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

Tracking Information

• First Submitted Date: December 11, 2018
• First Posted Date: December 13, 2018
• Results First Submitted Date: June 29, 2023
• Results First Posted Date: August 21, 2023
• Last Update Posted Date: August 21, 2023
• Actual Study Start Date: August 22, 2019
• Actual Primary Completion Date: May 23, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 24, 2023)

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

Original Primary Outcome Measures (submitted: December 11, 2018)

Platelet reactivity index (PRI) [ Time Frame: 6 hours ]

Comparison of of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD

Current Secondary Outcome Measures (submitted: June 29, 2023)

Clopidogrel Active Metabolite Concentration [ Time Frame: 6 hours ]

Comparison of clopidogrel active metabolite plasma concentrations by means of AUC

Original Secondary Outcome Measures (submitted: December 11, 2018)

Clopidogrel active metabolite concentration [ Time Frame: 6 hours ]

Comparison of clopidogrel active metabolite plasma concentrations, Tmax, Cmax and AUC

Current Other Pre-specified Outcome Measures (submitted: July 24, 2023)

• 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
• 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

Original Other Pre-specified Outcome Measures (submitted: December 11, 2018)

• P2Y12 reaction units (PRU) [ 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
• Platelet reactivity index (PRI) [ 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

Descriptive Information

• Brief Title: Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus
• 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• 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

Study Arms

• 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.

  Interventions:

  • Drug: Clopidogrel
  • Drug: Clopidogrel active metabolite
• 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.

  Interventions:

  • Drug: Clopidogrel
  • Drug: Clopidogrel active metabolite

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 29, 2023): 61
• Original Estimated Enrollment (submitted: December 11, 2018): 60
• Actual Study Completion Date: May 31, 2022
• Actual Primary Completion Date: May 23, 2022 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03774394
• Other Study ID Numbers: IRB201801870 -A
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Florida
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Florida
• Original Study Sponsor: Same as current
• Collaborators: Scott R. MacKenzie Foundation

Investigators

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

• PRS Account: University of Florida
• Verification Date: July 2023