Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

NCT ID: NCT03774394

Last Updated: 2023-08-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 61 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-22
• Study Completion Date: 2022-05-31

Brief Summary

Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD). However, despite its benefits, many patients still experience recurrent atherothrombotic events. The proposed study will test the central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12 inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12 signaling pathway and impaired clopidogrel metabolism.

Detailed Description

Patients with diabetes mellitus (DM) and coexisting chronic kidney disease (CKD) are at increased risk of atherothrombotic events, underscoring the importance of secondary prevention antiplatelet therapy in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD). However, despite its clinical benefits, many patients still experience recurrent atherothrombotic events. This is in part due to the impaired effects of clopidogrel in DM patients, particularly among those with coexisting CKD. However, underlying mechanism(s) leading to magnification of impaired clopidogrel response among DM patients with CKD remain unexplored. The ever growing prevalence of CKD in patients with DM and their high risk of recurrent events underscores the need to define such mechanism(s) as this may set the basis for identifying treatment regimens leading to more effective platelet inhibition and cardiovascular protection in these high-risk patients. The proposed study will test the central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12 inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12 signaling pathway and impaired clopidogrel metabolism. Comprehensive pharmacokinetic and pharmacodynamic assessments, including ex vivo and in vitro experiments, evaluating the impact of CKD on antiplatelet drug response in DM patients are proposed.

Conditions

Chronic Kidney Disease (CKD); Type 2 Diabetes Mellitus (T2DM); Coronary Artery Disease (CAD)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Diabetes Mellitus patients with Chronic Kidney Disease

Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.

Blood samples collected at baseline will be incubated with clopidogrel active metabolite.

Group Type: EXPERIMENTAL

Clopidogrel

Intervention Type: DRUG

Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.

Clopidogrel active metabolite

Intervention Type: DRUG

In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)

Diabetes Mellitus patients without Chronic Kidney Disease

Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.

Blood samples collected at baseline will be incubated with clopidogrel active metabolite.

Group Type: ACTIVE_COMPARATOR

Clopidogrel

Intervention Type: DRUG

Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.

Clopidogrel active metabolite

Intervention Type: DRUG

In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)

Interventions

Clopidogrel

Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.

Intervention Type: DRUG

Clopidogrel active metabolite

In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)

Intervention Type: DRUG

Other Intervention Names

Plavix; Plavix

Eligibility Criteria

Inclusion Criteria

• Type 2 DM, defined according to ADA definition, on treatment with oral hypoglycemic agents and/or insulin
• Angiographically documented CAD
• On treatment with low-dose aspirin (81mg/day) for ≥30 days as part of standard of care.

Exclusion Criteria

• Use of any antiplatelet therapy (except aspirin) in prior 30 days
• Use of parenteral or oral anticoagulation
• Active bleeding
• High risk of bleeding
• Clinical indication to be on a P2Y12 receptor inhibitor
• End-stage renal disease on hemodialysis
• Any active malignancy
• Platelet count < 100x106/µl
• Hemoglobin <9 g/dl
• Severe known liver disease
• Hemodynamic instability
• Known allergy to clopidogrel
• Pregnant / lactating females (women of childbearing age must use reliable birth control).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Scott R. MacKenzie Foundation

OTHER

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Francesco Franchi, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

University of Florida Jacksonville

Jacksonville, Florida, United States

Countries

United States

References

Ortega-Paz L, Franchi F, Rollini F, Galli M, Been L, Ghanem G, Shalhoub A, Ossi T, Rivas A, Zhou X, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Mahowald MK, Langaee T, Jakubowski JA, Cavallari LH, Angiolillo DJ. Clopidogrel-Mediated P2Y12 Inhibition According to Renal Function in Patients With Diabetes Mellitus and CAD. JACC Basic Transl Sci. 2024 Mar 25;9(7):865-876. doi: 10.1016/j.jacbts.2024.03.003. eCollection 2024 Jul.

Reference Type: DERIVED

PMID: 39170956 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Other Identifiers

IRB201801870 -A

Identifier Type: -

Identifier Source: org_study_id