Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

Impact of Chronic Kidney Disease (CKD) on Pharmacodynamic Profiles of the P2Y12 Receptor Inhibitor Clopidogrel in the Setting of Type 2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD)

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease (CAD); Type 2 Diabetes Mellitus (T2DM); Chronic Kidney Disease (CKD)
• Intervention / Treatment: Drug: Clopidogrel; Drug: Clopidogrel active metabolite

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Jacksonville

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: Plavix; 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); Other Names: Plavix
Active Comparator: 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.	Drug: 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.; Other Names: Plavix; 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); Other Names: Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%	Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clopidogrel Active Metabolite Concentration	Comparison of clopidogrel active metabolite plasma concentrations by means of AUC	6 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is >208.	Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD	6 hours
Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%	Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD	Baseline

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Scott R. MacKenzie Foundation
• Investigators: Principal Investigator: Francesco Franchi, MD, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2019
• Primary Completion (Actual): May 23, 2022
• Study Completion (Actual): May 31, 2022

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 13, 2018

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: July 24, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: clopidogrel; pharmacokinetic (PK); pharmacodynamics (PD)
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Urologic Diseases; Endocrine System Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: IRB201801870 -A

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