Aspirin Dosing for Type 2 Diabetes

(APPEASEDII Trial)

Overseen By Marie Lordkipanidzé B. Pharm, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Montreal Heart Institute

Must be taking: Oral antihyperglycemics, Insulin

Must not be taking: Anticoagulants, Antiplatelets, NSAIDs, Steroids

Disqualifiers: Atherosclerotic disease, Dialysis, Hepatic insufficiency, GI bleeding, Cancer, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase 2 study will include patients suffering from type 2 diabetes mellitus and will first study their response to enteric coated aspirin at a dose of 80 mg per day for a 7-day period. Participants with an incomplete platelet inhibition after exposure to EC aspirin at doses of 80 mg once daily will be randomized to a random order of 3 different ASA regimens: EC ASA 162 mg once daily, EC ASA 81 mg twice daily and chewable ASA 40 mg twice daily. The aims are to determine the feasibility of a larger scale trial, and to determine the regimen associated with the lowest proportion of non-responders after randomization. Platelet function will be assessed at baseline and at day 7 of each arms of the study.

Will I have to stop taking my current medications?

The trial requires that participants do not take aspirin regularly before joining, and those on certain medications like anticoagulants, antiplatelet agents, NSAIDs, or systemic steroids cannot participate. If you're on these medications, you may need to stop them to join the trial.

Is aspirin safe for humans?

Aspirin, also known as acetylsalicylic acid (ASA), has been shown to affect platelet function and increase bleeding times in healthy people, especially at doses around 100 mg daily. It is generally considered safe for use in humans, but it can increase the risk of bleeding. ^{1 2 3 4 5}

How does aspirin dosing differ for type 2 diabetes treatment?

Aspirin, when taken twice daily at a low dose, may be more effective for people with type 2 diabetes because it better inhibits platelet activity, which is important for preventing blood clots. This is different from the usual once-daily dosing and is particularly relevant for those with diabetes who have increased platelet turnover. ^{1 5 6 7 8}

Research Team

Guillaume Marquis Gravel, MD, MSc

Principal Investigator

ICM Co. Ltd.

Eligibility Criteria

Adults with type 2 diabetes who haven't taken aspirin regularly in the past 3 months can join. They must be willing to attend all study visits and not have any planned major surgeries, bleeding disorders, severe liver issues, active cancer, chronic inflammatory diseases needing anti-inflammatory drugs, high-risk GI bleeding conditions or need for dialysis.

Inclusion Criteria

I haven't taken ASA regularly in the last 3 months or at all in the last 2 weeks.

I have type 2 diabetes.

I am willing to attend all required study visits.

Exclusion Criteria

I am on regular medication for a chronic inflammatory condition.

I have had blood cancer or a condition that affects how my blood cells form.

Your blood platelet count or hemoglobin levels are not within the normal range.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Run-in

Participants receive 80 mg of enteric-coated aspirin daily for 7 days to assess initial response

1 week

2 visits (in-person)

Randomized Treatment

Participants are randomized to one of three ASA regimens for 7 days each, with washout periods in between

3 weeks (plus washout periods)

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aspirin

Trial Overview The trial is testing how different doses and forms of aspirin affect blood platelet function in people with type 2 diabetes over a week. It compares daily enteric-coated aspirin (81 mg twice or 162 mg once) versus chewable aspirin (40 mg twice), focusing on which regimen best prevents platelets from clumping together.

Participant Groups

Group I: chewable ASA 40 mg twice daily for 7 days Experimental Treatment 1 Intervention

chewable ASA 40 mg twice daily for 7 days

Group II: EC ASA 81 mg twice daily for 7 days Experimental Treatment 1 Intervention

EC ASA 81 mg twice daily for 7 days

Group III: EC ASA 162 mg once daily for 7 days Experimental Treatment 1 Intervention

EC ASA 162 mg once daily for 7 days

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

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

Montreal Heart Institute

Lead Sponsor

Trials

125

Recruited

85,400+

Heart and Stroke Foundation of Canada

Collaborator

Trials

131

Recruited

72,600+

Institut de Recherches Cliniques de Montreal

Collaborator

Trials

72

Recruited

10,300+

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]

Aspirin (ASA) significantly reduced urinary 11-dehydro-thromboxane B2 levels by about 71.5% in patients with type 2 diabetes and 75.1% in healthy controls, indicating its effectiveness in inhibiting platelet activation through COX-1 inhibition.

Despite the reduction in thromboxane levels, many patients with type 2 diabetes were identified as 'poor responders' to ASA, suggesting that oxidative stress may counteract the effects of ASA and maintain platelet function, highlighting a potential challenge in treating this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus. Ames, PR., Batuca, JR., Muncy, IJ., et al.[2013]

In a study involving 2539 patients with type 2 diabetes, low-dose aspirin did not reduce the risk of cardiovascular events over a median follow-up of 10.3 years, indicating it may not be effective for primary prevention in this population.

However, the use of low-dose aspirin was associated with an increased risk of gastrointestinal bleeding, with 2% of patients in the aspirin group experiencing this side effect compared to 0.9% in the no-aspirin group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: 10-Year Follow-Up of a Randomized Controlled Trial. Saito, Y., Okada, S., Ogawa, H., et al.[2020]

In a study involving 2539 patients with type 2 diabetes over a median follow-up of 4.37 years, low-dose aspirin did not significantly reduce the overall risk of atherosclerotic events compared to a nonaspirin group.

However, the aspirin group had a significantly lower incidence of fatal coronary and cerebrovascular events, suggesting that while aspirin may not reduce all cardiovascular risks, it could be beneficial in preventing severe outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. Ogawa, H., Nakayama, M., Morimoto, T., et al.[2023]

From 1997 to 2000, only 2.1% to 5.7% of diabetic patients over 30 with cardiovascular risk factors were prescribed low-dose aspirin (ASA) for primary prevention, indicating very low adherence to the American Diabetes Association (ADA) guidelines.

Factors that increased the likelihood of receiving ASA included being male, older than 44, having cardiovascular risk factors, and receiving preventative counseling, highlighting the need for targeted efforts to improve adherence rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin for primary prevention in patients with diabetes mellitus. Nguyen, KX., Marinac, JS., Sun, C.[2013]

In a study involving 25 patients with type 2 diabetes and vascular complications, taking low-dose aspirin twice daily (75 mg BID) showed improved platelet response compared to once daily dosing (75 mg OD) and was more effective than higher doses (320 mg OD) in reducing platelet aggregation.

The findings suggest that twice daily dosing of aspirin may enhance its effectiveness in managing platelet activity in high-risk patients with type 2 diabetes, warranting further research to see if this dosing strategy can lead to better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications. Spectre, G., Arnetz, L., Östenson, CG., et al.[2013]

In a study involving 38 healthy volunteers and 38 type 2 diabetic patients, it was found that diabetic patients had significantly higher aspirin esterase activity, leading to faster hydrolysis of aspirin, which may reduce its effectiveness as an antiplatelet drug.

The increased degradation of aspirin in diabetic patients was linked to a weaker response of their platelets to the medication, suggesting that diabetes may affect the efficacy of aspirin therapy in preventing cardiovascular events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased blood plasma hydrolysis of acetylsalicylic acid in type 2 diabetic patients: a role of plasma esterases. Gresner, P., Dolník, M., Waczulíková, I., et al.[2017]

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]

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

Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus. [2013]

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

Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: 10-Year Follow-Up of a Randomized Controlled Trial. [2020]

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

Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. [2023]

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

Aspirin for primary prevention in patients with diabetes mellitus. [2013]

6. Germany pubmed.ncbi.nlm.nih.gov

Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications. [2013]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Increased blood plasma hydrolysis of acetylsalicylic acid in type 2 diabetic patients: a role of plasma esterases. [2017]

8. 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]