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Trial registered on ANZCTR


Registration number
ACTRN12620001141932
Ethics application status
Approved
Date submitted
29/09/2020
Date registered
2/11/2020
Date last updated
16/01/2023
Date data sharing statement initially provided
2/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Study of AP02 (Nintedanib Solution for Inhalation) Delivered via the PARI eFlow®
Nebulizer System in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis or
Progressive Fibrosing Interstitial Lung Disease
Scientific title
A Phase 1 Study to evaluate the Pharmacokinetics, Safety and Tolerability of AP02 (Nintedanib Solution for Inhalation) Delivered via the PARI eFlow® Nebulizer System (registered) in Normal Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis or Progressive Fibrosing Interstitial Lung Disease
Secondary ID [1] 302364 0
None
Universal Trial Number (UTN)
U1111-1258-5679
Trial acronym
None
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Progressive, Fibrosing Interstitial Lung Diseases 319147 0
Idiopathic Pulmonary Fibrosis 319531 0
Condition category
Condition code
Respiratory 317107 317107 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a placebo-controlled study of 3 doses of Nintedanib Solution for Inhalation (AP02) (0.25 mg/mL) administered using the eFlow (registered) nebulizer to assess the pharmacokinetics, safety, and tolerability of AP02 in normal healthy volunteers (NHV), idiopathic pulmonary fibrosis patients and progressive fibrosing interstitial lung disease patients to be undertaken at a single site (Nucleus Network Melbourne). A total of 38 subjects are expected to be enrolled and each subject may only participate in one cohort.

Cohorts 1, 2, and 3 (NHV) (n = 2 placebo; n = 6 active in each cohort) will be run sequentially. Cohorts 1, 2, and 3 will receive a single ascending dose, at 0.5, 1, and 2 mg dose of AP02, respectively, administered once via inhalation using a single subject use eFlow nebulizer. Total administration time will vary with no administration expected to exceed 20 minutes. In each of these cohorts, the first 2 (sentinel) subjects (1 placebo/1 active) will be dosed initially. If no significant safety/tolerability events occur within 24 hours, the remaining 6 subjects in that cohort (1 placebo/5 active) will be dosed.

Cohort 4 (NHV) will receive AP02 at the maximum tolerated dose (MTD) and Cohort 5 (NHV) will receive oral nintedanib at 150 mg. Cohort 6 will enroll patients with IPF/PFILD and will receive AP02 at the MTD. Cohorts 4 – 6 will be conducted after the MTD is established in the first 3 cohorts. Cohorts 4 – 6 may be run simultaneously.

Cohort 4 (NHV) (n = 4 active) will be administered AP02 at the MTD from Cohorts 1-3. Cohort 4 will undergo bronchoalveolar lavage (BAL) 30 – 45 minutes post exposure. Cohort 5 (NHV) (n = 4 active) will be administered oral nintedanib at 150mg. Cohort 5 will undergo BAL 9 hours after dose. Cohort 6 (IPF/PFILD patients) (n = 6 active) will be administered AP02 at the MTD from Cohorts 1-3. Subjects with concomitant COPD or with smoking history or with current smoking status will be pretreated with 2 puffs (200µg) of salbutamol metered dose inhaler device within 30 minutes prior to inhalation of study drug.

If forced expiratory volume in one second (FEV1) in two or more subjects in any ascending dose cohort falls by greater than 10% at 15 minutes post-dose, all subsequent subjects will be pretreated with (90-100 µg) of salbutamol. Subjects will remain in the phase 1 clinic for 24 hours post-dose and then participate in a follow-up visit 7 days after dosing. The study may proceed to the next ascending dose cohort if no significant safety/tolerability events occur following review and as confirmed by the Safety Review Committee.

The Principal Investigator will oversee patient participation in the study. Specific training and procedures, such as eFlow instructions for use, will be outlined in the protocol and participant's informed consent form.

Study drug and eFlows will be shipped to the site pharmacy. Study drug will contain labeled vials packaged into individual kits for each subject. The designated unblinded Pharmacist at the site will dispense the kit (AP02 or placebo) to the blinded dose administrator for use based on the randomization. Further details are included in the 'Study Design' section.

The Investigator and Medical Monitor will oversee the safety of the subjects participating in the study. The Sponsor and Clinical Research Organization (CRO) will be responsible for study operations.
Intervention code [1] 318651 0
Treatment: Drugs
Comparator / control treatment
Inhaled Placebo. Those assigned to placebo will receive a single dose of placebo that is volume equivalent to the AP02 dose. Placebo contains:
- 0.0125 mg/mL riboflavin
- 0.45% (4.5 mg/mL) sodium chloride
- 0.5 mM (0.1206 mg/mL) sodium saccharin dihydrate
- Water
Control group
Placebo

Outcomes
Primary outcome [1] 325194 0
To evaluate the safety and tolerability of AP02 in normal healthy volunteers (NHV). Safety and tolerability will be assessed by reviewing the incidence and severity of adverse events, serious adverse events and suspected unexpected serious adverse reactions; clinically significant changes from pre-dose to post-dose in physical examination, vital signs, laboratory values, oximetry and spirometry results. Adverse events will be collected from the time of informed consent until the completion of the follow-up visit. Adverse events will be followed until event resolution and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
Timepoint [1] 325194 0
Immediately post-dose, at 24 hours post dose and at 7 days post dose
Secondary outcome [1] 387149 0
To determine the maximum tolerated dose (MTD) of AP02. The MTD will be evaluated in conjunction with the primary objective and assessed at the end of each cohort by the Safety Review Committee (SRC) which will consist of the Principal Investigator, Medical Monitor and a physician from Avalyn Pharma. The SRC will review the data for the following potential dose limiting events;
- Possible or probably drug-related moderate or severe adverse event
- Saturated oxygen (SaO2) less than 80% post-dose measured using pulse oximeter
- SaO2 decrease greater than 10% from baseline measured using pulse oximeter
- FEV1 decrease of greater than 15% measured using spirometry and symptomatic occurring after pretreatment with salbutamol

If the committee determines that a dose limiting event has occurred, the previous tolerated dose level will be the MTD. The committee may also recommend repeating a dose level or de-escalation of a dose level. Further if a dose limiting event occurs, the SRC may request the subsequent cohort is tested by adjusting the AP02 active concentration by dilution with a 0.125 mg/mL formulation.
Timepoint [1] 387149 0
Immediately post-dose and 24 hours post-dose
Secondary outcome [2] 387374 0
To determine the nintedanib plasma pharmacokinetics (PK) following delivery of a single dose of AP02. Analysis of plasma nintedanib concentrations will be completed with the following parameters to be calculated for each dose;
- Maximum Concentration (Cmax)
- Time to Peak Concentration (Tmax)
- Area Under the Curve (AUC)
- Estimated drug concentration from Time 0 to 24 Hours Post-Dose (AUC(0-24))
- Half-life (T1/12)
Timepoint [2] 387374 0
Analysis will be completed at pre-dose, 10 minutes, 30 minutes, 1, 2, 4, 6, 8 and 24 hours post-dosing
Secondary outcome [3] 402390 0
To determine the nintedanib bronchoalveolar lavage (BAL) pharmacokinetics (PK) following delivery of a single dose of AP02 (Cohort 4) or 150 mg oral nintedanib (Cohort 5). Analysis of BAL nintedanib concentrations will be completed with the following parameters to be calculated for each dose; - Maximum Concentration (Cmax) - Time to Peak Concentration (Tmax) - Area Under the Curve (AUC) - Estimated drug concentration from Time 0 to 24 Hours Post-Dose (AUC(0-24)) - Half-life (T1/12).
Timepoint [3] 402390 0
BAL fluid concentrations analysis will be completed at pre-dose and 30-45 minute timepoint after dosing for Cohort 4 and from pre-dose and 9 hours after dosing timepoint for Cohort 5.

Eligibility
Key inclusion criteria
A subject must meet all of the following inclusion criteria to be eligible to enroll in the clinical trial:

Inclusion Criteria for all Cohorts:
1. Males or females 18 to 55 years of age.
2. Female subjects must be:
• Of non-childbearing potential [surgically sterilized or post–menopausal (12 months with no menses without alternative medical cause)] OR
• Not pregnant, breast feeding or planning to become pregnant AND willing to comply with the medically acceptable contraceptive requirements of the study from Screening to at least 30 days after the last study drug administration.
3. Must be able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form (ICF).
4. Have not had any coronavirus disease 2019 vaccines within 7 days of the AP02 dose (Day 1) and, willing to not receive any coronavirus vaccine 7 days after receiving AP02.
5. Have not had any Influenza virus vaccines within 7 days of the AP02 dose (Day 1) and, willing to not receive any Influenza virus vaccine 7 days after receiving AP02.

Additional Inclusion Criteria for Cohort 6 only:
6. Diagnosis of IPF based on American Thoracic Society (ATS)/ European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) 2018 Guidelines OR
Diagnosis of PFILD by at least one of the following criteria within 24 months of screening visit:
a. Clinically significant decline in Forced Vital Capacity (FVC) % predicted based on a relative decline of greater than or equal to 10%
b. Marginal decline in FVC % predicted based on a relative decline of greater than or equal to 5 to less than 10% combined with worsening of respiratory symptoms
c. Marginal decline in FVC % predicted based on a relative decline of greater than or equal to 5 to less than 10% combined with increasing extent of fibrotic changes on chest imaging
d. Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging [Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Off label medications used in the clinical practice to treat PFILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus].
7. Males or females 18 to 80 years of age.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
The presence of any of the following exclusion criteria excludes a subject from study enrollment:

Exclusion Criteria for all Cohorts:
1. History of previous allergy or sensitivity to nintedanib.
2. History of reactive airways disease (such as asthma or chronic obstructive pulmonary disease (COPD), cystic fibrosis, or bronchiectasis (Cohorts 1-5 only). Cohort 6 will exclude cystic fibrosis and bronchiectasis but will allow a history of COPD or asthma. Patients with fully resolved childhood asthma with no recurrences or medical needs as an adult are permitted.
3. History of bleeding disorders or currently being treated with anticoagulants.
4. Human Immunodeficiency Virus Positive (HIV+) Result.
5. Active Hepatitis B or C.
6. Cigarette/e-Cigarette smoking or use of other nicotine or tobacco containing products within 7 days prior to study drug administration.
7. Positive for drugs of abuse or alcohol use at screening or admission to Phase 1 facility. A breathalyzer test will be used to screen for the presence of alcohol. A standard urine panel will be used to test for the following substances (with repeat testing for confirmation, as needed) (Cohorts 1-5 only):
• Opiates
• Methadone
• Cocaine
• Tetrahydrocannabinol
• Benzodiazepines
• Amphetamines / Methamphetamines
• Barbiturates
• 3,4-methylenedioxy-methamphetamine
• Phencyclidine
8. Participation in a clinical study with administration of an investigational drug product within the previous 30 days or 5 half-lives (t1/2) of the previously administered investigational product.
9. Donation of blood or significant blood loss within the 8 weeks prior to admission to Phase 1 facility.
10. Donation of plasma within the week prior to admission to Phase 1 facility.
11. Any other condition, which in the view of the investigator is likely to interfere with the study or put the subject at risk.
12. Use of any medication, which in the opinion of the investigator that that might interact with study drug or may lead to abnormal chemistry of hematology tests.
13. Aspartate aminotransferase or alanine aminotransferase (AST or ALT) > 1.5X upper limit of normal.
14. Clinically significant abnormality in the opinion of the principal investigator in baseline hematology or chemistry tests.
15. Use of anti-platelet drugs with the exception of low-dose aspirin for patients in Cohort 6.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Study drug assignment will be blinded to study subjects and study site personnel except for designated unblinded Pharmacist/s who will undertake subject randomization and dispensation against the provided randomization schedule. Unblinded Pharmacist/s will be located off-site to study subjects and have no contact with them.
Individual treatment disclosure envelopes (code-break envelopes) will also be provided to the unblinded Pharmacist. These code-break envelopes will be kept in a secure location) and the Investigator will be able to access these during the study for safety reasons. The code-break envelopes will be used by the Investigator if it is necessary to break the blind for an individual subject in an emergency. After completion of the study, all code-break envelopes will be destroyed with confirmation to Avalyn.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table created by computer software (i.e. computerized sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
As this is not a powered efficacy study, no formal sample size calculations were performed. The number of subjects proposed per cohort is considered sufficient for an exploratory study to assess the PK and safety of nebulized nintedanib. A sample size of 38 subjects is planned for this study.

Intent-to-Treat (ITT):
The ITT population will comprise all subjects and will be based on the treatment assignment, regardless of which dose level the subject actually received.

Per-Protocol (PP):
The PP population will comprise all subjects who have no major protocol deviations. The details of major protocol deviations will be defined in the statistical analysis plan. The PP population will be identified prior to unblinding.

Pharmacokinetic (PK):
The PK population will comprise all dosed subjects who have nintedanib concentrations for PK profiling and parameter calculations. These will be based on the actual dose level received. Placebo subjects will not be included in this analysis.

Safety:
The safety population will comprise all subjects who receive any amount of study drug and will be based on the cohort to which the subject was assigned.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/12/2020
Actual
3/12/2020
Date of last participant enrolment
Anticipated
31/10/2022
Actual
26/11/2022
Date of last data collection
Anticipated
7/11/2022
Actual
12/12/2022
Sample size
Target
38
Accrual to date
Final
38
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17596 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 31340 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 306795 0
Commercial sector/Industry
Name [1] 306795 0
Avalyn Pharma Pty Ltd
Country [1] 306795 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Avalyn Pharma Pty Ltd
Address
Level 17 HWT Tower 40 City Road Southbank VIC 3006
Country
Australia
Secondary sponsor category [1] 307346 0
None
Name [1] 307346 0
Address [1] 307346 0
Country [1] 307346 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306953 0
Alfred Health Human Research Ethics Committee
Ethics committee address [1] 306953 0
The Alfred Hospital 55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 306953 0
Australia
Date submitted for ethics approval [1] 306953 0
30/09/2020
Approval date [1] 306953 0
27/10/2020
Ethics approval number [1] 306953 0

Summary
Brief summary
This is a placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of 3 doses of Nintedanib Solution for Inhalation (AP02) (0.25 mg/mL) administered using the eFlow nebulizer in normal healthy volunteers, patients with idiopathic pulmonary fibrosis and patients with progressive, fibrosing interstitial lung disease. Eligible subjects in the normal healthy volunteer (NHV) cohorts (1 - 3) will be assigned to one of three cohorts, where they will receive a single dose of AP02 (or matching placebo) via inhalation for up to approximately 20 minutes.

Cohort 4 (NHV) will receive AP02 at the maximum tolerated dose (MTD) established in the first 3 cohorts and Cohort 5 (NHV) will receive oral nintedanib at 150 mg. Cohort 6 will enroll patients with IPF/PFILD and will receive AP02 at the MTD established in the first 3 cohorts.

The primary objective of this study is to evaluate the safety and tolerability of AP02, with this to be evaluated in each cohort by the Safety Review Committee and through review of the adverse events, physical examination, vital signs, laboratory, oximetry and spirometry values prior to and after dosing. The secondary objectives are to determine the maximum tolerated dose (MTD) of AP02, and the nintedanib plasma and bronchoalveolar lavage (BAL) pharmacokinetics (PK) following delivery of a single dose of AP02.

Sentinel dosing will be employed in the first three cohorts for this single site study with a total of approximately 24 volunteers (NHV) to be enrolled - up to 8 in each cohort with 2 sentinel subjects dose 24 hours before the remaining 6 subjects. Cohorts 4 – 6 may be run simultaneously and will enroll a total of 8 volunteers (NHV) and 6 IPF/PFILD patients.
Trial website
Trial related presentations / publications
Public notes
The only study cohort that is still open and actively recruiting participants (subjects) is Cohort 6. All others (Cohorts 1-5) have completed enrollment and are therefore now closed to recruitment. All 6 cohorts have received approval from the study’s Ethics Committee. The most recently approved study protocol amendment included a revision to the criteria for study participation that is related to COVID-19 vaccinations. In order to participate in the study, subjects must have not had any COVID-19 vaccines within 7 days of the AP02 dose (Day 1) and must be willing to not receive any COVID-19 vaccine 7 days after receiving AP02.

Contacts
Principal investigator
Name 105566 0
Dr Jason Lickliter
Address 105566 0
Nucleus Network, Level 5, Burnet Building, AMREP Precinct, 89 Commercial Rd, Melbourne, VIC 3004
Country 105566 0
Australia
Phone 105566 0
+61 3 9076 8960
Fax 105566 0
Email 105566 0
[email protected]
Contact person for public queries
Name 105567 0
Felix Woodhead
Address 105567 0
Avalyn Pharma Pty Ltd, Level 17 HWT Tower 40 City Road Southbank VIC 3006
Country 105567 0
Australia
Phone 105567 0
+61 398695922
Fax 105567 0
Email 105567 0
[email protected]
Contact person for scientific queries
Name 105568 0
Felix Woodhead
Address 105568 0
Avalyn Pharma Pty Ltd, Level 17 HWT Tower 40 City Road Southbank VIC 3006
Country 105568 0
Australia
Phone 105568 0
+61 398695922
Fax 105568 0
Email 105568 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual results will not be shared. Only aggregate data through publications will be shared.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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