Aspirin Dosing for COPD

Overseen By Wendy Lorizio, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Johns Hopkins University

Must not be taking: Antiplatelets, Anticoagulants, Immunosuppressants, Corticosteroids

Disqualifiers: Myocardial infarction, Stroke, Active malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 10 weeks

48 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop taking any current antiplatelet or anticoagulant medications, as well as oral corticosteroids and immunosuppressant medications. If you are on these medications, you would need to discontinue them to participate in the trial.

What evidence supports the effectiveness of the drug aspirin for COPD?

Aspirin, in various formulations, has been shown to significantly inhibit platelet function, which is beneficial for preventing blood clots. Additionally, enteric-coated aspirin formulations like Ecotrin cause less stomach damage compared to other aspirin products, suggesting they may be better tolerated. ^{1 2 3 4 5}

Is aspirin generally safe for humans?

Aspirin is generally safe for most people, but it can cause issues like increased bleeding times and platelet dysfunction, especially at higher doses. People with aspirin-induced asthma should avoid it, as it can provoke asthma symptoms. ^{1 2 4 5 6}

How does aspirin dosing for COPD differ from other drug treatments?

Aspirin dosing for COPD is unique because it involves using different doses of aspirin, a common anti-inflammatory and blood-thinning medication, which is not typically used for COPD. This approach is novel compared to standard COPD treatments that usually focus on bronchodilators and inhaled corticosteroids to manage symptoms and improve lung function. ^{7 8 9 10 11}

Research Team

Ashraf Fawzy, MD, MPH

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for individuals over 40 years old with a history of smoking and diagnosed COPD, indicated by specific lung function tests. It's not suitable for those who've had recent heart problems or strokes, are pregnant or planning to be, have certain heart findings on CT scans, bleeding disorders, uncontrolled high blood pressure, or are on immunosuppressants.

Inclusion Criteria

Your breathing test shows that you have trouble exhaling air from your lungs.

I am 40 years old or older.

You have smoked the equivalent of at least 10 packs of cigarettes per year for multiple years.

Exclusion Criteria

I have an active cancer other than non-melanoma skin cancer.

I cannot take aspirin due to a health condition or recent major surgery.

I am currently on medication to prevent blood clots.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive randomized doses of aspirin (81mg, 162mg, 325mg) in a 3-period crossover design with a 14-day washout period between doses

10 weeks

3 visits (in-person) at 2, 6, and 10 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aspirin 162 mg
• Aspirin 325mg
• Aspirin 81mg

Trial Overview The study aims to find the best aspirin dose (81mg, 162mg, or 325mg) for reducing platelet activation in COPD patients without cardiovascular disease. This could lead to fewer respiratory symptoms and flares. The results will help design larger trials focused on clinical outcomes.

Participant Groups

Group I: Sequence 6 Experimental Treatment 3 Interventions

* Week 1-2: aspirin 81mg * Week 5-6: aspirin 325mg * Week 9-10: aspirin 162mg

Group II: Sequence 5 Experimental Treatment 3 Interventions

* Week 1-2: aspirin 162mg * Week 5-6: aspirin 325mg * Week 9-10: aspirin 81mg

Group III: Sequence 4 Experimental Treatment 3 Interventions

* Week 1-2: aspirin 325mg * Week 5-6: aspirin 162mg * Week 9-10: aspirin 81mg

Group IV: Sequence 3 Experimental Treatment 3 Interventions

* Week 1-2: aspirin 325mg * Week 5-6: aspirin 81mg * Week 9-10: aspirin 162mg

Group V: Sequence 2 Experimental Treatment 3 Interventions

* Week 1-2: aspirin 162mg * Week 5-6: aspirin 81mg * Week 9-10: aspirin 325mg

Group VI: Sequence 1 Experimental Treatment 3 Interventions

* Week 1-2: aspirin 81mg * Week 5-6: aspirin 162mg * Week 9-10: aspirin 325mg

Aspirin 162 mg is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Cardiovascular disease prevention
• Anti-inflammatory

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Cardiovascular disease prevention
• Anti-inflammatory
• Myocardial infarction prevention
• Stroke prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Cardiovascular disease prevention
• Anti-inflammatory

Approved in Japan as Aspirin for:

• Pain relief
• Fever reduction
• Cardiovascular disease prevention
• Anti-inflammatory

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Cardiovascular disease prevention
• Anti-inflammatory

Approved in Switzerland as Aspirin for:

• Pain relief
• Fever reduction
• Cardiovascular disease prevention
• Anti-inflammatory

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study involving healthy volunteers who took varying doses of acetylsalicylic acid (ASA) for one week, all doses significantly inhibited platelet function and increased bleeding times, indicating its effectiveness in thrombosis prophylaxis.

The research found that a daily dose of around 100 mg of ASA maximized the effects on platelet function and bleeding time, suggesting that higher doses do not provide additional benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of different doses of some acetylsalicylic acid formulations on platelet function and bleeding times in healthy subjects. McLeod, LJ., Roberts, MS., Cossum, PA., et al.[2019]

In a study involving 10 patients with aspirin intolerance, Asacard (a controlled-release form of aspirin) was tolerated by only half of the participants, indicating potential risks for those with aspirin-induced asthma.

The study concluded that any form of aspirin, including Asacard, should be avoided in patients with aspirin-induced asthma, as it can trigger bronchospasm and other symptoms of intolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tolerability of Asacard--controlled-release aspirin and aspirin-induced asthma]. Bochenek, G., Swierczyńska, M., Nizankowska-Mogilnicka, E., et al.[2017]

In two endoscopic studies comparing various aspirin products, encapsulated enteric-coated aspirin granules (Ecotrin) caused significantly less stomach damage than other tested products, including Ascriptin A/D, Bayer, and Bufferin.

The Ecotrin capsule also resulted in less damage to the proximal duodenum compared to Bayer, suggesting it may be a safer option for gastrointestinal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of enteric-coated aspirin granules with plain and buffered aspirin: a report of two studies. Petroski, D.[2013]

The new buffered acetylsalicylic acid (ASA) formulation showed equivalent bioavailability to the plain ASA tablet, with a relative bioavailability of 102.49%, indicating it can be used interchangeably with the standard formulation.

Buffered ASA reached peak plasma concentration significantly faster (28 minutes) compared to the plain tablet (38 minutes), suggesting quicker absorption and potentially faster onset of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers. Viganò, G., Garagiola, U., Gaspari, F.[2013]

All six aspirin preparations tested effectively inhibited platelet aggregation to a similar extent, indicating their efficacy in reducing blood clotting, which is important for preventing heart attacks and strokes.

Ecotrin and S.R.A. showed delayed effects and inhibited platelet aggregation without measurable levels of aspirin in the bloodstream, suggesting a unique mechanism of action possibly involving acetylation of cyclooxygenase in the liver.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin kinetics and platelet aggregation in man. Siebert, DJ., Bochner, F., Imhoff, DM., et al.[2019]

Ascolong, a new buccal form of aspirin with a very low dose of 12.5 mg, demonstrated a reliable antiaggregant effect in both single and regular doses, although it was less pronounced than that of standard 100 mg aspirin tablets.

The study, involving 43 healthy men and 19 patients with coronary or cerebrovascular disorders, found that Ascolong was well tolerated and effectively delivered acetylsalicylic acid (ASA) into the bloodstream, reducing its metabolism into a less active form, making it a promising option for patients who cannot take traditional oral aspirin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ascolong: a new buccal dosage form of acetylsalicylic acid to be used and antiaggregant]. Kokurina, EV., Suslina, ZA., Khromov, GL., et al.[2013]

In a Phase II study involving 733 adults with COPD, glycopyrronium bromide (GB) at doses of 25 and 50 µg twice daily significantly improved lung function compared to placebo, with a clear dose-response effect up to 25 µg.

