Chronic Kidney Disease (CKD), Coronary Artery Disease (CAD), Type 2 Diabetes Mellitus (T2DM)
Conditions
Keywords
pharmacodynamics (PD), pharmacokinetic (PK), clopidogrel
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.
Interventions
DRUGClopidogrel
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.
DRUGClopidogrel 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)
Sponsors
Scott R. MacKenzie Foundation
University of Florida
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50% | 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
| Measure | Time frame | Description |
|---|---|---|
| Clopidogrel Active Metabolite Concentration | 6 hours | Comparison of clopidogrel active metabolite plasma concentrations by means of AUC |
Other
| Measure | Time frame | Description |
|---|---|---|
| P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is >208. | 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% | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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.
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) | 31 |
| 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.
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.
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) | 30 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Diabetes Mellitus Patients With Chronic Kidney Disease | Diabetes Mellitus Patients Without Chronic Kidney Disease | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 13 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 17 Participants | 26 Participants |
| Age, Continuous | 68.4 years STANDARD_DEVIATION 10.8 | 65.2 years STANDARD_DEVIATION 6.8 | 66.7 years STANDARD_DEVIATION 8.9 |
| Prior myocardial infarction | 12 Participants | 9 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 15 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 21 Participants | 15 Participants | 36 Participants |
| Region of Enrollment United States | 31 participants | 30 participants | 61 participants |
| Sex: Female, Male Female | 17 Participants | 17 Participants | 34 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 0 / 31 | 0 / 30 |
| serious Total, serious adverse events | 0 / 31 | 0 / 30 |
Outcome results
Primary
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
Time frame: 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetes Mellitus Patients With Chronic Kidney Disease | Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50% | 67.5 PRI% | Standard Deviation 27.4 |
| Diabetes Mellitus Patients Without Chronic Kidney Disease | Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50% | 67.2 PRI% | Standard Deviation 30.2 |
Secondary
Clopidogrel Active Metabolite Concentration
Comparison of clopidogrel active metabolite plasma concentrations by means of AUC
Time frame: 6 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diabetes Mellitus Patients With Chronic Kidney Disease | Clopidogrel Active Metabolite Concentration | 47.1 ng*h/mL |
| Diabetes Mellitus Patients Without Chronic Kidney Disease | Clopidogrel Active Metabolite Concentration | 39.6 ng*h/mL |
Other Pre-specified
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
Time frame: 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetes Mellitus Patients With Chronic Kidney Disease | P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is >208. | 164 PRU | Standard Deviation 91 |
| Diabetes Mellitus Patients Without Chronic Kidney Disease | P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is >208. | 156 PRU | Standard Deviation 92 |
Other Pre-specified
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
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetes Mellitus Patients With Chronic Kidney Disease | Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50% | 92.7 PRI% | Standard Deviation 5.6 |
| Diabetes Mellitus Patients Without Chronic Kidney Disease | Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50% | 94.4 PRI% | Standard Deviation 3.5 |