Trial to Determine Effective Aspirin Dose in COPD

Randomized Trial to Determine Effective Aspirin Dose in COPD

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. Current treatments for COPD focus on inhaler therapies that do not address manifestations of the disease on other organ systems. Platelets, which are small blood cells that typically help with clotting, are also involved in generalized inflammation and dysfunctionality of immune cells when these cells become activated. Activated platelets have long been known to play a role in the development of cardiovascular disease. However, there is recent evidence that activated platelets may be involved in worse respiratory symptoms in COPD independent of cardiovascular disease. Individuals with COPD who are taking aspirin, which is an antiplatelet agent that blocks activation of platelets, have been shown to have improved respiratory symptoms, fewer COPD flares, and lower mortality. The investigators' ultimate goal is to study whether aspirin use improves respiratory symptoms independent of cardiovascular disease. The investigators are conducting the current pilot trial to determine the optimal dose of aspirin that blocks platelet activation in this population and investigate whether there are any blood or urine tests that can help with understanding response to therapy. The results will inform the design of a larger trial investigating clinical outcomes. The investigators hypothesize that daily low-dose aspirin will not be sufficient to adequately suppress platelet activation and that an aspirin dose of at least 162mg daily will be necessary.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Aspirin 81mg; Drug: Aspirin 162 mg; Drug: Aspirin 325mg

Detailed Description

The trial will enroll individuals with chronic obstructive pulmonary disease (COPD). The primary design will be a randomized double-blind 6-sequence, 3-period, 3-treatment sequential crossover trial for which the investigators will randomize participants to receive 81mg, 162mg, and 325mg aspirin in one of six pre-specified sequences with a 14-day washout period between doses. Participants will have three follow-up visits after randomization.

Individuals who agree to participate in the clinical trial will be randomized to one of six treatment sequences using a computer algorithm at the baseline study visit. Study drug will be provided by the Johns Hopkins Research Pharmacy and participants instructed to take one pill once per day at the same time. All study drug doses will be compounded to appear identical and placed in identical containers fitted with an electronic cap for monitoring medication adherence. Participants will be scheduled to return for a follow-up visit at two weeks, six weeks, and ten weeks after randomization. Blood and urine samples will be collected at each visit. Data will be collected by the principal investigator or trained study coordinator and will be electronically entered into a database stored on the secure Johns Hopkins servers through an online interface that is password protected. Urine will be collected and analyzed for 11-dehydro-thromboxane B2 at each study visit and constitutes the primary outcome of the study. Secondary outcomes will include measurement of platelet reactivity to U46619, a thromboxane A2 agonist, through identification of platelet surface markers CD62P, CD63, CD154 and PAC1.

The following adherence measurements will also be collected:

1. Drug discontinuation rate
2. Date and time of each dose of study medication obtained through electronic monitoring to assess adherence

The following clinical data will be collected at randomization:

1. Spirometry performed before and after administration of albuterol per American Thoracic Society protocol in a certified laboratory

The following clinical data will be collected at randomization and each subsequent study visit:

1. Respiratory symptom and quality of life questionnaires
2. Occurrence of COPD flares (exacerbations)

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Wendy Lorizio, MD, MPH; Phone Number: 410-510-2449; Email: wlorizi1@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Recruiting
      • Johns Hopkins Bayview Medical Center
      • Contact: Wendy Lorizio, MD, MPH; Phone Number: 410-510-2449; Email: wlorizi1@jhmi.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥40 years
• Former smoker
• At least 10 pack-year smoking history
• Post-bronchodilator ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) < 0.7

Exclusion Criteria:

• History of myocardial infarction, percutaneous coronary intervention, or stroke
• Presence of coronary artery calcification on computed tomography (CT) scan by visual assessment
• Currently taking antiplatelet therapy or anticoagulant medication
• Contraindication to aspirin (including low platelet count, hematocrit <25%, known aspirin-exacerbated respiratory disease, bleeding disorder, history of bleeding or gastrointestinal (GI) ulcer, coagulopathy, or major surgery within 6 weeks before randomization)
• Oral corticosteroids within the past 6 weeks
• Currently taking immunosuppressant medication
• Active malignancy (other than non-melanoma skin cancer)
• Uncontrolled hypertension
• Pregnant or planning pregnancy in the next year
• Plans to move residence away from the immediate area within the next 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1; Week 1-2: aspirin 81mg; Week 5-6: aspirin 162mg; Week 9-10: aspirin 325mg	Drug: Aspirin 81mg; Aspirin 81mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 162 mg; Aspirin 162 mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 325mg; Aspirin 325mg once daily; Other Names: Acetylsalicylic acid
Experimental: Sequence 2; Week 1-2: aspirin 162mg; Week 5-6: aspirin 81mg; Week 9-10: aspirin 325mg	Drug: Aspirin 81mg; Aspirin 81mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 162 mg; Aspirin 162 mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 325mg; Aspirin 325mg once daily; Other Names: Acetylsalicylic acid
Experimental: Sequence 3; Week 1-2: aspirin 325mg; Week 5-6: aspirin 81mg; Week 9-10: aspirin 162mg	Drug: Aspirin 81mg; Aspirin 81mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 162 mg; Aspirin 162 mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 325mg; Aspirin 325mg once daily; Other Names: Acetylsalicylic acid
Experimental: Sequence 4; Week 1-2: aspirin 325mg; Week 5-6: aspirin 162mg; Week 9-10: aspirin 81mg	Drug: Aspirin 81mg; Aspirin 81mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 162 mg; Aspirin 162 mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 325mg; Aspirin 325mg once daily; Other Names: Acetylsalicylic acid
Experimental: Sequence 5; Week 1-2: aspirin 162mg; Week 5-6: aspirin 325mg; Week 9-10: aspirin 81mg	Drug: Aspirin 81mg; Aspirin 81mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 162 mg; Aspirin 162 mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 325mg; Aspirin 325mg once daily; Other Names: Acetylsalicylic acid
Experimental: Sequence 6; Week 1-2: aspirin 81mg; Week 5-6: aspirin 325mg; Week 9-10: aspirin 162mg	Drug: Aspirin 81mg; Aspirin 81mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 162 mg; Aspirin 162 mg once daily; Other Names: Acetylsalicylic acid; Drug: Aspirin 325mg; Aspirin 325mg once daily; Other Names: Acetylsalicylic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urinary 11-dehydro-thromboxane B2 level	Urine 11-dehydro-thromboxane B2 level (pg/mg Creatinine) - a urinary metabolite of thromboxane A2.	Baseline, week 2, week 6, week 10
Change in serum thromboxane B2 level	Serum thromboxane B2	Baseline, week 2, week 6, week 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in proportion of platelets displaying CD62P	Proportion of platelets displaying CD62P (activated platelets) following stimulation with U46619, a thromboxane A2 agonist.	Baseline, 2 weeks, 6 weeks, 10 weeks
Change in proportion of platelets displaying CD63	Proportion of platelets displaying CD63 (activated platelets) following stimulation with U46619, a thromboxane A2 agonist.	Baseline, 2 weeks, 6 weeks, 10 weeks
Change in proportion of platelets displaying CD154	Proportion of platelets displaying CD154 (activated platelets) following stimulation with U46619, a thromboxane A2 agonist	Baseline, 2 weeks, 6 weeks, 10 weeks
Change in proportion of platelets displaying PAC1	Proportion of platelets displaying PAC1 (activated platelets) following stimulation with U46619, a thromboxane A2 agonist	Baseline, 2 weeks, 6 weeks, 10 weeks

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Ashraf Fawzy, MD, MPH, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: February 22, 2022
• First Submitted That Met QC Criteria: February 22, 2022
• First Posted (Actual): March 3, 2022

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Lung Diseases, Obstructive; Chronic Disease; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: IRB00309828; 1K23HL151758-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No