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Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT03774394
Recruitment Status : Not yet recruiting
First Posted : December 13, 2018
Last Update Posted : April 1, 2019
Sponsor:
Information provided by (Responsible Party):
University of Florida

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 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)
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Clopidogrel active metabolite concentration [ Time Frame: 6 hours ]
    Comparison of clopidogrel active metabolite plasma concentrations, Tmax, Cmax and AUC


Other Outcome Measures:
  1. 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

  2. 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



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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 for at least 2 months without any changes in treatment regimen;
  • 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03774394


Contacts
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Contact: Francesco Franchi, MD 9042442092 francesco.franchi@jax.ufl.edu
Contact: Andrea Goosen 9042445617 Andrea.Goosen@jax.ufl.edu

Locations
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United States, Florida
University of Florida Jacksonville Not yet recruiting
Jacksonville, Florida, United States, 32209
Contact: Francesco Franchi, MD         
Sponsors and Collaborators
University of Florida
Investigators
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Principal Investigator: Francesco Franchi, MD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03774394     History of Changes
Other Study ID Numbers: IRB201801870 -A
First Posted: December 13, 2018    Key Record Dates
Last Update Posted: April 1, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Platelet Aggregation Inhibitors
Diabetes Mellitus
Diabetes Mellitus, Type 2
Kidney Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Renal Insufficiency, Chronic
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Renal Insufficiency
Clopidogrel
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs