Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

• ClinicalTrials.gov Identifier: NCT03774394
• Recruitment Status: Completed
• First Posted: December 13, 2018
• Results First Posted: August 21, 2023
• Last Update Posted: August 21, 2023
• Sponsor: University of Florida
• Collaborator: Scott R. MacKenzie Foundation
• Information provided by (Responsible Party): University of Florida

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Disease (CKD); Type 2 Diabetes Mellitus (T2DM); Coronary Artery Disease (CAD)	Drug: Clopidogrel; Drug: Clopidogrel active metabolite	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: August 22, 2019
• Actual Primary Completion Date: May 23, 2022
• Actual Study Completion Date: May 31, 2022

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: Plavix

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Clopidogrel Active Metabolite Concentration [ Time Frame: 6 hours ]
   Comparison of clopidogrel active metabolite plasma concentrations by means of AUC

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, Florida

University of Florida Jacksonville

Jacksonville, Florida, United States, 32209

Sponsors and Collaborators

University of Florida

Scott R. MacKenzie Foundation

Investigators

• Principal Investigator: Francesco Franchi, MD; University of Florida

  Study Documents (Full-Text)

Documents provided by University of Florida:

Study Protocol  [PDF] October 21, 2021

No Statistical Analysis Plan (SAP) exists for this study.

More Information

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03774394
• Other Study ID Numbers: IRB201801870 -A
• First Posted: December 13, 2018
• Results First Posted: August 21, 2023
• Last Update Posted: August 21, 2023
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by University of Florida:

pharmacodynamics (PD); pharmacokinetic (PK); clopidogrel

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Clopidogrel; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents