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| ID | Type | Description | Link |
|---|---|---|---|
| U01GM074518 | U.S. NIH Grant/Contract | View source | |
| U01HL105198 | U.S. NIH Grant/Contract | View source | |
| 128475 | Other Grant/Funding Number | NIH | |
| ZICSC006536 | U.S. NIH Grant/Contract | View source | |
| ZICSC006537 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Food and Drug Administration (FDA) | FED |
| National Cancer Institute (NCI) | NIH |
| National Institute of General Medical Sciences (NIGMS) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) |
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Clopidogrel (also known as Plavix) is used commonly in patients to prevent heart attacks and conditions caused by blood clots. Although clopidogrel works in many individuals, some people do not respond as well to this drug. The variation in treatment response may be linked to genetics. This study will examine the effects of clopidogrel in a population in which sequencing for certain genes has been performed in order to determine the role that genes play in the response to various clopidogrel maintenance doses.
Clopidogrel is a prodrug with high inter-individual response variability. Clopidogrel is converted to an active drug in part through an enzyme encoded by the gene named CYP2C19. Individuals with genetically-impaired CYP2C19 metabolism have lower capacity to convert the prodrug to its active form. Consequently, these individuals have lower blood levels of the activated form of clopidogrel, diminished antiplatelet responses, and higher rates of cardiovascular events and stent thrombosis. Increasing doses of clopidogrel in such patients represents a possible approach to managing the gene-drug interaction.
The purpose of this study is to evaluate whether increasing the dose of clopidogrel increases antiplatelet responses and active metabolite exposure in individuals with genetically reduced CYP2C19 metabolism relative to those with normal CYP2C19 metabolism.
The primary objective is to assess changes in clopidogrel response and exposure at three clopidogrel dose levels and with coadministration of omeprazole.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clopidogrel in poor metabolizers | Experimental | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 poor metabolizers (PM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. |
|
| Clopidogrel in intermediate metabolizers | Experimental | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers (IM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. |
|
| Clopidogrel in extensive metabolizers | Experimental | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers (EM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clopidogrel | Drug | Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Platelet Aggregation Following Therapy With Clopidogrel | Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1. | Day 1, 4 hours post clopidogrel dose |
| Change in Platelet Aggregation Following Therapy With Clopidogrel | ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose | 4 hours post Day 8 dose |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | The change in maximum platelet aggregation in response to ADP 4-hours post dose on day 8 of therapy with clopidogrel and omeprazole will be compared to the baseline measure of platelet aggregation at day 1 prior to drug therapy | Baseline, Day 8 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Richard B Horenstein, M.D. | University of Maryland, Baltimore | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amish Research Clinic | Lancaster | Pennsylvania | 17601 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19706858 | Background | Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232. | |
| 26524713 | Background | Jiang XL, Samant S, Lewis JP, Horenstein RB, Shuldiner AR, Yerges-Armstrong LM, Peletier LA, Lesko LJ, Schmidt S. Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults. Eur J Pharm Sci. 2016 Jan 20;82:64-78. doi: 10.1016/j.ejps.2015.10.024. Epub 2015 Oct 30. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Poor Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI (NCT00799396)) will be recruited. We will select 6 poor metabolizers to clopidogrel 75 mg from participants who previously received clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| FG001 | Intermediate Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI (NCT00799396)) will be recruited. We will select 6 intermediate metabolizers to clopidogrel 75 mg in PAPI (NCT00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| FG002 | Extensive Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI (NCT00799396)) will be recruited. We will select 6 extensive metabolizers to clopidogrel 75 mg in PAPI (NCT00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clopidogrel 75 mg |
| |||||||||||||
| Clopidogrel 150 mg |
| |||||||||||||
| Clopidogrel 225 mg |
| |||||||||||||
| Clopidogrel Plus Omeprazole |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Poor Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 poor metabolizers to clopidogrel 75 mg from participants who previously received clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| 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 | Change in Platelet Aggregation Following Therapy With Clopidogrel | Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1. | Posted | Mean | Standard Deviation | percentage of aggregation | Day 1, 4 hours post clopidogrel dose |
|
Six weeks
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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 | Poor Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 poor metabolizers to clopidogrel 75 mg from participants who previously received clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | CTCAE (4.0) | poison ivy |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Richard Horenstein M.D., Associate Professor of Medicine | University of Maryland School of Medicine | 410-706-0154 | rhorenst@medicine.umaryland.edu |
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| ID | Term |
|---|---|
| D000077144 | Clopidogrel |
| D009853 | Omeprazole |
| ID | Term |
|---|---|
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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| NIH |
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Not provided
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Not provided
|
| Omeprazole/Clopidogrel in PM | Experimental | PM participants who have completed Arm 1 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
|
| Omeprazole/Clopidogrel in IM | Experimental | IM participants who have completed Arm 2 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
|
| Omeprazole/Clopidogrel in EM | Experimental | EM participants who have completed Arm 3 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
|
|
| Omeprazole/Clopidogrel | Drug | After a washout of at least 1 week, participants will have the option to participate in a final intervention in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
|
|
| Level of Active Clopidogrel Metabolite |
The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the Day One dose is administered for pharmacokinetic analysis. The analysis will measure the Area Under the Curve. |
| Baseline, 0.25, 0.5, 1, 2, and 4 hours |
| 24710841 | Background | Horenstein RB, Madabushi R, Zineh I, Yerges-Armstrong LM, Peer CJ, Schuck RN, Figg WD, Shuldiner AR, Pacanowski MA. Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers. J Clin Pharmacol. 2014 Aug;54(8):865-73. doi: 10.1002/jcph.293. Epub 2014 Apr 7. |
| NOT COMPLETED |
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| NOT COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | Intermediate Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers to clopidogrel 75 mg in PAPI (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| BG002 | Extensive Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers to clopidogrel 75 mg in PAPI (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Intermediate Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers to clopidogrel 75 mg in PAPI (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
| OG002 | Extensive Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers to clopidogrel 75 mg in PAPI (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. |
|
|
| Secondary | Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | The change in maximum platelet aggregation in response to ADP 4-hours post dose on day 8 of therapy with clopidogrel and omeprazole will be compared to the baseline measure of platelet aggregation at day 1 prior to drug therapy | Posted | Mean | Standard Deviation | percentage of aggregation | Baseline, Day 8 |
|
|
|
| Secondary | Level of Active Clopidogrel Metabolite | The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the Day One dose is administered for pharmacokinetic analysis. The analysis will measure the Area Under the Curve. | Posted | Mean | Standard Deviation | ng h/mL | Baseline, 0.25, 0.5, 1, 2, and 4 hours |
|
|
|
| Primary | Change in Platelet Aggregation Following Therapy With Clopidogrel | ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose | Posted | Mean | Standard Deviation | percentage of aggregation | 4 hours post Day 8 dose |
|
|
|
| 0 |
| 6 |
| 0 |
| 6 |
| EG001 | Intermediate Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers to clopidogrel 75 mg in PAPI (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. | 0 | 6 | 1 | 6 |
| EG002 | Extensive Metabolizers | Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers to clopidogrel 75 mg in PAPI (NCT 00799396). Clopidogrel, Omeprazole: Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. | 0 | 6 | 1 | 6 |
| vasovagal reaction | Nervous system disorders | CTCAE (4.0) |
|
| skin infection | Infections and infestations | CTCAE (4.0) | Fifths disease |
|
Not provided
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| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D001562 | Benzimidazoles |
|
| Clopidogrel 300mg |
|
|
| Clopidogrel 300mg |
|