A study to evaluate the safety and effectiveness of inhaled nintedanib in patients with idiopathic pulmonary fibrosis

Trial ID: 2025-523431-19-00
Protocol: AP02-003
Sponsor: Avalyn Pharma Inc.

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Diseases & Conditions

Idiopathic pulmonary fibrosis

Objectives

The primary objective is to evaluate the effect of inhaled nintedanib (AP02) compared to placebo on lung function over a 12-week period in participants with idiopathic pulmonary fibrosis. The secondary objectives include:

Evaluation of disease progression from baseline to week 12.
Assessment of changes in quantitative high-resolution computed tomography (HRCT) metrics from baseline to week 12.

The study also evaluates safety, efficacy, and pharmacokinetic properties.

Participants

The study population consists of 64 participants diagnosed with idiopathic pulmonary fibrosis. Eligible individuals include male and female participants aged 40 years or older. Selection is based on a diagnosis confirmed via medical records according to established clinical guidelines, supported by high-resolution computed tomography patterns or surgical lung biopsy results. Inclusion criteria require a diffusing capacity of the lungs for carbon monoxide between 30% and <80% of the predicted normal value and a forced vital capacity of at least 45% of the predicted normal value. Females of childbearing potential and males are required to utilize highly effective contraception methods throughout the study period.

Plans and Procedures

This Phase 2, randomized, double-blind, placebo-controlled, proof of concept study evaluates the safety, tolerability, and efficacy of an inhaled nintedanib solution in participants with idiopathic pulmonary fibrosis. The research methodology involves comparing the effects of two different doses of the test product against a placebo on lung function over a 12-week period. The study sequence begins with a screening visit to assess eligibility based on criteria such as age, diagnosis, and specific pulmonary function measurements including forced vital capacity and diffusing capacity of the lungs for carbon monoxide. Following successful screening, participants proceed to the treatment phase. The primary endpoint is the change from baseline in morning pre-dose forced vital capacity at week 12. Secondary endpoints include time to disease progression and changes in quantitative lung fibrosis metrics on high-resolution computed tomography. The total duration of participant involvement in the treatment period is 12 weeks.

Treatment

The experimental treatment AP02 High consists of nintedanib formulated as an inhalation solution. The administration involves an inhalation route at a dosage of 8 mg administered twice daily.

The experimental treatment AP02 Low consists of nintedanib formulated as an inhalation solution. The administration involves an inhalation route at a dosage of 4 mg administered twice daily.

The control group receives AP02 Placebo, which is an inactive substance administered as a placebo to evaluate the efficacy and safety of the test products in participants with idiopathic pulmonary fibrosis.

Efficacy

The efficacy of nintedanib inhalation solution will be evaluated in participants with idiopathic pulmonary fibrosis. The primary endpoint is the change from baseline in morning pre-dose forced vital capacity (FVC) measured in mL at Week 12.

Secondary efficacy assessments include:

