, with 


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minimum of 1 minute between subsequent ECGs. Mean triplicate ECGs will be used for 
the purpose of summary statistics (see Section 7.1 for definition of baseline for each study 
part). 
 
For assessment of time windows, the time of the first ECG of the triplicate will be used. 
8.11.6. 
Pulmonary Function Tests 
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) 
• forced vital capacity (FVC) 
• peak expiratory flow rate (PEFR) 
• FEV1/FVC 
 
The tests will be performed according to the schedule of activities presented in Section 
1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). Predicted values will be 
calculated according to GLI-2012 Quanjer [25] and adjusted for age, gender and race. 
Throughout the study, 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 manoeuvre commencing within 15 
to 30 minutes of salbutamol administration.  
 
8.11.7. 
Sputum Induction (Part 2 and Part 3 only) 
Sputum induction will be performed according to the schedule of activities presented in 
Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3) and in accordance with European 
Respiratory Society guidelines [23] and site-specific SOPs. The start time of the sputum 
induction will be recorded as the first inhalation of saline. 
 
 
8.11.8. 
Procedures In case of Bronchospasm 
For all parts of the study, salbutamol via metered dose inhaler plus spacer and nebuliser, 
and oxygen will be immediately available if required for the treatment of bronchospasm/ 
bronchoconstriction. 
 


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8.11.9. 
Part 1 (Healthy Subjects) 
Any subject requiring treatment for bronchoconstriction will have their FEV1 monitored 
frequently until their FEV1 has returned to within 90% of their baseline value or to a level 
considered acceptable by the investigator. 
 
8.11.10. 
Part 2 and Part 3 (Asthmatic Subjects) 
Any subject requiring treatment for bronchoconstriction will have their FEV1 monitored 
frequently until their FEV1 has returned to within 90% of their baseline value or to a level 
considered acceptable by the investigator. 
 
Any subject who does not respond adequately as per the investigator’s judgment to 
treatment with bronchodilators will be withdrawn from the IMP and from further sputum 
induction attempts. Site SOPs will be followed at all times. 
 
8.11.11. 
Additional Safety Procedures 
Additional non-invasive procedures that are already specified in the protocol may be 
performed, if it is believed that an important effect of the IMP(s) is occurring or may occur 
at a time when no measurements are scheduled, or if extra procedures are needed in the 
interests of safety. 
 
Additional blood samples for safety assessments may be taken if required by the 
investigator at any point. 
 
8.11.12. 
Clinical Safety Laboratory Assessments 
Available blood and urine sample results will be reviewed by a physician before the 
subject is dosed or receives their next dose, or is released from the study, as is 
appropriate. 
 
A list of the laboratory parameters measured is presented in Appendix 2. 
 
8.11.12.1. Haematology and Clinical Chemistry 
Laboratory tests will be performed by the site’s local laboratory according to the schedule 
of activities presented in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 
(Part 3). Repeats are permitted on the day and/or on another day at the discretion of the 
investigator. 
 
Site standard collection and processing procedures for blood samples will be adhered to 
throughout the study. Scheduled blood samples for clinical chemistry will be taken 
following at least an 8 hour fast (water is permitted). 


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8.11.12.2. SARS-CoV-2 
SARS-CoV-2 testing will be performed by the site’s local laboratory according to the 
schedule of activities presented in Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). Site 
standard collection and processing procedures for samples will be adhered to 
throughout the study. 
8.11.12.3. Urinalysis 
Urinalysis will be performed by the site’s local laboratory according to site-specific SOPs 
according to the schedule of activities presented in Section 1.2.1 (Part 1), Section 1.2.2 
(Part 2) and Section 1.2.3 (Part 3). Repeats are permitted on the day and/or on another 
day at the discretion of the investigator. Site standard collection and processing 
procedures for urine samples will be adhered to throughout the study. 
 
8.11.12.4. Pregnancy Test 
Pregnancy tests (serum test at screening [performed by site’s local laboratory], on-site 
urine dipstick testing at all other time points will be performed for all female subjects, as 
detailed in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). 
Repeats are permitted on the day and/or on another day at the discretion of the 
investigator. Site standard collection and processing procedures for samples will be 
adhered to throughout the study. 
 
8.11.12.5. Follicle-Stimulating Hormone Test 
Serum FSH tests may be performed by the site’s local laboratory for post-menopausal 
female subjects at the discretion of the Investigator to confirm post-menopausal status at 
screening. Site standard collection and processing procedures for blood samples will be 
adhered to throughout the study. 
 
8.11.12.6. Drug Screen and Urine Cotinine 
A urine drug screen, including urine cotinine, will be performed on-site using a dipstick 
method according to the schedule of activities presented in Section 1.2.1 (Part 1), Section 
1.2.2 (Part 2) and Section 1.2.3 (Part 3). Repeats are permitted on the day and/or on 
another day at the discretion of the investigator. Site standard collection and processing 
procedures for urine samples will be adhered to throughout the study. Subjects will be 
screened for the drugs of abuse listed in Appendix 2. 
 
8.11.12.7. Alcohol Breath Test 
An alcohol breath test will be performed according to the schedule of activities presented 
in Section 1.2.1 (Part 1), Section 1.2.2 (Part 2) and Section 1.2.3 (Part 3). Repeats are 
permitted on the day and/or on another day at the discretion of the investigator. A 
confirmed positive result will exclude the subject from screening or dosing during 
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8.11.12.8. Abnormal Laboratory Findings 
In cases where laboratory findings are outside the normal range and the investigator 
believes that the results may be of clinical significance, repeat sampling may be 
requested as clinically indicated. If the abnormal finding is clinically significant, 
appropriate actions will be taken e.g. the subject will not be entered into the study or the 
subject may be withdrawn from the study. The subject will be referred to their GP or other 
appropriate provider for further care. The same will apply if the results of the HBsAg, HCV 
Ab or HIV test are positive and in addition the investigator will ensure that adequate 
counselling is available if requested. 
 
Abnormal results at follow-up assessments will also require repeat testing if the 
investigator believes the results may be of clinical significance. 
 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
 
Additional blood and/or urine samples may be taken for safety tests. Furthermore, 
additional assays outside those specified in the protocol may be performed for safety 
reasons as requested by the investigator. 
 
8.12. 
Adverse Events and Serious Adverse Events 
The definition of an AE or SAE can be found in Appendix 3. 
 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study IMP/s, DPI (RS01) or 
study procedures, or that caused the participant to discontinue IMP (see Section 7.1). 
8.12.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) 
until the follow-up phone call (Section 1.2). 
 
All SAEs will be recorded and reported to the sponsor’s Drug Safety Unit and Medical 
Monitor immediately and under no circumstance should this exceed 24 hours, as 
indicated in Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
 


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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event 
to be reasonably related to the study IMP/s or study participation, the investigator must 
promptly notify the sponsor. 
8.12.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.12.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and AESIs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the subject is lost to follow-up (as 
defined in Section 7.4). Further information on follow-up procedures is provided in 
Appendix 3. 
 
8.12.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and 
the safety of the IMP under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of the IMP under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Independent 
Ethics Committees (IEC), and investigators. 
• 
For all studies, except those utilising medical devices, investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g. summary or listing of SUSARs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and will 
notify the IEC, if appropriate according to local requirements. 
 


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8.12.5. 
Pregnancy 
• 
Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after first dose of IMP and until 30 days after the last dose as 
outlined in Appendix 4. 
• 
If a pregnancy in a female subject or the partner of a male subject is reported, 
the investigator should inform the sponsor within 24 hours of learning of the 
pregnancy and should follow the procedures outlined in Appendix 3. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.12.6. 
Cardiovascular and Death Events 
Voriconazole has been associated with QTc interval prolongation. There have been rare 
cases of torsade de pointes in patients taking voriconazole, who also had risk factors 
such as cardiomyopathy. 
 
Voriconazole should be administered with caution to patients with predisposing cardiac 
related problems and also with concomitant therapy which is known to prolong QTc 
interval. Additionally, any patients taking medications that are known to prolong QTc 
interval will be excluded from the study. 
8.12.7. Adverse Events of Special Interest 
 
An AESI is an adverse event of scientific and medical interest specific to the 
understanding of the investigational product and may require close monitoring and 
collecting additional information by the investigator. An AESI may be serious or non-
serious. The rapid reporting of AESIs allows ongoing surveillance of these events in order 
to characterise and understand them in association with the use of this investigational 
product. 
 
Adverse events of special interest (AESIs) with onset after the dosing (Day 1) to end of 
the safety follow-up period will be recorded. 
 
The following adverse events of special interest (AESIs), that may occur and will be 
monitored during the study. 
 
1. Respiratory Events: 
Moderate or severe dyspnoea/wheeze,  


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Moderate or severe cough,  
Moderate or severe bronchospasm 
2. Moderate or severe visual impairment/hallucination 
3. Anaphylaxis and severe allergic reaction 
4. Hepatotoxicity ≥3XULN for AST, ALT and bilirubin. 
 
8.13. 
Treatment of Overdose 
There is no antidote for voriconazole. In the advent of an adverse reaction, supportive 
and symptomatic treatment is indicated relevant to the clinical scenario. In serious cases 
subjects should be hospitalised for observation and/or further intervention as necessary. 
 
8.14. 
Pharmacokinetics 
8.14.1. 
Pharmacokinetic Blood Sampling 
Venous blood samples will be withdrawn via an indwelling cannula or by venepuncture 
according to the schedule of activities presented in Section 1.2.1 (Part 1), Section 1.2.2 
(Part 2) and Section 1.2.3 (Part 3). 
 
Samples will be collected into appropriate tubes as specified by the bioanalytical 
laboratory. Site standard collection and processing procedures for blood samples will be 
adhered to throughout the study. 
 
