Metabolism of ClopidogrelPGXB2BNCT01341600
Clopidogrel Pharmacogenetics (PGX) Bench to Bedside
A study testing Clopidogrel and Omeprazole/Clopidogrel in people with Metabolism of Clopidogrel, run by University of Maryland, Baltimore at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 20 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Metabolism of Clopidogrel
- What is being tested?
- Clopidogrel and Omeprazole/Clopidogrel
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2010to May 2011
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Amish men or women between 20 and 70 years of age who participated in PAPI
Who cannot join
- Severe hypertension (bp > 160/95 mm Hg)
- Co-existing malignancy
- Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 2 times normal
- Creatinine >2.0
- Hct < 32 or Hct > 50
- Thyroid Stimulating Hormone (TSH) < 0.40 or >5.50
Show all 17Show fewer
- History of bleeding disorder or gastrointestinal bleeding
- History of unstable angina, myocardial infarction (MI), angioplasty, coronary artery bypass surgery
- History of atrial fibrillation, stroke or transient ischemic attacks or deep vein thrombosis
- Type 2 diabetes
- Thrombocytosis (platelet count > 500,000) or thrombocytopenia (platelet count < 150,000)
- Surgery within six months
- Clopidogrel allergy
- Pregnant women
- Currently breast feeding
- Omeprazole allergy
- Prospective participants taking medications that would affect the outcome(s) to be measured and who cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation, or who are taking vitamins and/or other supplements and who are unwilling to discontinue their use for at least 1 week prior to study
Trial locations and contacts
1 site in 1 country.
United States1 site
Amish Research Clinic
Lancaster, Pennsylvania, 17601
About this study
Official title: Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application
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.
Read the detailed description
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.
- Conditions
- Metabolism of Clopidogrel
- Being tested
- Clopidogrel, Omeprazole/Clopidogrel
- Keywords
- Clopidogrel, Pharmacogenetics, Platelets, Healthy Subjects
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClopidogrelDrug
Also called Plavix
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.
Omeprazole/ClopidogrelDrug
Also called Prilosec, Plavix
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Clopidogrel |
| 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. Receives: Drug: Clopidogrel |
| 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. Receives: Drug: Clopidogrel |
| 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. Receives: Drug: Omeprazole/Clopidogrel |
| 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. Receives: Drug: Omeprazole/Clopidogrel |
| 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. Receives: Drug: Omeprazole/Clopidogrel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Platelet Aggregation Following Therapy With Clopidogrel
Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1.
Measured: 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
Measured: 4 hours post Day 8 dose
Secondary outcomes (2)
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
Measured: Baseline, Day 8
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.
Measured: Baseline, 0.25, 0.5, 1, 2, and 4 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2011 (estimated)
- Study startJul 2010
- Primary completionMay 2011
- Study completionMay 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Metabolism of ClopidogrelStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Maryland, Baltimore
- Sponsor type
- University, hospital or other
- Collaborators
- Food and Drug Administration (FDA), National Cancer Institute (NCI), National Institute of General Medical Sciences (NIGMS), National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Alan Shuldiner, University of Maryland, Baltimore
- Investigators
- Richard B Horenstein, M.D., Principal investigator, University of Maryland, Baltimore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01341600
- Sponsor's protocol ID
- HP-00044487
- Other IDs
- U01GM074518, U01HL105198, 128475, ZICSC006536, ZICSC006537
- Acronym
- PGXB2B
- Status last verified
- Jan 2024
- First submitted
- 22 Apr 2011
- Last updated
- 30 Jan 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 19706858Jiang 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.
PubMed 26524713Horenstein 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.
PubMed 24710841
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application
- ClinicalTrials.gov ID
- NCT01341600
- Acronym / sponsor ID
- PGXB2B / HP-00044487
- Conditions
- Metabolism of Clopidogrel
- Keywords
- Clopidogrel, Pharmacogenetics, Platelets, Healthy Subjects
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- University of Maryland, BaltimoreUniversity, hospital or other
- Collaborators
- Food and Drug Administration (FDA), National Cancer Institute (NCI), National Institute of General Medical Sciences (NIGMS), National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Jul 2010
- Primary completion
- May 2011 (actual)
- Study completion
- May 2011 (actual)
- First posted
- 25 Apr 2011 (estimated)
- Results
- Posted 27 Jul 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Clopidogrel in poor metabolizers | Experimental | Drug: ClopidogrelHealthy 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 | Drug: ClopidogrelHealthy 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 | Drug: ClopidogrelHealthy 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. |
| Omeprazole/Clopidogrel in PM | Experimental | Drug: Omeprazole/ClopidogrelPM 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 | Drug: Omeprazole/ClopidogrelIM 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 | Drug: Omeprazole/ClopidogrelEM 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. |
Who may qualify
- Ages
- 20 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Amish men or women between 20 and 70 years of age who participated in PAPI
Key exclusion criteria (17 listed)
- Severe hypertension (bp > 160/95 mm Hg)
- Co-existing malignancy
- Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 2 times normal
- Creatinine >2.0
- Hct < 32 or Hct > 50
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ClopidogrelAlso: PlavixOver 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. | Drug | Clopidogrel in extensive metabolizers, Clopidogrel in intermediate metabolizers, Clopidogrel in poor metabolizers |
| Omeprazole/ClopidogrelAlso: Prilosec, PlavixAfter 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. | Drug | Omeprazole/Clopidogrel in EM, Omeprazole/Clopidogrel in IM, Omeprazole/Clopidogrel in PM |
Primary outcome
Change in Platelet Aggregation Following Therapy With Clopidogrel
Time frame: Day 1, 4 hours post clopidogrel dose
Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1.
Change in Platelet Aggregation Following Therapy With Clopidogrel
Time frame: 4 hours post Day 8 dose
ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose
2 secondary outcomes
Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole
Time frame: Baseline, Day 8
Level of Active Clopidogrel Metabolite
Time frame: Baseline, 0.25, 0.5, 1, 2, and 4 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19706858Shuldiner 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.
- Background: PubMed 26524713Jiang 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.
- Background: PubMed 24710841Horenstein 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Richard B Horenstein, M.D. principal investigator
University of Maryland, Baltimore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Clopidogrel and Omeprazole/Clopidogrel in people with Metabolism of Clopidogrel, run by University of Maryland, Baltimore at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Platelet Aggregation Following Therapy With Clopidogrel (time frame: Day 1, 4 hours post clopidogrel dose). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01341600, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2024.