Time to disease progression, defined as a decline in FVC percent predicted of ≥10% prior to Week 12, respiratory hospitalization, or death.
Change from baseline in quantitative lung fibrosis metrics on high-resolution computed tomography (HRCT) at Week 12.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Able to understand and sign a written informed consent form (ICF) consistent with International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) and local laws prior to study enrollment.
Able to understand the importance of adherence to study treatment and the study protocol, willing to follow all study requirements, including the concomitant medication restrictions, throughout the study, and willing and able to fully attend and complete all study visit days in the clinic.
Aged ≥40 years at Visit 1 (Screening).
Chest HRCT performed within 52 weeks prior to Visit 1 (Screening) with results available for documentation in site files.
A diagnosis of IPF, as confirmed by the Investigator via written medical records, according to American Thoracic Society (ATS)/ European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Asociación Latinoamericana de Tórax (ALAT) IPF guideline (Raghu et al., 2022) within 5 years of Visit 1 (Screening). If IPF diagnosis occurred greater than 5 years before Visit 1 (Screening), the Investigator should review eligibility with the Sponsor Medical Monitor.
Combination of HRCT pattern, and if available, surgical lung biopsy pattern, as assessed by the Investigator, consistent with a diagnosis of IPF.
DLCO (corrected for hemoglobin [Visit 1]): ≥30% to <80% predicted of normal performed within 52 weeks of Visit 1 (Screening).
FVC ≥45% predicted normal at Visit 1 (Screening) and Visit 2 (Day 1).
Male participants and female participants of childbearing potential (FOCBP; defined as females who are fertile, following menarche and until becoming post-menopausal unless permanently sterile*) agree to use highly effective contraception measures from the time of first dose of study drug (for the male participant) or the signing of the ICF (for the female participant), during the study, and until 90 days after the last dose of study drug. Participants agree not to donate eggs or sperm during the same period. Male participants must use a condom and female partners of male participants who are of childbearing potential must use a highly effective method of contraception. Highly effective contraception is defined below: a. A highly effective method of contraception is one that results in a low failure rate (i.e., <1% per year) when used consistently and correctly. Such methods of highly effective contraception include: i. sexual abstinence, defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. ii. a vasectomized partner iii. bilateral tubal occlusion iv. any effective intrauterine device/hormone-releasing system, and progesteroneonly (oral, injectable, or implantable) or combined (estrogen- and progesterone- containing; oral, intravaginal, or transdermal) hormonal contraception associated with inhibition of ovulation. Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not highly effective methods and are not acceptable methods of contraception for this study. b. The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced. Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.

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Exclusion Criteria

Current treatment with oral nintedanib or oral pirfenidone, or previous treatment with oral nintedanib or pirfenidone within 3 months prior to screening. Participants who previously received combination modality therapy with oral nintedanib and pirfenidone will be excluded.
Use of the following prohibited medications is exclusionary: a. Oral pirfenidone, or any other approved drug indicated for the treatment of IPF at any time unless used to treat an acute IPF exacerbation or disease progression (Section 11.3, Section 11.4) and in discussion with the Sponsor Medical Monitor. If the participant is treated with oral nintedanib during the study, the participant will discontinue study drug but continue with study visits. b. Azathioprine, cyclophosphamide, cyclosporine A received within 8 weeks of Visit 1 (Screening); NOTE: use is prohibited for the full study duration unless used to treat an acute IPF exacerbation or disease progression (Section 11.3, Section 11.4) and in discussion with the Sponsor Medical Monitor. c. Prednisone >15 mg/day or equivalent received within 2 weeks of Visit 1 (Screening). NOTE: use is prohibited for the full study duration unless used to treat an acute IPF exacerbation or disease progression (Section 11.3, Section 11.4) and in discussion with the Sponsor Medical Monitor. d. Any other investigational therapy received within the 30 days prior to Visit 1 (Screening), or 5 half-lives of the previously administered investigational therapy, whichever is longer. NOTE: use is prohibited for the full study duration. e. Vaccines for influenza, respiratory syncytial virus, pneumonia, or coronavirus disease 2019 (COVID-19) received within 2 weeks of Visit 1 (Screening).
Laboratory parameters at Visit 1 (Screening) a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ˃3x the upper limit of normal (ULN) or b. Total bilirubin >1.5x ULN
Lung function at Visit 1 (Screening) a. Pre-bronchodilator forced expiratory volume in 1 second (FEV1)/FVC ratio <0.7 as per Global Lung Function Initiative lower limit of normal (Quanjer et al., 2012; Stanojevic et al., 2022)
Bleeding risk a. Known genetic predisposition to bleeding b. Participants who require fibrinolysis, full-dose therapeutic anticoagulation (e.g., vitamin K antagonists, dabigatran, heparin, hirudin etc.), or high dose antiplatelet therapy i. Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g., enoxaparin 4000 I.U. subcutaneous per day), as well as prophylactic use of antiplatelet therapy (e.g., acetyl salicylic acid up to 325 mg/d, or clopidogrel at 75 mg/d, or equivalent doses of other antiplatelet therapy including dual therapy) is not excluded. c. History of severe hemoptysis
Thrombotic risk a. Known inherited predisposition to thrombosis. b. History of thrombotic event (including stroke and transient ischemic attacks) within 12 months of Visit 1 (Screening) c. Coagulation parameters: International normalized ratio >2, prolongation of prothrombin time and partial thromboplastin time by >50% of ULN.
Risk of gastrointestinal perforation a. Recent abdominal surgery within 4 weeks of Visit 1 (Screening) b. History of diverticular disease c. Receiving concomitant corticosteroids or non-steroidal anti-inflammatory drugs
Any of the following within 12 weeks of Visit 1 (Screening): a. Mild to moderate hemoptysis b. Hematuria c. Active gastrointestinal bleeding or ulcers d. Major injury or surgery, in the opinion of the Investigator
Life expectancy for any comorbidities/disease, including IPF, of <1 year, per Investigator assessment.
Likely to undergo a single or double lung transplant within 52 weeks in the opinion of the Investigator. Participants may be registered on the transplant list and still participate in the study if they are otherwise fully eligible.
Unstable asthma or chronic obstructive pulmonary disease (COPD) (i.e., requiring oral corticosteroids for an exacerbation of either asthma or COPD in the previous 12 weeks).
Active respiratory tract infection requiring treatment (whether on antimicrobial treatment or not) within 4 weeks of Visit 1 (Screening) and at any time throughout the Screening Period.
Current smokers of any product or material, or prior smokers who have smoked within the past 12 weeks before Visit 1 (Screening) and have an inability to refrain from smoking. This includes products containing nicotine and vaping; nicotine patches and nicotine gum are permitted. Cotinine testing will be done at Screening to confirm smoking status.
Current users of illicit drugs or drugs of abuse.
Women who are pregnant, nursing, or who plan to become pregnant while in the study.
Have symptoms consistent with bronchospasm and/or a decline in FEV1 of ≥20% after saline nebulization during the Screening Period. At the discretion of the Investigator, a marked increase in cough following saline nebulization not ameliorated by inhaled bronchodilator therapy may also constitute exclusion from participation in the study.
In the opinion of the Investigator, any other clinically significant pulmonary or pleural abnormalities.
Cardiovascular diseases, any of the following: a. Severe hypertension (systolic blood pressure [SBP] >180 mmHg and/or diastolic blood pressure [DBP] >110 mmHg), and participants with severe hypotension (SBP <90 mmHg and/or DBP <50 mmHg), within 12 weeks of Visit 1 (Screening) b. Hypertension or hypotension considered not controlled in line with clinical standards c. Myocardial infarction within 24 weeks of Visit 1 (Screening) d. Unstable cardiac angina within 24 weeks of Visit 1 (Screening) e. Class IV New York Heart Association chronic heart failure.
Moderate to severe hepatic impairment per the Child-Pugh scoring system (Class B or C) or end-stage liver disease.
Severe renal impairment: less than 30 mL/min creatinine clearance as determined via the central laboratory testing of screening blood samples.
History of malignancy within the past 5 years (except for carcinoma in situ of the uterine cervix, basal cell carcinoma, non-periorificial squamous cell carcinoma of the skin that has been treated with no evidence of recurrence, and squamous cell carcinoma of the skin if fully resected).
Any chronic or clinically significant medical condition that in the opinion of the Investigator would jeopardize the safety or rights of the participant or which would impact interpretation of their study data.
Previous participation in an Avalyn-sponsored clinical study of AP01 (pirfenidone inhalation solution) or AP02 (nintedanib solution for inhalation).
Participation in a concurrent clinical study or in a clinical study in which an investigational drug product was administered within the previous 30 days, or 5 half-lives of the previously administered investigational drug product, whichever is longer. Note: Participants in registry studies can be included in this study.
Not a suitable candidate for enrollment or unlikely to comply with the requirements of this study, as assessed by the Investigator.