Serum samples will be shipped to Alderley Analytical for the analysis of voriconazole, and 
N-oxide voriconazole. 
 
Samples will be analysed according to a validated method. Analytical methods are 
validated according to internationally accepted standards. The quality and integrity of the 
analytical work generated in this study will be evaluated in accordance with the study 
plan, validated method and SOPs of Alderley Analytical. 
 
8.14.2. 
Induced Sputum Sampling (Part 2 and Part 3 only) 
Induced sputum samples will be collected according to the time schedule presented in 
Section 1.2.2 and Section 1.2.3. 
 
Samples will be collected into appropriate containers, as specified by the bioanalytical 
laboratory. Site standard collection and processing procedures for samples will be 
adhered to throughout the study. 


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Sputum samples will be shipped to Alderley Analytical for the analysis of voriconazole. 
 
Samples will be analysed according to a validated method. Analytical methods are 
validated according to internationally accepted standards. The quality and integrity of the 
analytical work generated in this study will be evaluated in accordance with the study 
plan, validated method and SOPs of Alderley Analytical. 
 
8.15. 
Biomarkers 
Biomarkers are not evaluated in this study. 
 
8.16. 
Medical Resource Utilisation and Health Economics 
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study. 


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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
Since the sample sizes for each study part are not statistically powered, there will be no 
formal hypothesis testing. 
9.2. 
Sample Size Determination 
. 
Part 1 (SAD - Healthy subjects) and Part 2 (MAD – Mild, Stable Asthma Subjects): 
This study is not powered for any formal hypothesis test. The sample size of up to 
30 subjects (24 subjects plus an additional 6 subjects in 1 optional cohort) in Part 1 and 
up to 30 subjects (18 subjects plus additional 12 subjects in 2 optional cohorts) in Part 2 
was chosen to minimise exposure to IMP while allowing an adequate assessment of 
safety at each dose in order to support dose escalation and an adequate number of 
subjects to assess mean PK parameters. A minimum of 4 evaluable subjects will be 
required for each cohort for both dose escalation decisions and assessment of mean PK 
parameters. 
 
Part 3 (Mild to Moderate, Stable Asthma Subjects): 
This study is not powered for any formal hypothesis test. A sample size of up to 16 
subjects was chosen to minimise exposure to IMP while allowing an adequate 
assessment of safety, PK parameters and drug concentration in sputum. No 
replacements are foreseen. However, should the drop-out rate for non-safety reasons be 
high, which may compromise the reliability of the study results, additional subjects could 
be randomised. 
 
9.3. 
Populations for Analyses 
Safety Analysis Set (SAF) will consist of all subjects who receive at least one dose of 
IMP. Subjects will be analysed according to the treatment actually taken.   
The Pharmacokinetic (PK) Concentration Set will consist of those subjects in the SAF 
who have at least one serum PK concentration recorded. Subjects will be analysed 
according to the treatment actually taken. 
The PK Parameter Set will consist of those subjects in the SAF with sufficient 
concentration-time data to determine at least one serum PK parameter. Subjects will be 
analysed according to the treatment actually taken. 
The PK Sputum Concentration Set will consist of those subjects in the SAF who have 
at least one induced sputum PK concentration recorded. Subjects will be analysed 
according to the treatment actually taken. 


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9.4. 
Statistical Analyses 
This section describes the statistical methods that will be used to analyse the safety and 
PK parameters from study Parts 1, 2 and 3. 
9.4.1. General considerations 
For study parts 1 and 2, background and demographic characteristics and safety data will 
be summarised by ZP-059 dose and overall doses. PK data will be summarised by ZP-
059 dose only. 
For study part 3, background and demographic characteristics will be summarised by 
treatment sequence and overall. Safety and PK data will be summarised by treatment: 
Test (ZP-059) or Reference (oral voriconazole).  
Full details of the statistical analyses will be provided in a separate statistical analysis 
plan (SAP), which will be finalised before database lock.  
 
9.4.2. 
Background and Demographic Characteristics 
Disposition, demographic data and other baseline characteristics (e.g. race, age, gender, 
ethnicity, weight and height) including medical history and prior/concomitant medication 
will be summarised as appropriate. 
 
9.4.3. 
 Safety Analysis 
Adverse events (AEs) will be coded using the latest MedDRA dictionary version.   
Incidence of treatment emergent adverse events (TEAEs) and incidence of TEAEs by 
system organ class (SOC) and preferred term (PT) will be presented as appropriate, with 
full detail provided in in the SAP. 
Clinical laboratory, vital signs, ECG, pulmonary function and pulse oximetry parameters 
will be summarised as appropriate using summary statistics, with full detail provided in 
the SAP. 
 
9.4.4. 
PK Analysis 
The PK endpoints for statistical analysis, which will be assessed using serum 
concentrations for both voriconazole and N-oxide voriconazole are: 
• Maximum observed serum concentration (Cmax) 


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• AUC Area under the serum concentration curve from zero to time of the last 
quantifiable concentration (AUC0-t), where t is 12 hours for Part 1, 24 hours for 
Part 2 and 96 hours for Part 3. 
• Area under the serum concentration curve from zero extrapolated to infinity 
(AUC0-inf). 
 
9.4.4.1. 
Dose proportionality 
 
Dose proportionality will be assessed by fitting a power model as follows: 
 
𝑙𝑜𝑔10(𝑦) = 𝛼+ 𝛽𝑙𝑜𝑔10(𝑑𝑜𝑠𝑒) 
 
Where a value of 1 for β indicates perfect dose proportionality. Therefore, the estimate of 
β together with the corresponding 90% CI will be used to quantify dose proportionality. 
Dose proportionality will be assessed for each of the primary PK endpoint and will be 
performed separately for Part 1 and Part 2 at Day 1 and Day 10. This analysis will be 
performed if 3 or more dose levels are used for the Part. 
9.4.4.2. 
Bioavailability 
 
The PK endpoints estimated from Part 3 will be analysed to assess relative bioavailability 
of Test to Reference by fitting a mixed effects ANOVA model to the loge transformed PK 
parameter including fixed effect terms for treatment, period, sequence and sex and a 
random effect term for subject (nested within sequence). The adjusted geometric mean 
ratio (GMR) (Test : Reference) and the corresponding 90% confidence interval (CI) for 
the adjusted GMR will be presented. 
 
In addition, the PK endpoints will be compared between asthma subjects in Part 3 and 
healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess relative 
bioavailability of the ZP-059 dose taken in Part 3 in these populations. An ANOVA model 
will be fitted to the loge transformed PK parameter including terms for the population group 
(i.e., healthy subjects or asthma subjects) and sex. The adjusted GMR and 90% CI for 
the adjusted GMR for the comparison between the two populations for the relevant dose 
will be provided, where the ratio is defined as either Part 3 subjects/Part 1 subjects or 
Part 3/Part 2 subjects, depending on the comparison. 
9.4.4.3. 
PK Summaries 
 
PK concentrations (including voriconazole concentrations in induced sputum) will be 
summarised and plotted over time. All PK parameters will also be summarised. 
 
Further statistical analysis of other PK parameters and induced sputum concentrations 
may be performed. Full detail will be provided in the SAP. 


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9.5. 
Interim Analyses  
 
No formal interim analyses are planned for this study. Details of interim safety data 
reviews to be performed are described in Section 6.6. 
 
9.6. 
Data Monitoring Committee (DMC) 
No data monitoring committee is planned for this study. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the 
following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
o 20 July 2017 EMEA/CHMP/SWP/28367/07 Rev. 1 Committee for Medicinal 
Products for Human Use (CHMP) Guideline on strategies to identify and 
mitigate risks for first-in-human and early clinical trials with investigational 
medicinal products 
o 21 July 2011 EMEA/CHMP/EWP/192217/2009 Committee for Medicinal 
Products for Human Use (CHMP) Guideline on bioanalytical method validation 
o London, 20 January 2010 Doc. Ref.: CPMP/QWP/EWP/1401/98 Rev. 1 
Guideline on the investigation of bioequivalence” 
o https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-
covid-19 guidance. 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IEC by the 
investigator and reviewed and approved by the IEC before the study is initiated. 
• 
Any substantial amendments to the protocol will require IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
• 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IEC 
o Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 


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10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the subject and answer all questions regarding the study. 
• 
Subjects must be informed that their participation is voluntary. Subjects or their 
legally authorised representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, General Data Protection Regulation (GDPR), and the IEC or study 
centre. 
• 
The medical record must include a statement that written informed consent was 
obtained before the subject performed any study procedures and the date the 
written consent was obtained. The authorised person obtaining the informed 
consent must also sign the ICF. 
• 
Subjects must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
• 
An original signed ICF(s) must be provided to the subject or the subject’s legally 
authorised representative. 
Subjects who are rescreened are required to sign a new ICF. 
 
10.1.4. 
Data Protection 
• 
Subjects will be assigned a unique identifier by the sponsor. Any subject records 
or datasets that are transferred to the sponsor will contain the identifier only; 
subject names or any information which would make the subject identifiable will 
not be transferred. 
• 
The subject must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the subject who will be required to give 
consent for their data to be used as described in the informed consent  
• 
The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by 


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the sponsor, by appropriate IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
Data reviews during the study will be performed by the Safety Advisory Committee (SAC). 
See section 6.6 for details of the committee structure. 
10.1.6. 
Dissemination of Clinical Study Data 
 
A clinical study summary report will be provided to the appropriate IEC and results 
uploaded to EudraCT within one year of the end of the clinical study. 
10.1.7. 
Data Quality Assurance 
• 
All subject data relating to the study will be recorded on an electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IEC review, and 
regulatory agency inspections and provide direct access to source data 
documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 


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unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the subject and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in source data verification 
agreement (or equivalent). 
10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up. 


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10.1.10. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements


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10.2. 
Appendix 2: Clinical Laboratory Tests 
 
Haematology 
Clinical Chemistry 
Virology 
Urinalysis 
Urine Drugs of Abuse 
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 
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) 
hCG (all female subjects) 
Gamma Glutamyl Transferase (GGT) 
Glucose 
Glucose (Fasting) 
Lactate dehydrogenase (LDH) 
Potassium 
Phosphate (Inorganic) 
Protein (Total) 
Sodium 
Urea 
Hepatitis B Surface 
Antigen 
Hepatitis B Surface 
Antibody 
Hepatitis B Core Antibody 
Hepatitis C Virus Antibody 
Hepatitis C Virus RNA HIV 
Antibody 
Test for SARS-COV-2 (RT-
PCR) 
 
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.  
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
Cotinine 
Marijuana/Cannabis 
Methadone 
Methamphetamine/ 
Ecstasy 
Morphine/ Opiates 
Phencyclidine 
Tricyclic Antidepressants 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 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. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after IMP administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study intervention or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition. 


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• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• In general, hospitalisation signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalisation are AEs. If a complication prolongs hospitalisation or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 


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e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalisation but 
may jeopardise the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalisation, or development of 
drug dependency or drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to the Sponsor in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the medical records 
before submission to the Sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with a SAE. Severe is a category 


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utilised for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. The relationship should be 
classified as follows:  
o 
Not related: a causal relationship between the study IMP and the AE is 
not a reasonable possibility 
o 
Related: a causal relationship between the study IMP and the AE is a 
reasonable possibility, and there are no other obvious causes for the AE.  
• A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 


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• The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the Sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
• If a subject dies during participation in the study or during a recognised follow-
up period, the investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to the Sponsor within 24 
hours of receipt of the information. 
10.3.4. 
Reporting of SAEs 
 
SAE Reporting to Sponsor via Paper Report Form 
• Facsimile/E-Mail transmission of the SAE paper form is the preferred method 
to transmit this information to Zambon Drug Safety and the Medical Monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator 
to complete and sign the SAE form within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found on protocol page 3 (Zambon Drug 
Safety Unit and Medical Monitor contact details. 
 
 
 


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10.4. 
Appendix 4: Contraceptive Guidance, Exposure, Sperm 
Donation and Collection of Pregnancy Information 
10.4.1. 
Contraception 
 
Male subjects who are sexually active with a partner of childbearing potential must use, 
with their partner, a condom plus an approved method of effective contraception from the 
time of informed consent until 14 days after their last dose of IMP.  
The following methods are acceptable:  
Highly Effective Methods of Contraception (to be used by male subjects and their 
partners)  
• Combined (estrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception: 
− oral 
− injectable 
− implantable 
 
• Intrauterine hormone-releasing system (IUS) 
• Implantable intrauterine device (IUD) 
• Surgical sterilisation (for example, vasectomy* or bilateral tubal occlusion/ligation)  
*For vasectomy, the procedure should have been confirmed as successful and 
documentation made of this in the subject’s notes. 
 
Female subjects who are sexually active and of childbearing potential must use,  an 
approved method of highly effective contraception from the time of informed consent until 
30 days after their last dose of IMP.  
Highly Effective Methods of Contraception (to be used by female subjects of childbearing 
potential)  
• Combined (estrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation:  
 
− oral   


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− intravaginal   
− transdermal   
• Progestogen-only hormonal contraception associated with inhibition of ovulation*  
 
− oral   
− injectable  
− implantable  
 
• IUS   
• IUD  
• Surgical sterilisation (for example, bilateral tubal occlusion/ligation)  
*The following are not considered highly effective, i.e. not associated with inhibition of 
ovulation: Micronor, Norgeston, Noriday. 
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred 
and usual lifestyle. If a subject is usually not sexually active but becomes active, they, 
with their partner, must comply with the contraceptive requirements detailed above.  
Female subjects who are not of childbearing potential do not need to use any methods of 
contraception. A woman is considered of childbearing potential unless post-menopausal 
or permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy and bilateral tubal occlusion/ligation. A post-
menopausal state is defined as no menses for 12 months without an alternative medical 
cause (without hormone replacement therapy [HRT]). If required by the investigator, this 
may be confirmed by a follicle stimulating hormone (FSH) result of ≥40 IU/L. 
10.4.2. 
Exposure to Partners during the Study  
There is a risk of drug exposure through the ejaculate (which also applies to vasectomised 
males) that might be harmful to the sexual partners (both male and female), including 
pregnant partners of male subjects. Therefore, a condom should be used by all male 
subjects throughout the study and for 14 days after their last dose of IMP.   
10.4.3. 
Sperm Donation  
Male subjects should not donate sperm for the duration of the study and for at least 14 
days after their last dose of IMP.  
 
10.4.4. 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 


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• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This 
applies only to male subjects who receive IMP. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will 
be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure.  
Female subjects who become pregnant 
• 
The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a subject's pregnancy.  
• 
The subject will be followed to determine the outcome of the pregnancy after 
signature of a specific Informed Consent for Pregnancy Follow up. The investigator 
will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
• 
Any post-study pregnancy-related SAE considered related to IMP by the 
investigator will be reported to the sponsor as described in Appendix 3. While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of an SAE through spontaneous reporting. 
• 
Any female subject who becomes pregnant while participating in the study will be 
withdrawn from IMP. A male subject will be withdrawn from IMP in the event that 
his female partner becomes pregnant. 
 


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All pregnancies during the study will be reported to Zambon Drug Safety and the 
Medical Monitor (contact details on protocol page 3). 
 
 


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10.5. 
Appendix 5: Abbreviations 
ABPA 
Allergic Bronchopulmonary Aspergillosis  
ADM 
Admission  
AE 
Adverse Event  
AESIs 
Adverse Event of Special Interest  
ALT  
Alanine Aminotransferase 
ANOVA 
Analysis of Variance  
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Serum Concentration-Time Curve  
AUC0-t 
Area under the Serum Concentration-Time Curve from Time Zero to 
the  
Last Measurable Concentration 
AUC0-inf 
Area Under the Serum Concentration-Time Curve from Time Zero to 
 
Infinity 
AUC0-tau 
Area Under the Serum Concentration-Time Curve from Time Zero to 
the  
End of the Dosing Period            
AUCtau 
Area Under the Serum Concentration-Time Curve to the End of the 
Dosing  
Interval 
BID 
Twice Daily 
BMI 
Body Mass Index  
CCF 
Congestive Cardiac Failure 
CE-marked 
Conformité Européene (European Conformity) 
CF 
Cystic Fibrosis  
CFR 
Code of Federal Regulations 
CI 
Confidence Interval  
CIOMS 
Council for International Organizations of Medical Sciences  
CK 
Creatine Kinase 
CL/F 
Apparent Total Clearance of the Drug from the Serum 
Cmax 
Maximum Serum Concentration 
Cmax,ss 
Maximum Steady-State Serum Concentration During a Dosing 
Interval 
Cmin 
Minimum Serum Concentration  
COVID-19 
Corona Virus Disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
Css,av 
Average Steady-State Serum Drug Concentration During Multiple-
Dose  
Administration 
Ctrough 
Trough Serum Concentration  


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           108 
CYP2C19 
Cytochrome p450 2C19 
CYP3A4 
Cytochrome p450 3A4  
DPI 
Dry Powder Inhaler 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee  
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EDV 
Early Discontinuation Visit  
EU 
European Union  
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FEV1 
Forced Expiratory Volume in 1 Sec  
FIH 
First in Human 
FSH 
Follicle Stimulating Hormone  
FVC 
Forced Vital Capacity 
g 
Grams  
GCP 
Good Clinical practice 
GDPR 
General Data Protection Regulation  
GGT 
Gamma Glutamyl Transferase 
GLI 
Global Lung Function Initiative 
GMP 
Good Manufacturing Practice 
GMR 
Geometric Mean Ratio  
GP 
General Practitioner  
HB 
Hepatitis B 
HBsAg 
Hepatitis B Surface Antigen  
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HCV Ab 
Hepatitis C Virus Antibody  
HIV 
Human Immunodeficiency Virus  
HIPAA 
Health Insurance Portability and Accountability Act 
HPMC 
Hydroxypropyl Methylcellulose  
HRT 
Hormone Replacement Therapy  
IB 
Investigator’s Brochure  
ICF 
Informed Consent Form  
ICH 
International Council for Harmonisation 
ICS 
Inhaled Corticosteroid  
IEC 
Independent Ethics Committees 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           109 
Ig 
Immunoglobulin 
IgE 
Immunoglobulin E  
IgG 
Immunoglobulin G 
IL-4 
Interleukin-4  
IL-5 
Interleukin-5 
IMP 
Investigational Medicinal Product 
HPMC 
Hydroxypropyl Methylcellulose  
ISF 
Investigator Site File  
IUD 
Intrauterine Device  
IUS 
Intrauterine Hormone-Releasing System  
Kel 
Apparent First-Order Terminal Elimination Rate Constant  
LABA 
Long-Acting Beta-Agonist  
LAMA 
Long-Acting Muscarinic Antagonists 
LDH 
Lactate Dehydrogenase 
Loge 
Natural Logarithmic 
MAD 
Multiple Ascending Dose  
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
Mg 
Milligrams  
MHRA 
Medicines and Healthcare Products Regulatory Agency  
MIC 
Minimum Inhibitory Concentration  
mL 
Millilitres  
msec 
Millisecond 
NOAEL 
No-Observed-Adverse-Effect Level  
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PEFR 
Peak Expiratory Flow Rate  
Ph. Eur 
European Pharmacopoeia  
PI 
Principal Investigator 
PIS 
Participant Information Sheet  
PK 
Pharmacokinetic(s) 
PKNCA 
Pharmacokinetic Complete Noncompartmental analysis 
PVC 
Packed Cell Volume 
QA 
Quality Assurance  
QD 
Once Daily  


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           110 
QP 
Qualified Person 
Q.s 
Quantum Satis  
QTcF 
QT Interval Corrected for Heart Rate Using Fridericia’s Formula 
R&D 
Research and Development 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid  
SABA 
Short-Acting Beta-Agonists  
SAC 
Safety Advisory Committee  
SAD 
Single Ascending Dose  
SAE 
Serious Adverse Event  
SAF 
Safety Analysis Set 
SAFS 
Severe Asthma Associated with Fungal Sensitization  
SAMA 
Short-Acting Muscarinic Antagonist  
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure  
SPF 
Sun Protection Factor 
Spp 
Several Species 
SQN 
Syne Qua Non 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
t1/2 
Elimination Half Life 
TBD 
To be Determined 
TDL 
The Doctor’s Laboratory    
Th2 
T-helper Type 2  
tmax 
Time to Reach Maximum Serum Concentration  
tmax,ss 
Time to Reach Maximum Serum Concentration Following Drug 
 
Administration at a steady state 
TP 
Treatment Period 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
Vz/F 
Volume of Distribution During Terminal Phase After Non-Intravenous 
 
Administration 
WBC 
White Blood Cell  
μg 
Micrograms 
% fluctuation 
Percentage Fluctuation Over the Dosing Interval 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           111 
% swing 
Percentage Swing Over the Dosing Interval  
 
10.6. 
Appendix 6: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the Table of Contents (TOC). 
 
Amendment 01, Protocol Version 1.1: dated 14 February 2020: 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
 
Overall Rationale for the Amendment: 
The overall rationale for the changes implemented in this protocol amendment is to 
correct Typographical errors throughout. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Appendix 10.4 
Typographical errors 
corrected 
‘Highly’ 
effective 
methods 
of 
contraception for males are to be 
followed to match inclusion criteria 4 
(Part 1), inclusion criteria 6 (Part 2 & 
Part 3). 
Contraception option for ‘Male condom 
with either female cap or diaphragm 
(double 
barrier) 
plus 
spermicide’ 
removed from list for male subjects 
since this is not listed as a CTFG 
‘highly 
effective’ 
method 
of 
contraception.  
IUS listed separately as a highly 
effective form of contraception for both 
male and female subjects, originally 
listed 
under 
progesterone 
only 
contraception in error 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           112 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.14.1, 
Section 9.3, 
Section 9.4.4, 
Section 10.5 
Typographical errors 
corrected 
Corrected to reflect the serum samples 
that are required for the serum PK 
analysis. 
 
Protocol Version 1.0: dated 13 December 2019. 
Original protocol. 
 
 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           113 
11. 
References 
1. 
Ashok Shah et.al (2016) Allergic Bronchopulmonary Aspergillosis: A Perplexing 
Clinical Entity; Allergy Asthma Immunol Res. 2016 Jul; 8(4): 282–297. Published 
online 2016 Mar 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853505/ 
 
2. 
Agarwal, R.; Aggarwal, A.N.; Gupta, D.; Jindal, S.K. Aspergillus hypersensitivity 
and allergic bronchopulmonary aspergillosis in patients with bronchial asthma: 
Systematic review and meta-analysis. Int. J. Tuberc. Lung Dis. 2009, 13, 936–944. 
 
3. 
Tracy MC, Okorie CUA, Foley EA, Moss RB. Allergic Bronchopulmonary 
Aspergillosis. J. Fungi 2016, 2, 17 
 
4. 
LIVINGSTONE CHISHIMBA et.al (2012); Journal of Asthma, 2012; 49(4): 423–
433; Voriconazole and Posaconazole Improve Asthma Severity in Allergic 
Bronchopulmonary Aspergillosis and Severe Asthma with Fungal Sensitization 
http://www.lifeworldwide.org/assets/uploads/files/Chishimba%20SAFS%20ABPA
%20vori%20posa%20J%20Asthma%202012.pdf 
 
5. 
O’Driscoll BR, Hopkinson LC, Denning DW. Mold sensitization is common amongst 
patients with severe asthma requiring multiple hospital admissions. BMC Pulm 
Med 2005; 5:4. 
 
6. 
Moss RB. Treatment options in severe fungal asthma and allergic 
bronchopulmonary aspergillosis. Eur Respir J 2014; 43: 1487–1500 
 
7. 
Stevens, D.A.; Schwartz, H.J.; Lee, J.Y.; Moskovitz, B.L.; Jerome, D.C.; 
Catanzaro, A.; Bamberger, D.M.; Weinmann, A.J.; Tuazon, C.U.; Judson, M.A.; et 
al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. 
N. Engl. J. Med. 2000, 342, 756–762. 
 
8. 
Wark, P.A.B.; Hensley, M.J.; Saltos, N.; Boye, M.J.; Toneguzzi, R.C.; Epid, G.D.; 
Simpson, J.L.; McElduff, P.; Gibson, P.G. Anti-inflammatory effect of itraconazole 
in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. J. 
Allergy Clin. Immunol. 2003, 111, 952–957 
 
9. 
Tracy MC, Okorie CUA, Foley EA, Moss RB. Allergic Bronchopulmonary 
Aspergillosis. J. Fungi 2016, 2, 17 
 
10. 
Wark, P.A.B.; Hensley, M.J.; Saltos, N.; Boye, M.J.; Toneguzzi, R.C.; Epid, G.D.; 
Simpson, J.L.; McElduff, P.; Gibson, P.G. Anti-inflammatory effect of itraconazole 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           114 
in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. J. 
Allergy Clin. Immunol. 2003, 111, 952–957 
 
11. 
Stevens, D.A.; Schwartz, H.J.; Lee, J.Y.; Moskovitz, B.L.; Jerome, D.C.; 
Catanzaro, A.; Bamberger, D.M.; Weinmann, A.J.; Tuazon, C.U.; Judson, M.A.; et 
al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. 
N. Engl. J. Med. 2000, 342, 756–762. 
 
12. 
Agarwal R, Dhooria S, Sehgal IS, Aggarwal AN, Garg M, Saikia B, Behera D, 
Chakrabarti A. A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage 
Allergic Bronchopulmonary Aspergillosis Complicating Asthma. Chest 2018; 
153(3):656-664 
 
13. 
Tucker RM, Haq Y, Denning DW, Stevens DA. Adverse events associated with 
itraconazole in 189 patients on chronic therapy. J Antimicrob Chemother 1990; 
26(4):561–566. 
 
14. 
Richard B. Moss et.al (2014) Treatment options in severe fungal asthma and 
allergic bronchopulmonary aspergillosis; European Respiratory Journal 43: 1487-
1500 https://erj.ersjournals.com/content/43/5/1487 
 
15. 
Chishimba L et.al (2012); Journal of Asthma, 2012; 49(4): 423–433; Voriconazole 
and Posaconazole Improve Asthma Severity in Allergic Bronchopulmonary 
Aspergillosis and Severe Asthma with Fungal Sensitization 
 
16. 
Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin 
Microbiol Rev. 2014 Jan; 27(1): 68–88. 
 
17. 
Xing Y, Chen L, Feng Y, Zhou Y, Zhai Y, Lu J. Meta-analysis of the safety of 
voriconazole in definitive, empirical, and prophylactic therapies for invasive fungal 
infections. BMC Infect Dis. 2017; 17: 798. 
 
18. 
Miao Q et.al (2019) Correlation of CYP2C19 genotype with plasma voriconazole 
exposure in South-western Chinese Han patients with invasive fungal infections. 
Medicine (Baltimore). 98(3):e14137. 
https://www.ncbi.nlm.nih.gov/pubmed/30653146 
 
19. 
Patterson K, Strek E. Allergic Bronchopulmonary Aspergillosis. Proc Am Thorac 
Soc Vol 7. pp 237–244, 2010 
 


CONFIDENTIAL 
Clinical Pharmacology Study in Healthy and Asthmatic Subjects  
Clinical Study Protocol – Study Z7240J01 Version 1.2; 04 June 2020 – 
Amendment 02 
 
  Zambon SpA SOP C.03.02.07_App 1                           115 
20. 
Moss RB. Treatment options in severe fungal asthma and allergic 
bronchopulmonary aspergillosis. Eur Respir J 2014; 43: 1487–1500 
 
21. 
Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, Moss R, Denning 
DW: Allergic bronchopulmonary aspergillosis: review of literature and proposal of 
new diagnostic and classification criteria. Clinical & Experimental Allergy, 2013 
(43), 850-873. 
 
22. 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2012 Edition (as amended 12 Nov 2014). 
 
23. 
Chanez, P., Djukanovic, R., Ind, P.W., Holz, O., Maestrelli, P. & Sterk, P.J. (2002) 
Sputum 
Induction. 
European 
Respiratory 
Journal, 
37, 
3-8. 
DOI: 
10.1183/09031936.02.00000302 
 
24. 
European Medicines Agency, 2017. Committee for Medicinal Products for Human 
Use (CHMP): Guideline on strategies to identify and mitigate risks for first-in-
human and early clinical trials with investigational medicinal products, 
EMEA/CHMP/SWP/28367/07 
Rev. 
1, 
London 
UK, 
2017. 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
strategies-identify-mitigate-risks-first-human-early-clinical-trials-
investigational_en.pdf 
 
25. 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Xaver Baur, Graham L. Hall, 
Bruce H. Culver, Paul L. Enright, John L. Hankinson, Mary S.M. Ip, Jinping Zheng, 
Janet Stocks and the ERS Global Lung Function Initiative, Multi-ethnic reference 
values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations. Eur Respir J 2012; 40: 1324–1343. 
 

SAP_001.pdf: 
Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
Page 1 of 20
Version: 2.0
ST/form/010/12
 
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)
Zambon Study No: Z7240J01 
Syne qua non Ltd Study No: MET19010
Statistical Analysis Plan
Version: 2.0
Date: 28 October 2020
SQN: Paula McSkimming
 
Approved By Zambon: Arnd Mueller
If signing manually, please include:  Signature + Date + Full Name + Position
 
Lead Statistician
SignNow e-signature ID: 89a275bc0f...
10/28/2020 13:19:21 UTC
Paula McSkimming (Signer)
SignNow e-signature ID: 8313ab8e8c...
10/28/2020 13:24:25 UTC
Arnd Mueller (Signer)


Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
Page 2 of 20
Version: 2.0
ST/form/010/12
Modification History
Version
Change History
Reason
Date
1.0
First Version
N/A
12AUG2020
2.0
1.
Update to protocol deviations listing to 
only important PDs
2.
Removed exposure table from 
analysis
3.
Updated AESI to tabulate if necessary
4.
Added Sputum plug and processed 
sputum to analysis
1.
To bring in line with 
SQN current processes
2.
Following client review 
of dry run TFL
28OCT2020


Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
Page 3 of 20
Version: 2.0
ST/form/010/12
Contents
1
INTRODUCTION ............................................................................................................................7
2
Changes from the Protocol Planned Analysis ................................................................................7
3
STUDY OBJECTIVES AND DESIGN.............................................................................................7
3.1
Study Objectives.........................................................................................................................7
3.1.1
Primary Objectives ..................................................................................................................7
3.1.2
Pharmacokinetic (PK) Objectives............................................................................................7
3.1.3
Exploratory Objectives ............................................................................................................7
3.2
Study Endpoints .........................................................................................................................8
3.2.1
Primary Endpoints ...................................................................................................................8
3.2.2
Pharmacokinetic (PK) Endpoints.............................................................................................8
3.2.3
Exploratory Endpoint(s)...........................................................................................................9
3.3
Study Design .............................................................................................................................9
3.4
Visit Structure .............................................................................................................................9
4
Sample Size....................................................................................................................................9
5
Randomisation and blinding .........................................................................................................10
6
Interim analysis.............................................................................................................................10
7
Analysis Plan ................................................................................................................................10
7.1
General.....................................................................................................................................10
7.2
General Derivations..................................................................................................................11
7.2.1
Baseline.................................................................................................................................11
7.2.2
Study Day..............................................................................................................................11
7.2.3
Period and Period Day ..........................................................................................................11
7.2.4
Treatment Start and End .......................................................................................................11
7.2.5
Planned dose and actual dose received ...............................................................................12
7.2.6
Incomplete Dates ..................................................................................................................12
7.2.7
Non-Numeric Values Recorded in Numeric Fields................................................................12
7.3
Missing Data and Withdrawals .................................................................................................12
7.4
Analysis Sets............................................................................................................................12
7.5
Data presentations ...................................................................................................................13
7.5.1
Parts 1 & 2 Specific Presentations ........................................................................................13
7.5.2
Part 3 Specific Presentations ................................................................................................13
7.5.3
General Presentations...........................................................................................................13
7.6
Disposition of Subjects .............................................................................................................14
7.7
Protocol Deviations...................................................................................................................14
7.8
Background and Demographic Characteristics ........................................................................14
7.8.1
Demography..........................................................................................................................14
7.8.2
Smoking History ....................................................................................................................14
7.8.3
Medical History......................................................................................................................14
7.9
Prior and Concomitant Medications..........................................................................................15
7.10
Administration of Study Treatment and Exposure....................................................................15
7.11
Efficacy Analysis.......................................................................................................................16
7.12
Pharmacokinetics .....................................................................................................................16
7.12.1
Serum concentrations ...........................................................................................................16
7.12.2
Induced Sputum Concentrations ...........................................................................................17
7.12.3
Dose proportionality ..............................................................................................................17
7.12.4
Bioavailability.........................................................................................................................17
7.13
SAFETY EVALUATION............................................................................................................18
7.13.1
Adverse Events .....................................................................................................................18
7.13.2
Clinical Laboratory Evaluation...............................................................................................20
7.13.3
Vital Signs .............................................................................................................................20
7.13.4
Pulmonary Function (Spirometry)..........................................................................................20
7.13.5
Electrocardiography (ECG) ...................................................................................................21
7.13.6
Physical Examination ............................................................................................................21
7.13.7
Pregnancy test ......................................................................................................................21
7.13.8
Urine Drug Screen.................................................................................................................21
7.13.9
Alcohol Breath Test ...............................................................................................................21
7.13.10
SARS-CoV-2 Test .................................................................................................................21
7.14
References ...............................................................................................................................21


Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
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LIST OF ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANOVA
Analysis of Variance
AST
Aspartate Aminotransferase
AUC0-t
Area Under the Concentration time curve over the Dosing Interval
AUC0-inf
Area Under the Concentration time curve from time Zero to Infinity
AUCtau
Area Under the Concentration curve from time Zero to the End of the 
dosing period
BLQ
Below limit quantification
BMI
Body Mass Index
CI
Confidence Interval
CL/F
Apparent total clearance of the drug from the serum
Cmin
Minimum Observed Concentration
Cmax
Maximum Observed Concentration
Cmax,ss
Maximum Observed Concentration following drug administration at a 
steady state
CS
Clinically Significant
CV
Coefficient of Variation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
GMR
Geometric Mean Ratio
IMP
Investigational Medicinal Product
Kel
Apparent First-Order Terminal Elimination Rate Constant
Loge
Natural Logarithm
MAD
Multiple Ascending Dose
MedDRA
Medical Dictionary for Regulatory Activities
NC
Not calculated
NCS
Not Clinically Significant
NR
No Result
PEFR
Peak Expiratory Flow Rate
PK
Pharmacokinetic
PT
Preferred Term


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Date: 28OCT2020 
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Rac
Accumulation Ratio
SAC
Safety Advisory Committee
SAD
Single Ascending Dose
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
t1/2
Terminal Elimination Half-Life
TEAE
Treatment Emergent Adverse Event
tmax
Time of the Maximum Observed Concentration
tmax,ss
Time of the Maximum Observed Concentration following drug 
administration at a steady state
ULN
Upper Normal Limit
Vz/F
Volume of Distribution During Terminal Phase After Non-Intravenous 
Administration
WHO Drug
World Health Organization Drug Dictionary
% fluctuation 
Percentage Fluctuation Over the Dosing Interval 
% swing 
Percentage Swing Over the Dosing Interval 


Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
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1
INTRODUCTION
This document details the statistical analysis that will be performed for the Zambon 
study: 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). 
The proposed analysis is based on the contents of the Final Version of the protocol 
(dated 13th December 2019), amendment 1 (dated 14th February 2020) and 
amendment 2 (dated 04 June 2020).  In the event of future amendments to the 
protocol, this statistical analysis plan (SAP) may be modified to account for changes 
relevant to the statistical analysis. 
The table, listing and figure shells are supplied in a separate document.
2
CHANGES FROM THE PROTOCOL PLANNED ANALYSIS
For the PK analysis, linearity ratios will not be reported due to the likelihood that AUC0-
inf cannot be obtained.
3
STUDY OBJECTIVES AND DESIGN
3.1
Study Objectives
3.1.1 Primary Objectives
The primary objectives of the study are:

Part 1: To determine the safety and tolerability of single inhaled doses of ZP-
059 in healthy subjects. 

Part 2: To determine the safety and tolerability of multiple inhaled doses of ZP-
059 in subjects with mild stable asthma. 

Part 3: To determine the safety and tolerability of single inhaled doses of ZP-
059 and Oral Voriconazole in subjects with mild to moderate stable asthma.
3.1.2 Pharmacokinetic (PK) Objectives
The PK objectives of the study are:

Part 1: To characterise systemic PK of voriconazole and N-oxide voriconazole 
after single doses of ZP-059 in healthy subjects. 

Part 2: To characterise systemic PK of voriconazole and N-oxide voriconazole 
after multiple doses of ZP-059 in subjects with mild, stable asthma. 

Part 3: To characterise 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. 
3.1.3 Exploratory Objectives
The exploratory objectives of the study are:


Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
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
Part 1: None

Part 2: To characterise voriconazole and N-oxide voriconazole concentrations  
in induced sputum after multiple doses of ZP-059 (i.e. on Day 7; both pre-dose 
and post-dose) in subjects with mild, stable asthma. 

Part 3: To characterise voriconazole concentrations and N-oxide voriconazole 
in induced sputum after single inhaled doses of ZP-059 and after single doses 
of oral voriconazole in subjects with mild to moderate stable asthma.
3.2
Study Endpoints
3.2.1 Primary Endpoints 
The primary endpoint for each Part (Part 1, 2, & 3) of the study is:

Safety and tolerability, as assessed by monitoring of adverse events (AEs), 
physical examinations, changes in vital signs, clinical laboratory parameters, 
electrocardiogram (ECG), pulse oximetry and spirometry assessments (forced 
expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak 
expiratory flow rate (PEFR) and FEV1/FVC). 
3.2.2 Pharmacokinetic (PK) Endpoints 
The PK endpoints to analyse both voriconazole and N-oxide voriconazole for each 
part (Part 1, 2, & 3) of the study are:

Parts 1, 2 and 3 (in Part 3, Day 1 of Treatment Period 1 and Day 1 of Treatment 
Period 2): 
o
AUC0-t; where ‘t’ is the last timepoint at which concentrations were 
quantifiable, nominally 12 h, 24 h & 96 h for Parts 1, 2 and 3 
respectively. Note that the last timepoint, t, may differ depending on the 
actual data and dose regimen.
o
AUC0-inf. Note that if dosing is twice daily robust estimation of AUC0-inf 
on Day 1 part 2 may prove challenging.
o
AUCtau; Part 2, Day 1 only
o
Cmax
o
tmax 
o
Kel; except Part 2 (day 1)
o
t1/2; except Part 2 (day 1)

Part 2 (Day 10): 
o
AUCtau,
o
Cmax,ss 
o
tmax,ss
o
Css,av
o
%fluctuation and swing (as appropriate and when applicable)
o
Accumulation (Rac) based on the ratio of Day 10 AUCtau to Day 1 
AUCtau
o
Pre-dose concentrations measured on Days 3 to 10 will be designated 
as Cmin values

For voriconazole only CL/F and Vz/F will be estimated from Part 1, Part 2 (Day 
10) and Part 3 serum concentration data


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These will be assessed using the serum concentration for voriconazole and N-oxide 
voriconazole.
3.2.3 Exploratory Endpoint(s)
The exploratory endpoint for Parts 2 & 3 of the study is:

Induced sputum concentrations dependent on data availability of voriconazole 
and N-oxide voriconazole on Day 7 for Part 2 and Days 1, 2 and 3 of each 
treatment period for Part 3
3.3
Study Design 
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).
Part 1 is comprised of 4 separate cohorts containing 6 subjects each. Each subject 
will receive a single dose of ZP-059 with the dose increasing per cohort following 
review of safety data from the preceding cohort. The study will have an interleaved 
design.  A further cohort may be enrolled if deemed appropriate to repeat a dose level, 
assess an interim dose or a dose higher than planned.
Part 2 is comprised of 3 separate cohorts containing 6 subjects each. The treatment 
period will be for 10 consecutive days with each subject receiving daily doses of ZP-
059 (either once daily for 10 days, or twice daily for the first 9 days and once on Day 
10), of which the dose and frequency is determined following a safety review of the 
data from Part 1 Cohort 2. Dose escalation in the next cohort will proceed following 
completion of the safety assessments 24 hours post dose on Day 10 for a minimum 
of 4 subjects. A further 2 cohorts may be enrolled if deemed appropriate to repeat a 
dose level, assess an interim dose, a different dosing regimen or a dose higher than 
planned.
Part 3 is a two period, randomised crossover study in 16 subjects with a minimum of 
6 sputum producers and comprises of 2 cohorts to receive a single dose of ZP-059 in 
one period, of which the dose is determined following a safety review of the data from 
Part 1 (Cohorts 1 to 4), and a single dose of 200mg oral voriconazole in the other 
period. Subjects are randomised to the sequence in which they receive treatment. 
There will be a minimum wash out period of 96 hours between treatments. Dosing of 
Part 3 may occur prior to or in parallel with Part 2 of the study.
Further details of the study design can be found in section 4 of the protocol.
3.4
Visit Structure
The visit structure and the schedule of activities for each part of the study are detailed 
in section 1.2 of the protocol. Details of the residential stays, study assessments and 
procedures at each visit can be found in section 8 of the protocol.


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4
SAMPLE SIZE
 Part 1 (Single Ascending Dose (SAD) - Healthy subjects) and Part 2 (Multiple 
Ascending Dose (MAD) – Mild, Stable Asthma Subjects):
This study is not powered for any formal hypothesis test. The sample size of up to 30 
subjects (24 subjects plus an additional 6 subjects in 1 optional cohort) in Part 1 and 
up to 30 subjects (18 subjects plus additional 12 subjects in 2 optional cohorts) in Part 
2 was chosen to minimise exposure to Investigational Medicinal Product (IMP) while 
allowing an adequate assessment of safety at each dose in order to support dose 
escalation and an adequate number of subjects to assess mean PK parameters. A 
minimum of 4 evaluable subjects will be required for each cohort for both dose 
escalation decisions and assessment of mean PK parameters. 
Part 3 (Mild to Moderate, Stable Asthma Subjects): 
This study is not powered for any formal hypothesis test. A sample size of up to 16 
subjects was chosen to minimise exposure to IMP while allowing an adequate 
assessment of safety, PK parameters and drug concentration in sputum. No 
replacements are foreseen. However, should the drop-out rate for non-safety reasons 
be high, which may compromise the reliability of the study results, additional subjects 
could be randomised.
5
RANDOMISATION AND BLINDING 
Subjects will only be randomised in Part 3 of the study. They will be randomised in a 
1:1 fashion to the sequence in which they will receive treatments for the crossover 
design. There will be no stratification.
As this is an open-label study, no blinding is required.
6
INTERIM ANALYSIS
No interim analysis is planned. 
Interim safety data reviews will be held to make decisions on the dose escalations 
during Parts 1 & 2 and the dose of ZP-059 to administer in Parts 2 (starting dose) and 
3 of the study. The reviews are conducted by the safety advisory committee (SAC) 
which is made up of the Principal Investigator ((PI) or delegate) and the sponsor’s 
medical monitor as a minimum. Further details are available in section 6.6 of the 
protocol.
No outputs will be produced by SQN for these reviews.
7
ANALYSIS PLAN
7.1
General
Summary statistics for continuous variables will consist of the number of non-missing 
observations (n), mean, standard deviation (SD), minimum, 25th percentile, median, 
75th percentile and maximum, unless specified otherwise.  The precision of these 
variables is defined in the table, figure and listing shells document.


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For categorical variables the number and percentage of subjects in each category will 
be presented, based on the number of non-missing observations apart from the 
disposition of subjects, protocol deviations, background and demographic 
characteristics, prior and concomitant medications/procedures and AEs where the 
percentage will be based on the number of subjects in the analysis set.  
The number of missing observations will also be presented for each variable.
7.2
General Derivations
This section provides details of general derivations. Derivations specific to the 
parameter of interest are detailed within the specific SAP section.
7.2.1 Baseline
For Parts 1 & 2 of the study, baseline is defined as the pre-dose value on Day 1. If that 
is missing it will be defined as the last non-missing value prior to the subject receiving 
study treatment (pre-dose) on Day 1.
For Part 3 of the study, within-period baseline is defined as the last non-missing value 
(including scheduled and unscheduled assessments) pre-dose on Day 1 for each of 
the respective study treatments. Overall baseline is defined as the pre-dose value on 
Day 1 of Period 1. If that is missing it will be defined as the last non-missing value prior 
to the subject receiving study treatment (pre-dose) on Day 1.
7.2.2 Study Day
Throughout this SAP any references to “Day XX” refer to the pre-specified visits 
defined in the protocol (where the study treatment administration visit is Day 1).  
Data listings by visit will additionally present study day.  Study day will be calculated 
relative to the first date of administration of study treatment (Study Day 1).  For Part 3, 
the treatment period (Period 1/Period 2) and period day will also be referenced as per 
section 7.2.3.
7.2.3 Period and Period Day
Period is defined as a subject’s treatment window, where Period 1 relates to the 
treatment period of the first study treatment received by the subject and Period 2 refers 
to the treatment period of the second study treatment received by the subject. 
For the purposes of reporting, data collected from the administration of first study 
treatment in Period 1 until the day prior to administration of first study treatment in 
Period 2 will be assigned to Period 1.  Data collected on or after the day of the 
administration of first study treatment in Period 2 will be assigned to Period 2.  
Period day will be calculated relative to the first date of administration of study 
treatment in each period.  Data listings by visit will additionally present period and 
study day where appropriate.
7.2.4 Treatment Start and End
Treatment start is defined as the first day of administration of study drug (Day 1) for 
Parts 1 & 2 of the study. For Part 3, Treatment start is defined as Day 1 of treatment 
period 1. 
In Part 1 of the study, treatment is received as a single dose therefore treatment end 
is also Day 1.


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For Part 2, treatment end is defined as the final day of administration of study drug 
which is scheduled as Day 10. 
In Part 3, treatment is received as a single dose within the treatment period therefore 
treatment end is Day 1 of treatment period 2.
7.2.5 Planned dose and actual dose received
Planned dose of study drug depends on the cohort to which the subject was enrolled 
and will be determined by the SAC. Actual dose received is defined as the actual dose 
of study drug received regardless of enrolled cohort and is recorded on the electronic 
Case Report Form (eCRF).
7.2.6 Incomplete Dates
For calculation purposes, incomplete dates will be completed using worst-case, the 
most conservative value possible. For example, if the start date has a missing day 
value, the first day of the month will be imputed for study day computations. If day is 
missing for an end date, the last day of the month will be imputed. Similar logic will be 
assumed for missing month and year components.
7.2.7 Non-Numeric Values Recorded in Numeric Fields
In the case where a variable is recorded as “>x”, “≥x”, “<x” or “≤x” rather than an exact 
number, then for analysis purposes a value of x will be taken.  Where a range of values 
is quoted the midpoint of the range will be taken. 
7.3
Missing Data and Withdrawals
In general, data will not be imputed.  Where imputation may be deemed appropriate, 
information is detailed in the analysis descriptions.  
7.4
Analysis Sets
The Screened Set includes all subjects screened for the study irrespective if they were 
enrolled into the study.
The Enrolled Set includes all subjects who passed screening irrespective of whether 
they received the study treatment.
The Safety Analysis Set (SAF) will consist of all subjects who receive at least one 
dose of study treatment. Subjects will be analysed according to the treatment actually 
taken.   
The PK Concentration Set will consist of those subjects in the SAF who have at least 
one quantifiable serum PK concentration recorded. Subjects will be analysed 
according to the treatment actually taken. 
The PK Parameter Set will consist of those subjects in the SAF with sufficient 
concentration time data to determine at least one quantifiable serum PK parameter. 
Subjects will be analysed according to the treatment actually taken. 
The PK Sputum Concentration Set will consist of those subjects for Parts 2 & 3 in 
the SAF who have at least one quantifiable induced sputum PK concentration 
recorded. Subjects will be analysed according to the treatment actually taken.
All protocol deviations will be assessed by Zambon and documented on a case-by-
case basis prior to the database lock, and important deviations considered having a 


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serious impact on the PK analysis will lead to the relevant subject being excluded from 
the relevant sets.  
The definitions for the analysis sets are sufficient to determine the subjects included 
within these analysis sets and so do not require listing and agreeing prior to database 
lock.
For Part 3 of the study, planned study treatment sequence will be determined from the 
randomisation list. Actual treatment received will be derived by reconciling the kit 
number entered in to the CRF with the kit list supplied by Zambon. 
7.5
Data presentations
7.5.1 Parts 1 & 2 Specific Presentations
For each study part, safety and PK data will be summarised by ZP-059 dose only and 
all other data will be summarised in tabular form by ZP-059 dose group and overall.
Listings will be sorted by study part, ZP-059 dose group, screening number and 
date/time of assessment. 
Dose groups will be presented in the following order using these labels: 

ZP-059 5mg

ZP-059 XXmg, etc.
7.5.2 Part 3 Specific Presentations
Safety and PK data will be summarised by treatment group and all other data will be 
summarised in tabular form by treatment sequence and overall. 
Listings will be sorted by treatment or treatment sequence as appropriate, screening 
number and date/time of assessment.  
Treatment groups will be presented in the following order using these labels: 

ZP-059

Oral Voriconazole 
Treatment sequences will be presented in the following order using these labels: 

ZP-059 / Oral Voriconazole 

Oral Voriconazole / ZP-059
7.5.3 General Presentations
Graphical presentations of the data will also be provided where appropriate.
Only scheduled post-baseline assessments will be tabulated; post-baseline 
repeat/unscheduled assessments will not be tabulated, although they will be listed.
Eligibility, screen failures and analysis sets will be summarised using the Screened 
set.  Background and demographic characteristics, study completion/withdrawal, and 
protocol deviations will be summarised using the Enrolled Set. Prior/concomitant 
medications, administration of study treatment and exposure and safety will be 
summarised using the SAF.
All other data will be summarised using the SAF apart from PK, which will be 
summarised using the relevant PK sets. 


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Eligibility 
and 
screen 
failures 
will 
be 
listed 
using 
the 
Screened 
set. 
Completion/withdrawal and analysis set listings will be based on the Enrolled set. PK 
listings will be based on the PK sets. Safety listings will be based on the SAF set. All 
other listings will be based on the Enrolled set.
7.6
Disposition of Subjects
The number of all screened subjects will be presented overall. The number and 
percentage of all subjects enrolled and included in the SAF and PK analyses sets who 
completed the study and prematurely discontinued the study, who completed study 
treatment and prematurely discontinued study treatment, study duration and treatment 
duration (Part 2 only), will be summarised. The number and percentage of subjects 
will be summarised by their reasons for withdrawal from the study and study treatment.  
Study duration will be derived as the number of days between study Day 1 and the 
date of study completion or the date of early study withdrawal. 
Eligibility for each of the analysis sets along with reasons for exclusion will be listed.  
Inclusion and exclusion criteria will be listed.  Study completion/withdrawal data will be 
listed. Informed consent date and the protocol version enrolled under will also be 
listed.
7.7
Protocol Deviations
Prior to database lock, Zambon will provide the individual deviations and their 
classifications prior to database lock and analysis set assignment. 
Details of all important protocol deviations (date, deviation group, deviation category 
and specific details) will be listed.  
7.8
Background and Demographic Characteristics
7.8.1 Demography
Demographic characteristics (age, sex, and race), body measurements (height, weight 
and body mass index (BMI)) collected at Screening and time since diagnosis of 
asthma (Parts 2 & 3 only) will be summarised. For part 3, asthma severity will also be 
summarised.
Age is calculated in years on the date of first administration of study treatment.  
BMI will be reported using the values entered into the eCRF.
Time since asthma diagnosis is derived using the date of informed consent.  
All subject demographic data including informed consent will be listed.
7.8.2 Smoking History
Smoking history data will be listed only.
7.8.3 Medical History
Medical history events (not including asthma diagnosis) will be coded using the latest 
Medical Dictionary for Regulated Activities (MedDRA) dictionary version.  The version 
used will be indicated in the data summaries and listings.  The number and percentage 
of subjects will be presented for ongoing conditions and previous conditions (stop date 
prior to screening) separately by system organ class (SOC), and preferred term (PT), 


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where SOC and PT will be presented in decreasing frequency of the total number of 
subjects with medical history events. Subjects will only be counted once per SOC and 
PT term. All events will be listed.
7.9
Prior and Concomitant Medications
Medications will be coded using the latest World Health Organization Drug dictionary 
(WHO Drug) version.  The version used will be indicated in the data summaries and 
listings. 
Prior medications are defined as those taken within 28 days prior to screening.  
Medications that are ongoing at screening or started after screening will be deemed 
to be concomitant medications.  If medication dates are incomplete and it is not clear 
whether the medication was concomitant, it will be assumed to be concomitant.
For Part 3, the following rules will be used to define whether a medication is 
concomitant and which treatment they should be assigned to:

Concomitant to Period 1 only is defined as medication administered from first 
administration of study drug for Period 1 and finishing prior to the first 
administration of study drug for Period 2. 

Concomitant to Period 2 only is defined as starting from first administration of 
study drug in Period 2. 

A treatment starting before the end of Period 1 and continuing into Period 2 will 
be reported under both periods.

If medication dates are incomplete and it is not clear whether the medication 
was concomitant to a single treatment period, it will be assumed to be 
concomitant to both periods
The number and percentage of subjects taking concomitant medications will be 
summarised by medication class and standardised medication name, where 
medication class and standardised medication name will be presented alphabetically.  
In summary tables, subjects taking multiple medications in the same medication class 
or having the same standardised medication recorded multiple times in the study will 
be counted only once for that specific medication class and standardised medication 
name. 
Prior and concomitant medication data will be listed and flagged accordingly.
7.10
Administration of Study Treatment and Exposure
Details of the timings of treatment administration will be listed along with the number 
of doses of study treatment administered, total exposure, and the number and cause 
of dose interruptions. This will be listed by treatment period for Part 3 and include the 
treatment received.
7.11
Efficacy Analysis
Not applicable.


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7.12
Pharmacokinetics
7.12.1 Serum concentrations 
Serum concentrations of both voriconazole and N-oxide voriconazole will be 
summarised over time and listed for those in the PK Concentration set. Mean, SD, 
minimum, maximum and median will be presented.
Similar analyses will be completed for the PK parameters listed in section 3.2.2 for 
those subjects in the PK Parameters set. Additionally, the geometric mean, CV% and 
geometric SD will also be presented. 
Mean (±SD) serum concentration profiles will be plotted on the original scale and on 
the log scale. Samples below limit of quantification (BLQ) prior to the first quantifiable 
concentration will be set to zero. Samples with concentrations BLQ after the first 
quantifiable concentration will be set to ‘missing’ and omitted from the analysis. Other 
PK parameters will be calculated according to standard equations. 
If a value is considered to be anomalous due to being inconsistent with the expected 
PK profile, it may be appropriate to exclude this point from the PK analysis. However, 
the exclusion of data must have strong justification and will be documented in the raw 
data and in the clinical study report. The following conditions for PK parameter 
inclusion may also be applied:

AUC0-inf, kel, t½, CL/F (exception Part 2, Day 10) and Vz/F to be excluded if the 
regression does not include at least 3 different time points in the terminal phase 
(after Cmax, but excluding the concentration at tmax)

AUC0-inf, CL/F (exception Part 2, Day 10) and Vz/F, t½, kel to be excluded if the 
coefficient of determination, Adjusted R2 in the regression, is less than 0.8

AUC0-inf, CL/F and Vz/F is excluded if the %extrapolated area is greater than 
20% (exception CL/F and Vz/F in Part 2, Day 10)
Metabolite parent ratios will be estimated for Cmax and AUC across all parts of the 
study.
The following rules will be applied if there are BLQ or missing values (e.g. no result 
(NR)) in serum concentration data series to be summarised:

If an embedded BLQ value was set to missing for PK analysis, this value will 
be excluded from the summary statistics. Other BLQ values will be set to 0.

NR results will be set to missing.

If all the values are BLQ, then the arithmetic mean, arithmetic standard 
deviation (SD), median, min and max will be presented as zero, and the 
geometric mean and geometric coefficient of variation (CV) will be denoted as 
NC (not calculable).
The PK parameters will be listed together with the sample collection details for each 
study Part.
7.12.2 Induced Sputum Concentrations
For subjects in the PK Sputum Concentration set for Parts 2 (Day 7) and 3 (Days 1, 2 
and 3 for each treatment period) of the study, induced sputum plug and processed 
sputum concentrations of voriconazole and n-oxide voriconazole will be listed. Where 
there is sufficient data, induced sputum plug and processed sputum concentrations 
and PK parameters of voriconazole and n-oxide voriconazole may be summarised 


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over time. Mean (±SD) induced sputum concentration profiles may also be plotted on 
the original scale and on the log scale.  
7.12.3
Dose proportionality
Dose proportionality of ZP-059 will be assessed by fitting a power model as follows: 
 
𝑙𝑜𝑔10(𝑦) = 𝛼 + 𝛽 𝑙𝑜𝑔10(𝑑𝑜𝑠𝑒)
 
Where 𝛼 represents the random subject effects for intercept and dose. A value of 1 for 
β indicates perfect dose proportionality. Therefore, the estimate of β together with the 
corresponding 90% confidence interval (CI) will be used to quantify dose 
proportionality. The increase in concentration over the dose range will be estimated 
by the ratio of the expected concentration with the highest dose to that of the lowest 
dose.  This will be derived by back-transforming the difference on the log10 scale 
between the two doses and will be accompanied by its associated 90% confidence 
interval.  If the exposure is dose proportional there should be a fold increase equal to 
the ratio of highest: lowest dose across the dose range. 
If it isn’t possible to fit random subject slopes a common fixed effect slope will be fitted.
Dose proportionality will be assessed for each of the following PK endpoints for 
voriconazole and n-oxide voriconazole separately:

Cmax

AUC0-t, where t is 12 hours for Part 1, 24 hours for Part 2 and 96 hours for Part 
3. 

AUC0-inf
These will be performed separately for Part 1 and Part 2 at Day 1 and Day 10. This 
analysis will be performed if 3 or more dose levels are used for the Part. 
Dose proportionality will also be assessed using an analysis of variance (ANOVA) 
method. A mixed effects model will be fitted with fixed effects for dose and random 
effects for subject. The difference between the dose levels will be presented along 
with a 90% confidence interval and p-value.
7.12.4 Bioavailability
The PK endpoints (see Section 7.12.3) estimated from Part 3 of the study will be 
analysed to assess relative bioavailability of Inhaled Voriconazole (ZP-059) to Oral 
Voriconazole (VFEND®) by fitting a mixed effects analysis of variance (ANOVA) model 
to the loge transformed PK parameter including fixed effect terms for treatment, period, 
sequence and sex and a random effect term for subject (nested within sequence). The 
adjusted geometric mean ratio (GMR) (Inhaled: Oral) and the corresponding 
90%confidence interval (CI) for the adjusted GMR will be presented. 
In addition, the PK endpoints will be compared between asthma subjects in Part 3 and 
healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess 
relative bioavailability of the Inhaled Voriconazole (ZP-059) dose taken in Part 3 in 
these populations. An ANOVA model will be fitted to the loge transformed PK 


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parameter including terms for the population group (i.e., healthy subjects or asthma 
subjects) and sex. The adjusted GMR and 90% CI for the adjusted GMR for the 
comparison between the two populations for the relevant dose will be provided, where 
the ratio is defined as either Part 3 subjects/Part 1 subjects or Part 3/Part 2 subjects, 
depending on the comparison. 
7.13
SAFETY EVALUATION
The safety and tolerability of ZP-059 will be assessed based on AEs, clinical laboratory 
assessments, vital signs, ECGs, pulmonary function and pulse oximetry parameters.
Details regarding the evaluation of these data are given in the following respective 
sections. 
7.13.1 Adverse Events
AEs will be coded using the latest MedDRA dictionary version.  The version used will 
be indicated in the data summaries and listings. 
7.13.1.1
Treatment-emergent Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an AE that started on or 
after the start of the administration of study treatment.  If adverse event dates are 
incomplete and it is not clear whether the adverse event was treatment-emergent, it 
will be assumed to be treatment-emergent.
In Part 3 of the study, AEs are treatment emergent and accountable to the Period 1 
treatment if they started on or after the start of the administration of study treatment in 
Period 1 up to the first administration of study treatment in Period 2.  For Period 2, 
AEs are treatment emergent and accountable to the Period 2 treatment if they started 
on or after the start of the administration of study treatment in Period 2 up to the end 
of the follow-up period.  
A treatment related TEAE is defined as a TEAE that is related to the study treatment.  
If the TEAE has a missing relationship it is assumed to be related to the study 
treatment for analysis purposes. 
A summary table will present the following: 

TEAEs (events and subjects). 

Serious TEAEs (events and subjects). 

Serious study treatment related TEAEs (events and subjects).

TEAEs by severity (mild/moderate/severe) (events and subjects).

TEAEs by relationship to study treatment (events and subjects). 

TEAEs leading to withdrawal from study (subjects only). 

TEAEs leading to discontinuation of study treatment (subjects only).

Study treatment related TEAEs leading to discontinuation of study treatment 
(subjects only).

TEAEs leading to death (subjects only).
In the above summaries, if a subject experienced more than one TEAE, the subject 
will be counted once using the most related event for the “by relationship to study 


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treatment” and “related to study treatment” summaries, and by the worst severity for 
the “by severity” summary.
The following tables will be presented:

TEAEs by SOC and PT.
o
If a subject experienced more than one TEAE assigned to the same 
treatment, the subject will be counted once for each SOC and once for 
each PT within that treatment .  

TEAEs by PT.
o
If a subject experienced more than one TEAE assigned to the same 
treatment, the subject will be counted once for each PT within that 
treatment .  

TEAEs by SOC, PT and severity.
o
If a subject experienced more than one TEAE assigned to the same 
treatment, the subject will be counted once for each SOC and once for 
each PT at the worst severity/CTC grade within that treatment .  

TEAEs by SOC, PT and relationship to study treatment and the related 
categories (related/unrelated).
o
If a subject experienced more than one TEAE assigned to the same 
treatment, the subject will be counted once for each SOC and once for 
each PT using the most related event within that treatment .  
For all of the above, SOC and PT will be presented in decreasing frequency of the 
total number of subjects with TEAEs.
7.13.1.2
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an AE of scientific and medical interest 
and is defined as an AE that started on or after the start of administration of study 
treatment to the end of the safety follow up period.  
The following AESIs will be monitored during the study. 

Respiratory Events: 
o
Moderate or severe dyspnoea/wheeze
o
Moderate or severe cough
o
Moderate or severe bronchospasm 

Moderate or severe visual impairment/hallucination 

Anaphylaxis and severe allergic reaction 

Hepatotoxicity 
≥3X 
Upper 
Normal 
Limit 
(ULN) 
for 
Aspartate 
Aminotransferase (AST), Alanine Aminotransferase (ALT) and bilirubin

COVID-19
If necessary, a summary table will present the following

AESI (events and subjects). 

Non-serious AESIs (events and subjects). 


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Zambon study no: Z7240J01
Date: 28OCT2020 
Page 19 of 20
Version: 2.0
ST/form/010/12

Serious AESIs (events and subjects). 

Serious study treatment related AESIs (events and subjects).

AESIs by severity (mild/moderate/severe) (events and subjects).

AESIs by relationship to study treatment (events and subjects). 

AESIs leading to withdrawal from study (subjects only). 

AESI leading to discontinuation of study treatment (subjects only).

Study treatment related AESIs leading to discontinuation of study treatment 
(subjects only).

AESIs leading to death (subjects only).
7.13.1.3
Adverse Event Listings
Adverse event data will be listed in full and will include a treatment emergent flag, a 
special interest flag, the time of onset and cessation of event relative to first dosing of 
study treatment and duration of AE.
7.13.2 Clinical Laboratory Evaluation
Observed values and change from baseline in clinical chemistry, haematology, and 
urinalysis assessments will be summarised over time.  If the test results are reported 
in categorical format, the results will be summarised by subject counts and percentage 
for each category. Parameters will be presented as recorded in the external data. Each 
clinical chemistry, haematology and urinalysis parameter will be classed as low, 
normal and high based on the reference ranges.  
Clinical chemistry, haematology and urinalysis data will be listed separately including 
change from baseline and reference ranges. Flags will be populated to indicate all out 
of range values, classifications of values based on reference ranges and clinically 
significant values. Post-baseline unscheduled assessments will be also listed.
7.13.3 Vital Signs
Vital sign observed values and change from baseline by parameter will be summarised 
over time. Parameters will be presented in the same order as the eCRF. For vital signs 
data recorded on continuous scales, if more than one value is recorded at any one 
timepoint, the mean value will be presented. 
All vital sign data will be listed including change from baseline and reference ranges 
with flags to indicate all out of range values.
7.13.4 Pulmonary Function (Spirometry)
Spirometry observed values and change from baseline by parameter will be 
summarised over time. Parameters will be presented in the same order as the eCRF.
All spirometry data will be listed including change from baseline and reference ranges 
with flags to indicate all out of range values.
7.13.5 Electrocardiography (ECG)
ECG observed values and change from baseline by parameter will be summarised 
over time. Parameters will be presented in the same order as the eCRF.


Syne qua non study no: MET19010
Zambon study no: Z7240J01
Date: 28OCT2020 
Page 20 of 20
Version: 2.0
ST/form/010/12
For data recorded on continuous scales, if more than one value is recorded per 
assessment, the mean value will be presented.  For overall interpretation if more than 
one value is recorded per assessment, then the most severe of the respective 
readings will be taken.
All ECG results will be listed including change from baseline values and reference 
ranges with flags to indicate all out of range values and overall interpretation of the 
ECG (Normal, Abnormal Not Clinically Significant (NCS), and Abnormal Clinically 
Significant (CS)).
7.13.6 Physical Examination
Details of timings of physical examinations will be listed. 
7.13.7 Pregnancy test
Pregnancy test details will be listed.
7.13.8 Urine Drug Screen
Urine drug test details will be listed. Parameters will be presented in the same order 
as the eCRF.
7.13.9 Alcohol Breath Test
Alcohol breath test details will be listed.
7.13.10 SARS-CoV-2 Test
SARS-CoV-2 test details will be listed.
7.14
References
Not applicable.


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