The safety profile of GB was favorable, with low incidence of adverse events similar across all treatment groups, leading to the conclusion that 25 µg BID is the optimal dose for efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Inhaled Glycopyrronium Bromide in COPD: A Randomized, Parallel Group, Dose-Ranging Study (GLIMMER). Kerwin, E., Feldman, G., Pearle, J., et al.[2021]

In a study involving 20 patients with acute exacerbations of COPD, both salmeterol and salbutamol significantly improved lung function (FEV1, IC, and FVC) in a dose-dependent manner, indicating their efficacy in treating bronchospasm.

Salmeterol was found to be effective and safe for managing acute exacerbations of COPD, with no significant adverse effects on heart rate or oxygen saturation, supporting its use in this clinical scenario.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute effects of higher than customary doses of salmeterol and salbutamol in patients with acute exacerbation of COPD. Cazzola, M., Califano, C., Di Perna, F., et al.[2019]

In a study involving 65 patients with moderate-to-severe COPD, glycopyrronium bromide (GB) significantly improved lung function (FEV1) compared to placebo, with higher doses showing greater efficacy.

GB was found to be safe, with all adverse events being mild to moderate in severity and a lower incidence compared to placebo, suggesting that a dose of 25 μg twice daily may be optimal for treating COPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study. Singh, D., Scuri, M., Collarini, S., et al.[2018]

In a study involving 40 patients (20 with bronchial asthma and 20 with COPD), higher doses of Atrovent (0.25 and 0.5 mg) significantly improved lung function in COPD patients, achieving a maximum increase in FEV1 of +22%.

For patients with bronchial asthma, Salbutamol was found to be a more effective bronchodilator than Atrovent, with an increase in FEV1 of +49% compared to +26% for Atrovent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of vaporizing high doses of ipratropium bromide on lung ventilation in patients with chronic obstructive pulmonary disease and bronchial asthma]. Dor, A., Krasnowska, M., Małolepszy, J.[2013]

In a study involving 178 COPD patients, the addition of glycopyrronium bromide (GB) to beclometasone dipropionate plus formoterol fumarate (BDP/FF) significantly improved lung function, as measured by FEV1 area under the curve, with clinically relevant improvements observed at doses of 25 and 50 μg.

The safety profile of GB was favorable, with adverse events occurring in 7.4% to 8.0% of patients receiving GB compared to 11.0% in the BDP/FF alone group, indicating that the 25 μg BID dose of GB provided the best balance of efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The bronchodilator effects of extrafine glycopyrronium added to combination treatment with beclometasone dipropionate plus formoterol in COPD: A randomised crossover study (the TRIDENT study). Singh, D., Schröder-Babo, W., Cohuet, G., et al.[2018]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

The effects of different doses of some acetylsalicylic acid formulations on platelet function and bleeding times in healthy subjects. [2019]

2. Poland pubmed.ncbi.nlm.nih.gov

[Tolerability of Asacard--controlled-release aspirin and aspirin-induced asthma]. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

A comparison of enteric-coated aspirin granules with plain and buffered aspirin: a report of two studies. [2013]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Aspirin kinetics and platelet aggregation in man. [2019]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Ascolong: a new buccal dosage form of acetylsalicylic acid to be used and antiaggregant]. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Inhaled Glycopyrronium Bromide in COPD: A Randomized, Parallel Group, Dose-Ranging Study (GLIMMER). [2021]

8. England pubmed.ncbi.nlm.nih.gov

Acute effects of higher than customary doses of salmeterol and salbutamol in patients with acute exacerbation of COPD. [2019]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study. [2018]

10. Poland pubmed.ncbi.nlm.nih.gov

[Effect of vaporizing high doses of ipratropium bromide on lung ventilation in patients with chronic obstructive pulmonary disease and bronchial asthma]. [2013]

11. England pubmed.ncbi.nlm.nih.gov

The bronchodilator effects of extrafine glycopyrronium added to combination treatment with beclometasone dipropionate plus formoterol in COPD: A randomised crossover study (the TRIDENT study). [2018]