Study to Compare the Pharmacokinetics and Pharmacodynamics of ASA Powder for Oral Inhalation With Non-enteric-coated Chewable Aspirin in Adult Subjects With Obstructive or Restrictive Pulmonary Function

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare the pharmacokinetics (PK) pharmacodynamics (PD), safety and tolerability of acetylsalicylic acid powder for oral inhalation (I-ASA) with non-enteric-coated chewable aspirin (C-ASA) in adult subjects with obstructive or restrictive pulmonary function. In the first treatment period, subjects will be randomized to receive either a single dose (100 mg) of I-ASA powder via a Dry Powder Inhaler (DPI) OR a single dose (162 mg) of C-ASA tablets. After a washout period, subjects will be crossed over to receive the other treatment in the second treatment period. All subjects will receive both treatments during the study. Each single dose treatment will be followed by up to 24 hours of serial post-dose PK, PD, and safety/tolerability assessments.

Detailed Description
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Up to 16 adult males and females subjects are planned for enrollment in this study, to achieve a minimum of 10 subjects with evaluable PD/PK, safety, and tolerability data: 5 subjects with obstructive lung function [i.e., diagnosed with chronic obstructive pulmonary disease (COPD)]; and 5 subjects with restrictive lung function

Official Title
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A Single-dose, Open-label, Multi-center, Randomized, 2-treatment Crossover Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Acetylsalicylic Acid Powder for Oral Inhalation With Non-enteric-coated Chewable Aspirin in Adult Subjects With Obstructive or Restrictive Pulmonary Function

Conditions
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Obstructive Pulmonary Function, Restrictive Pulmonary Function

Intervention / Treatment
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* Drug: single dose (100 mg) of ASA
* Drug: single dose (162 mg) of non-enteric-coated chewable aspirin tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Cohorts Subjects must meet all of the following criteria to be included in the study: Male or female, ≥ 40 years of age. BMI >18.0 and <35.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females. Clinically stable as determined by medical history, physical examination, vital signs, and clinical laboratory evaluation. Female subjects of non-childbearing potential must be: post-menopausal; or surgically sterile at least 3 months prior to first dosing. Sexually active female subjects of childbearing potential must be willing to use an acceptable contraceptive method throughout the study as detailed in protocol. Smoker (no more than 25 cigarettes or equivalent daily) or non-smoker. Obstructive Pulmonary Function Cohort Subject with a smoking history of at least 10 pack-years. Subject with an established diagnosis of COPD at least 12 months prior to the screening visit AND confirmed at screening by spirometry, with a post bronchodilator FEV1 greater than 40% and equal to or less than 70% of the subject's normal predicted value and a post-bronchodilator FEV1 greater than 40% and equal to or less than 70% of the subject's normal predicted value and a post-bronchodilator FEV1/ FVC ratio < 0.70. Subject on stable uninterrupted maintenance COPD therapy for at least 3 months prior to screening as per SoC and without any history of moderate or severe exacerbations within 6 months prior to screening. Restrictive Pulmonary Function Cohort Subject with a history and documented prior diagnosis of underlying chronic respiratory or cardiac disease with restrictive pulmonary function as confirmed at the screening visit by: FEV1/FVC ≥ 0. 7 and FVC < LLN (or < 80% predicted) and TLC < 5th percentile predicted (or < 80% predicted) and DLCO ≤ 75% to ≥ 35% predicted Continued uninterrupted SoC therapy for underlying disease for at least 12 consecutive weeks immediately prior to screening. Exclusion Criteria: All Cohorts: Presence of clinically significant uncontrolled or unstable cardiovascular, pulmonary, hepatic, renal, endocrinological, hematological, immunologic, metabolic, psychological, neurological, or gastrointestinal disease. Any new clinically significant abnormal finding at physical examination at screening. Positive serology test results for HBsAg, HCV antibody, or HIV antigen and antibody, or TB test at screening. Positive pregnancy test or lactating female subject. Positive urine drug screen or alcohol breath test. Positive test for active COVID-19. Known allergic reactions, hypersensitivity or contraindications to ASA, ibuprofen, other NSAID, or other related drugs, or to any excipient in the formulation. Known lack of response (lack of effect) to aspirin in the past. Clinically significant ECG abnormalities or vital signs abnormalities at screening. Clinically significant abnormal laboratory parameters at screening Presence of active or latent tuberculosis. History of asthma, including childhood asthma, syndrome of asthma, rhinitis (including allergic rhinitis), nasal polyps, angioedema, urticaria, angioedema, or bronchospasm that in investigator's opinion is not suitable to participate in the study. Subject with current asthma defined as post-bronchodilator FEV1 > 12% increase AND >200 ml absolute increase from pre-bronchodilator values. History of non-trauma related hemorrhage. Restrictive Pulmonary Function Cohort Subject had lung surgery, with lung removal, as the reason for restrictive pulmonary function. Subject receiving systemic corticosteroid treatment of prednisone > 10 mg/day or equivalent within 3 months of screening. Subject suffers from restrictive pulmonary function, co-existent with obstructive pulmonary function disease. Subject has baseline resting oxygen saturation of < 89% on room air. Subject in need of continuous oxygen use and/or prescribed long-term continuous home oxygen therapy. Other Protocol defined I/E criteria that apply

