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| Name | Class |
|---|---|
| Scott R. MacKenzie Foundation | OTHER |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Diabetes Mellitus patients with Chronic Kidney Disease | Experimental | 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. |
|
| Diabetes Mellitus patients without Chronic Kidney Disease | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clopidogrel | Drug | 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. |
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Clopidogrel Active Metabolite Concentration | Comparison of clopidogrel active metabolite plasma concentrations by means of AUC | 6 hours |
| 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% |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Francesco Franchi, MD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida Jacksonville | Jacksonville | Florida | 32209 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39170956 | Derived | Ortega-Paz L, Franchi F, Rollini F, Galli M, Been L, Ghanem G, Shalhoub A, Ossi T, Rivas A, Zhou X, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Mahowald MK, Langaee T, Jakubowski JA, Cavallari LH, Angiolillo DJ. Clopidogrel-Mediated P2Y12 Inhibition According to Renal Function in Patients With Diabetes Mellitus and CAD. JACC Basic Transl Sci. 2024 Mar 25;9(7):865-876. doi: 10.1016/j.jacbts.2024.03.003. eCollection 2024 Jul. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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) |
| FG001 | 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) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Patient with diabetes and stable coronary artery disease not on a P2Y12 inhibitor.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Mean | Standard Deviation | PRI% | 6 hours |
|
24 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Francesco Franchi, MD | University of Florida | +1-904-244-2060 | francesco.franchi@jax.ufl.edu |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 21, 2021 | Jul 20, 2023 | Prot_001.pdf |
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| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D003924 | Diabetes Mellitus, Type 2 |
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D000077144 | Clopidogrel |
| ID | Term |
|---|---|
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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|
| Clopidogrel active metabolite | Drug | 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) |
|
|
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 |
| BG001 | 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) |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Prior myocardial infarction | Count of Participants | Participants |
|
| OG001 | 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) |
|
|
| Secondary | Clopidogrel Active Metabolite Concentration | Comparison of clopidogrel active metabolite plasma concentrations by means of AUC | Posted | Median | Inter-Quartile Range | ng*h/mL | 6 hours |
|
|
|
| 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 | Posted | Mean | Standard Deviation | PRU | 6 hours |
|
|
|
| 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 | Posted | Mean | Standard Deviation | PRI% | Baseline |
|
|
|
| 0 |
| 31 |
| 0 |
| 31 |
| 0 |
| 31 |
| EG001 | 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) | 0 | 30 | 0 | 30 | 0 | 30 |
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| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |