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Trial registered on ANZCTR


Registration number
ACTRN12624000825550
Ethics application status
Approved
Date submitted
31/05/2024
Date registered
4/07/2024
Date last updated
5/11/2024
Date data sharing statement initially provided
4/07/2024
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 to Evaluate the Safety, Tolerability, and Pharmacokinetics of AP02 in Healthy Volunteers (AP02-002)
Scientific title
A Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of AP02 (nintedanib solution for inhalation) delivered via the eFlow® Nebulizer System in healthy volunteers
Secondary ID [1] 312178 0
None
Universal Trial Number (UTN)
U1111-1308-2472
Trial acronym
Linked study record
Study ACTRN12620001141932 (AP02-001) was a Phase 1 study that previously evaluated 3 single doses of AP02 (Nintedanib solution for inhalation) delivered via the PARI eFlow Nebulizer in both healthy volunteers and patients with idiopathic pulmonary fibrosis or progressive fibrosing interstitial lung disease. Study AP02-002 aims to further evaluate the safety, tolerability, and pharmacokinetics of additional single and multiple dose levels of AP02 in healthy volunteers.

Health condition
Health condition(s) or problem(s) studied:
Idiopathic Pulmonary Fibrosis 333832 0
Condition category
Condition code
Respiratory 330507 330507 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
AP02, or nintedanib solution for inhalation, is an investigational drug being studied as a potential treatment for Idiopathic Pulmonary Fibrosis (IPF). To better determine the safety, tolerability, and pharmacokinetic profile of AP02, this study will enroll healthy volunteers to either a Single Ascending Dose (SAD) arm, wherein they will receive a single dose of AP02 administered via nebulization, or to a Multiple Ascending Dose (MAD) arm, wherein participants will receive up to 13 doses of AP02 (administered twice daily) over the course of 7 days. Some participants will receive placebo instead of AP02.

Up to 68 total healthy volunteers will be enrolled between the SAD and MAD portions of the study. Cohorts 1-3 will receive a single ascending dose (2, 4, 8 mg of AP02, respectively). In each of these cohorts, the first 2 (sentinel) healthy volunteers (1 placebo/1 active) will be dosed initially. If no significant safety/tolerability events occur within 24 hours, the remaining 6 healthy volunteers in that cohort (1 placebo/5 active) will be dosed. The study may proceed to the next ascending dose cohort if no significant safety/tolerability events occur in the 6 healthy volunteers (dosed after sentinels). Following completion of Cohort 3, up to 12 healthy volunteers in Cohort 4 will be dosed with a single dose of AP02 (to be determined [TBD], not to exceed 8 mg, no sentinel subjects) and undergo a bronchoalveolar lavage (BAL) procedure post dose to collect BAL fluid for both BAL and ELF pharmacokinetic assessments. All participants in Cohort 4 will receive active AP02 (no placebo) based on the maximum tolerated dose as determined from Cohorts 1-3. An additional single dose cohort (Cohort 5) of up to 8 healthy volunteers (2 sentinel [1 placebo/1 active] following by 6 active) may be recruited and dosed up to 16 mg considering the safety observed at the lower dose levels.

In the MAD portion of the study, Cohorts 6-8 will receive multiple ascending doses twice daily (every 12 hours) for 6 days (2, 4, and 8 mg of AP02, respectively [doses may be adjusted at determination of the PI]) with the morning dose on Day 7 being the final dose. Two sentinel healthy volunteers will be designated and dosed in the same manner as described for Part 1 of the study. If no significant safety/tolerability events occur within 24 hours, the remaining 6 healthy volunteers in each Cohort 6-8 (1 placebo/5 active) will be dosed.

Healthy volunteers will present at the clinical site where site staff trained in use of the nebulizer will oversee administration of AP02 or placebo. The Principal Investigator will oversee healthy volunteer participation in the study. Each healthy volunteer on the study will receive either 1 (SAD) or 13 (MAD) doses of medication. Study site personnel will perform drug accountability procedures as outlined in the pharmacy manual for the study. Any healthy volunteers that are not compliant with study procedures will be documented as protocol deviations for the study.

Study drug and eFlow nebulizers will be shipped to the site pharmacy. Study drug will contain labeled ampoules packaged into individual kits, labeled in compliance with regulations. The site pharmacy staff will prepare the assigned investigational product dose for a given healthy volunteer in the pharmacy and the dose will be transferred to where the dose will be administered.

A Safety Review Committee (SRC) including the Principal Investigator, Medical Monitor, and a physician from the Study Sponsor will oversee the safety of volunteers participating in the clinical trial. The SRC will be responsible for reviewing data between dosing cohorts prior to allowing dose escalation to proceed.

Within one-week post-final dose, healthy volunteers will have a final, follow-up visit in the clinic. Any significant laboratory abnormalities collected during the study will be followed to resolution.
Intervention code [1] 328621 0
Treatment: Drugs
Comparator / control treatment
Healthy volunteers may receive placebo instead of active AP02 as part of the clinical trial. This placebo will be identical in appearance, volume, and taste to investigational AP02 and contain the same components with exception to nintedanib.
Control group
Placebo

Outcomes
Primary outcome [1] 338274 0
To assess the safety and tolerability profile of AP02 when administered in healthy volunteers as single ascending doses (SAD, Part 1).
Timepoint [1] 338274 0
Immediately post-dose, again 12-30 hours post-dose, and then within 3-5 days of final dose at the follow-up visit.
Primary outcome [2] 338515 0
To assess the safety and tolerability profile of AP02 when administered in healthy volunteers as multiple ascending doses (MAD, Part 2)
Timepoint [2] 338515 0
Immediately post-dose each day, and at intervals of 24 hours post-dose, and 30 hours post-final dose. A final assessment will occur within 5-7 days of final dose at the follow-up visit.
Secondary outcome [1] 436238 0
To characterize the pharmacokinetic (PK) plasma profile of AP02 following single dosing.
Timepoint [1] 436238 0
Pre-dose and at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12, hours, 24, hours, and 30 hours post-dose.
Secondary outcome [2] 436239 0
To characterize the pharmacokinetic (PK) plasma profile of the AP02 metabolite, BIBF1202, following single dosing.
Timepoint [2] 436239 0
Pre-dose and at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, and 30 hours post-dose.
Secondary outcome [3] 436240 0
To characterize the pharmacokinetic (PK) profile of AP02 following multiple dosing.
Timepoint [3] 436240 0
On Day 1 and Day 7, pre-dose and then post-dose at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 12 hours. Following the dose on Day 7, at 24 hours and 30 hours post-dose. On Day 2 and Day 5, pre-dose only.
Secondary outcome [4] 436241 0
To characterize the pharmacokinetic (PK) parameters of the AP02 metabolite, BIBF1202, following multiple dosing.
Timepoint [4] 436241 0
On Day 1 and Day 7, pre-dose and then post-dose at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 12 hours. Following the dose on Day 7, at 24 hours and 30 hours post-dose. On Day 2 and Day 5, pre-dose only.
Secondary outcome [5] 436242 0
To determine the bronchoalveolar fluid (BALF) pharmacokinetics (PK) of AP02 following single dose administration with the eFlow Nebulizer System (Cohort 4 only).
Timepoint [5] 436242 0
At 45 minutes, 4 hours, or 12 hours post-dose.
Secondary outcome [6] 436243 0
To determine the epithelial lining fluid (ELF) pharmacokinetics (PK) of AP02 following single dose administration with the eFlow Nebulizer System (Cohort 4 only).
Timepoint [6] 436243 0
At 45 minutes, 4 hours, or 12 hours post-dose.

Eligibility
Key inclusion criteria
Subjects will be enrolled into this study only if they meet all the following criteria:
1. Are willing and able to provide voluntary written informed consent for the healthy volunteer to participate in the study and consent will be documented.
2. Males or females, age 18-65 years.
3. Female healthy volunteers must be:
- Of non-childbearing potential [surgically sterilized or post–menopausal (12 months with no menses without alternative medical cause)] OR
- Not pregnant, breastfeeding 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.
- Male healthy volunteers must commit to using condoms during the course of the study.
4. Healthy volunteer’s body mass index (BMI) is between 18 and 32 kg/m2 (inclusive).
5. Healthy volunteer is medically healthy with no clinically significant or relevant abnormalities in medical history, physical exam, vital signs, ECG, or laboratory evaluations (hematology, chemistry, and urinalysis) as assessed by the Investigator.
6. Healthy volunteers must have an expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio of >0.80. Alternatively, if the healthy volunteer fails to qualify as per the required FEV1/FVC ratio of > 0.80, then eligibility can be assessed using the Global Lung Initiative Lower Limit of Normal (GLI LLN) calculator (gli-calculator.ersnet.org/index.html).
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers who meet any of the following criteria will be excluded from participating in the study:
1. History of previous allergy or sensitivity to nintedanib.
2. History of reactive airways disease (including asthma or chronic obstructive pulmonary disease [COPD]), cystic fibrosis, or bronchiectasis. Patients with fully resolved childhood asthma with no recurrences or medical needs as an adult are permitted”.
3. Healthy volunteers with known risk of gastrointestinal perforation, diverticular disease, and those who have undergone recent abdominal surgery.
4. History of bleeding disorders or currently being treated with anticoagulants.
5.Human Immunodeficiency Virus Positive (HIV+) Result.
6. Active Hepatitis B or C.
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or bilirubin >1.5× upper limit of normal (ULN).
8. Clinically significant abnormality in the opinion of the PI in baseline hematology or chemistry tests.
9. Positive for drugs of abuse or alcohol use at screening or admission to Phase 1 facility.
10. 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.
11. Active respiratory tract infection within 2 weeks before IP administration.
12. History of vasovagal collapses in past 3 years.

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 or placebo 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 the Study Sponsor.
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
This is not a powered efficacy study, therefore there is no formal statistical hypothesis. No formal sample size calculations were performed. The number of healthy volunteers proposed per cohort is considered sufficient for an exploratory study to assess the PK and safety of nebulized nintedanib single and repeat doses. Up to 68 healthy volunteers are planned for enrollment in this study.

The safety analysis population will include randomized healthy volunteers who receive any amount of study drug and have at least one postbaseline safety assessment (which can include a response from a healthy volunteer indicating that no adverse events occurred).

The PK population will include all dosed healthy volunteers who have nintedanib concentrations for PK profiling and parameter calculations. These will be based on the actual dose level received. Placebo healthy volunteers will not be included in this analysis.

The intent-to-treat population will include all randomized healthy volunteers who receive at least one dose of study drug.

The per protocol analysis set will include all healthy volunteers who have no major protocol deviations. The precise reasons for excluding healthy volunteers from the per protocol population will be fully defined and documented prior to unblinding.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
17/07/2024
Actual
24/07/2024
Date of last participant enrolment
Anticipated
28/12/2024
Actual
Date of last data collection
Anticipated
25/01/2025
Actual
Sample size
Target
68
Accrual to date
32
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26554 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 42594 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 316545 0
Commercial sector/Industry
Name [1] 316545 0
Avalyn Pharma, Inc.
Country [1] 316545 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Avalyn Pharma, Inc.
Address
Country
United States of America
Secondary sponsor category [1] 318727 0
Commercial sector/Industry
Name [1] 318727 0
Novotech CRO
Address [1] 318727 0
Country [1] 318727 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315338 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315338 0
https://www.alfredhealth.org.au/research/ethics-research-governance
Ethics committee country [1] 315338 0
Australia
Date submitted for ethics approval [1] 315338 0
27/05/2024
Approval date [1] 315338 0
01/07/2024
Ethics approval number [1] 315338 0

Summary
Brief summary
This is a placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of multiple dose levels of AP02 (Nintedanib Solution for Inhalation) administered using the eFlow Nebulizer in healthy volunteers, The purpose of this study is to learn about the study drug properties and determine what doses of AP02 are safe and well-tolerated in humans.

AP02 is a liquid solution that is inhaled into the lungs with a device known as a nebuliser (the eFlow Nebulizer). The nebuliser releases the liquid as tiny particles a person can breathe in through their mouth to directly target the lung tissue, which is the primary disease site.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134386 0
Dr Sam Francis
Address 134386 0
Nucleus Network Pty Ltd., Level 5, Burnet Tower, 89 Commercial Rd, Melbourne, VIC 3004
Country 134386 0
Australia
Phone 134386 0
+61 03 8593 9801
Fax 134386 0
Email 134386 0
[email protected]
Contact person for public queries
Name 134387 0
Dr. Craig Conoscenti
Address 134387 0
Avalyn Pharma, Inc., 245 First St., 18th Floor, Cambridge, MA 02142
Country 134387 0
United States of America
Phone 134387 0
+1 206 707 0304
Fax 134387 0
Email 134387 0
[email protected]
Contact person for scientific queries
Name 134388 0
Dr. Craig Conoscenti
Address 134388 0
Avalyn Pharma, Inc., 245 First St., 18th Floor, Cambridge, MA 02142
Country 134388 0
United States of America
Phone 134388 0
+1 206 707 0304
Fax 134388 0
Email 134388 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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No documents have been uploaded by study researchers.

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