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: I-ASA 100mg, then C-ASA 162mg tablet<br>Treatment A: Single dose of 100 mg ASA powder for oral inhalation (I-ASA) via DPI. Treatment B: Single dose of 162 mg chewable non-enteric-coated Aspirin (C-ASA) tablets. | Drug: single dose (100 mg) of ASA<br>* powder for oral inhalation via a Dry Powder Inhaler (DPI)<br>Drug: single dose (162 mg) of non-enteric-coated chewable aspirin tablets<br>* orally administered<br>|
| Experimental: Arm 2: C-ASA 162mg tablet, then I-ASA 100mg<br>Treatment A: Single dose of 162 mg chewable non-enteric-coated Aspirin (C-ASA)tablets. Treatment B: Single dose of 100 mg ASA powder for oral inhalation (I-ASA) via DPI. | Drug: single dose (100 mg) of ASA<br>* powder for oral inhalation via a Dry Powder Inhaler (DPI)<br>Drug: single dose (162 mg) of non-enteric-coated chewable aspirin tablets<br>* orally administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration of ASA (Cmax) |  | pre-dose and 24 hours post-dose | 
| Area under the ASA plasma concentration versus time curve (AUC0-inf) |  | pre-dose and 24 hours post-dose | 
| Area under the ASA plasma concentration versus time curve (AUC0-t) |  | pre-dose and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax of plasma concentrations of ASA. |  | assessed up to 24 hours post-dose | 
| Tmax of plasma concentrations of SA. |  | assessed up to 24 hours post-dose | 
| Peak Plasma Concentration (Cmax) of SA. |  | minutes post-dose: 2, 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 720 | 
| Area under the plasma concentration versus time curve (AUC0-inf) of SA. |  | minutes post-dose: 2, 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 720 | 
| Area under the plasma concentration versus time curve (AUC0-t) of SA. |  | minutes post-dose: 2, 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 720 | 
| Serum thromboxane B2 (TxB2) serum concentration - Area under the effect curve (AUEC) of the % Change from baseline (CFB) in serum TxB2 concentration (TxB2 suppression). |  | 24 hours post-dose | 
| TxB2 serum concentration - AUEC of the % CFB in serum TxB2 concentration (TxB2 suppression). |  | 20 minutes post-dose | 
| TxB2 serum concentration - AUEC of the % CFB in serum TxB2 concentration (TxB2 suppression) |  | 30 minutes post-dose | 
| Proportion of subjects achieving significant inhibition of platelet aggregation (<550 Aspirin Reaction Units [ARU]) |  | 2 minutes | 
| Time to significant reduction in platelet aggregation (<550 ARU) |  | assessed up to 24 hours post-dose | 
| Time to half-maximal % inhibition (suppression) of serum TxB2 (ID-50). |  | assessed up to 24 hours post-dose | 
| Time to maximum % inhibition of serum TxB2. |  | assessed up to 24 hours post-dose | 
| Time to maximum inhibition of platelet aggregation, assessed by VerifyNow Aspirin test. |  | assessed up to 24 hours post-dose | 
| Maximum % CFB in ARU assessed by VerifyNow tests. |  | assessed up to 24 hours post-dose | 
| Maximum % CFB in urinary 11-dehydro-TxB2. |  | assessed up to 24 hours post-dose | 
| Maximum % CFB in serum 6-keto-PGF1α levels. |  | assessed up to 24 hours post-dose | 
| Incidence and frequency of adverse events |  | Screening through the 7-day follow-up period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASA, acetylsalicylic acid, cyclooxygenase-1 enzyme, COPD, oral inhalation, inhaled, myocardial Infarction