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
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
Avalyn Pharma Pty Ltd
38 participants
Dec 3, 2020
Interventional
Conditions
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.
Eligibility
Inclusion Criteria14
- Males or females 18 to 55 years of age.
- 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.
- Must be able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form (ICF).
- 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.
- 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.
- 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].
- Males or females 18 to 80 years of age.
Exclusion Criteria24
- History of previous allergy or sensitivity to nintedanib.
- 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.
- History of bleeding disorders or currently being treated with anticoagulants.
- Human Immunodeficiency Virus Positive (HIV+) Result.
- Active Hepatitis B or C.
- Cigarette/e-Cigarette smoking or use of other nicotine or tobacco containing products within 7 days prior to study drug administration.
- 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
- ,4-methylenedioxy-methamphetamine
- Phencyclidine
- 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.
- Donation of blood or significant blood loss within the 8 weeks prior to admission to Phase 1 facility.
- Donation of plasma within the week prior to admission to Phase 1 facility.
- Any other condition, which in the view of the investigator is likely to interfere with the study or put the subject at risk.
- 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.
- Aspartate aminotransferase or alanine aminotransferase (AST or ALT) > 1.5X upper limit of normal.
- Clinically significant abnormality in the opinion of the principal investigator in baseline hematology or chemistry tests.
- Use of anti-platelet drugs with the exception of low-dose aspirin for patients in Cohort 6.
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Interventions
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.
Locations(1)
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ACTRN12620001141932