Assessing Pharmacokinetics and Pharmacodynamics of Daily Enteric-coated Aspirin in Patients With StablE Diabetes II

Overview

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.

Detailed description

APPEASED II is a triple crossover, open-label, randomized controlled pilot trial preceded by a 7-day run in period, aiming to determine the feasibility of a larger confirmatory randomized trial, and to determine the regimen associated with the lowest proportion of non-responders after randomization of EC ASA 162 mg once daily, EC ASA 81 mg twice daily and chewable ASA 40 mg twice daily in patients with type 2 diabetes.The primary endpoint will be to determine, among initial ASA non-responder participants in the run-in phase, the proportion of participants that remain ASA non-responders with different formulations and dosing regimens of ASA, including EC ASA 162 mg once daily, EC ASA 81 mg twice daily and chewable ASA 40 mg twice daily. The incomplete platelet aggregation will be evaluated by the response to arachidonic acid at a concentration of 1mM, measured by LTA (Light Transmission Aggregometry). For every platelet function assessment, serum salicylate concentration will also be measured. Upon the screening visit (day 0), blood will be drawn and baseline platelet function will be assessed. A 7 day supply of aspirin will be given to participants meeting the eligibility criteria. Participants will be instructed to take 1 dose of 80 mg of enteric coated aspirin per day at the same time every day. Upon day 7, participants will return for a second visit before the intake of their daily aspirin, and therefore 24 hours after the previous dose of aspirin was taken. Blood will be drawn and platelet function will be assessed in the same manner as described previously. Participants will then take their 7th dose of aspirin under supervision, and a blood sample will be collected and platelet function will be assessed two hours later. If participants have an incomplete platelet inhibition after exposure to EC aspirin at doses of 80 mg once daily, they 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. These participants will receive the pillbox containing the first assigned regimen on this visit. The 3 study arms and the run-in phase will last 7 days each, with at least 7 days of wash-out between each arm. To accommodate participants with busy schedules and to minimize follow-up losses, a longer washout period will be tolerated if the participant is unable to return to the research center after 14 days. At every visit of the randomized portion of the trial, participants will leave with the next 6-day ASA regimen in a pillbox, that is 6 doses for the once daily regimen and 13 doses for the twice daily regimens. On day 7 of all three study arms, patients will be questioned about medication adherence with the presence of the participant's pillbox. Two blood samples will be collected, one 24 hours after the last dose and one 2 hours after taking the last dose in front of the investigators. The platelet aggregation inhibition with arachidonic acid and platelet reactivity to various agonists will be assessed by LTA. Serum levels of TxB2 will also be assessed.

Interventions

• Drug Aspirin 81Mg Ec Tab twice daily for 7 days
  Participants with incomplete platelet aggregation will be instructed to take EC ASA 81 mg twice daily for 7 days.
• Drug Aspirin 40Mg Chew Tab twice daily for 7 days
  Participants with incomplete platelet aggregation will be instructed to take chewable ASA 40 mg twice daily for 7 days.
• Drug Aspirin 162 mg EC Tab once daily for 7 days
  Participants with incomplete platelet aggregation will be instructed to take EC ASA 162 mg once daily for 7 days.

Primary outcome measures

• Describe the screening rate to evaluate the feasibility of a larger scale randomized controlled trial. [Time frame: 1 year]
• Describe the enrollment rate by the proportion of referred participants who are eligible to evaluate the feasibility of a larger scale randomized controlled trial. [Time frame: 1 year]
• Describe the enrollment rate by the proportion of eligible participants who consent to evaluate the feasibility of a larger scale randomized controlled trial. [Time frame: 1 year]
• Describe the retention rate to evaluate the feasibility of a larger scale randomized controlled trial. [Time frame: 1 year]
• Among initial ASA non-responder participants, define the proportion of participants that remain ASA non-responders with different formulations and dosing regimens of ASA. [Time frame: 1 year]

Secondary outcome measures (6)

• Adherence rate to study protocol [Time frame: 1 year]
• Average time per participant required to complete study enrolment and all data collection. [Time frame: 1 year]
• Proportion of non-responders participants at day 7 of 40 mg twice daily chewable ASA regimen, 81 mg twice daily EC ASA regimen and 162 mg once daily EC ASA regimen. [Time frame: 1 year]
• For the run-in phase, characterize the prevalence of ASA non-responders at steady state following a 7-day treatment with ASA EC 81 mg once daily in participants with type 2 diabetes. [Time frame: 1 year]
• Proportion of participants who are non-responders to ASA with each dose as measured by serum levels of thromboxane B2 (TxB2). [Time frame: 1 year]
• Platelet response levels to various agonists not directly related to the pharmacological target of ASA, including ADP, collagen, epinephrine and thrombin receptor-activating peptide (TRAP). [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years;
• Participant must be naïve to ASA, defined as absence of chronic treatment with ASA within the previous 3 months, and of any ASA use within the previous 2 weeks;
• Type 2 diabetes, based on at least one of the following criteria: (5)

• Chronic treatment with oral antihyperglycemic agents or insulin therapy;
• Fasting Plasma Glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) (fasting is defined as no caloric intake for at least 8h);
• 2-h Plasma Glucose (2h-PG) ≥ 200 mg/dL (11.1 mmol/L) during the oral glucose tolerance test (OGTT);
• A1C ≥ 6.5% (48 mmol/ml);
• Willing to attend all study visits of both the run-in and randomized phases of the trial.

Exclusion criteria

• Definitive indication for ASA, including any evidence of clinical atherosclerotic disease, previous or current;
• Known hypersensitivity to ASA;
• Patient requiring dialysis;
• Severe hepatic insufficiency or ALT > 3 x ULN;
• High-risk GI bleeding features, such as known H. pylori infection, past or present ulcer, history of bleeding from the GI tract;
• Bleeding diathesis;
• Platelet count or hemoglobin levels outside of the normal reference range;
• Planned major surgical procedure or dental procedure during the course of the study;
• Chronic inflammatory disease requiring regular anti-inflammatory treatment;
• Chronic treatment with an oral anticoagulant, an antiplatelet agent, NSAIDs or systemic steroids;
• Active cancer;
• History of hematological malignancy or myelodysplasia;
• Pregnant or lactating women;

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Prevention

Study locations

Canada · 1 center

• Montreal Heart Institute — Montreal

Publications

• Marquis-Gravel G, Roe MT, Harrington RA, Munoz D, Hernandez AF, Jones WS. Revisiting the Role of Aspirin for the Primary Prevention of Cardiovascular Disease. Circulation. 2019 Sep 24;140(13):1115-1124. doi: 10.1161/CIRCULATIONAHA.119.040205. Epub 2019 Sep 23. PMID 31545683
• ASCEND Study Collaborative Group; Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. 2018 PMID 30146931
• Lordkipanidze M, Pharand C, Schampaert E, Palisaitis DA, Diodati JG. Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease. Int J Cardiol. 2011 Jul 1;150(1):39-44. doi: 10.1016/j.ijcard.2010.02.025. Epub 2010 Mar 7. PMID 20207433
• Bhatt DL, Grosser T, Dong JF, Logan D, Jeske W, Angiolillo DJ, Frelinger AL 3rd, Lei L, Liang J, Moore JE, Cryer B, Marathi U. Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2017 Feb 14;69(6):603-612. doi: 10.1016/j.jacc.2016.11.050. Epub 2017 Jan 11. PMID 28089180

Identifiers

NCT: NCT05702463 · ICM 2023-3231

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