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)
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
Avalyn Pharma, Inc.
68 participants
Jul 24, 2024
Interventional
Conditions
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.
Eligibility
Inclusion Criteria10
- Subjects will be enrolled into this study only if they meet all the following criteria:
- Are willing and able to provide voluntary written informed consent for the healthy volunteer to participate in the study and consent will be documented.
- Males or females, age 18-65 years.
- 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.
- Healthy volunteer’s body mass index (BMI) is between 18 and 32 kg/m2 (inclusive).
- 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.
- 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).
Exclusion Criteria13
- Healthy volunteers who meet any of the following criteria will be excluded from participating in the study:
- History of previous allergy or sensitivity to nintedanib.
- 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”.
- Healthy volunteers with known risk of gastrointestinal perforation, diverticular disease, and those who have undergone recent abdominal surgery.
- History of bleeding disorders or currently being treated with anticoagulants.
- Human Immunodeficiency Virus Positive (HIV+) Result.
- Active Hepatitis B or C.
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or bilirubin >1.5× upper limit of normal (ULN).
- Clinically significant abnormality in the opinion of the PI in baseline hematology or chemistry tests.
- Positive for drugs of abuse or alcohol use at screening or admission to Phase 1 facility.
- 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.
- Active respiratory tract infection within 2 weeks before IP administration.
- History of vasovagal collapses in past 3 years.
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Interventions
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.
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ACTRN12624000825550