Clinical trial NCT01330589: Pharmacodynamic Study on Efficacy of Clopidogrel With St. John's Wort
Official title: The Effect of Inducing the Cytochrome P450 System on the Pharmacodynamic Efficacy of Clopidogrel
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Acute Coronary Syndrome
Keywords: Percutaneous coronary intervention
Clopidogrel
St. John's Wort
CYP 2C19 loss-of-function allele
Lead sponsor: Lancaster General Hospital
Sponsor class: OTHER
Collaborators: name: H G Barsumian MD Memorial Fund
name: Louise von Hess Medical Research Institute
First posted: 2011-04-07
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate whether patients post PCI receiving clopidogrel who are carriers of at least one CYP 2C19 loss-of-function allele may achieve improved pharmacodynamic efficacy of clopidogrel when treated with the CYP 2C19 enzyme inducing agent, St. John's wort, as compared with placebo.

Hypothesis

1. Reduced platelet reactivity is present in patients receiving St. John's wort as compared to placebo when utilized in combination with clopidogrel
2. The combination or St. John's wort and clopidogrel results in enhanced platelet inhibition

Detailed description: Objective The purpose of this study is to evaluate whether patients post PCI receiving clopidogrel who are carriers of at least one CYP 2C19 loss-of-function allele may achieve improved pharmacodynamic efficacy of clopidogrel when treated with the CYP 2C19 enzyme inducing agent, St. John's wort, as compared with placebo.

Specific Aims

1. To identify the difference in platelet reactivity in patients receiving St. John's wort or placebo
2. To characterize the difference in platelet inhibition in patients receiving St. John's wort or placebo

Hypothesis

1. Reduced platelet reactivity is present in patients receiving St. John's wort as compared to placebo when utilized in combination with clopidogrel
2. The combination or St. John's wort and clopidogrel results in enhanced platelet inhibition

Study Design The study is a prospective, randomized, double-blind, placebo-controlled, cross-over study of patients post PCI who require dual-antiplatelet therapy with aspirin and clopidogrel. Approximately 84 patients will be enrolled and undergo pharmacogenetic testing to assess clopidogrel responsiveness utilizing CYP P450 2C19 genotyping (Plavitest®). Based upon an assumption of 30% genetic non-responsiveness and a dropout rate of 20%, to achieve a final sample size of 20 subjects in the randomized crossover portion of the study, the investigators need to enroll approximately 84 subjects. Patients identified as carriers of at least one CYP 2C19 loss-of-function allele (i.e. clopidogrel reduced-metabolizers) will remain in the study and be randomly assigned to receive placebo or St. John's wort. Patients not carrying a CYP 2C19 loss-of-function allele (i.e. clopidogrel normal metabolizers) will not require any further follow-up as these patients are considered to display a normal response to clopidogrel. On day 7 following the initiation of the study drug, platelet function testing will be performed. Following a 7 day washout period, patients will be crossed over into the other study group to receive 7 days of study medication. On day 21, the patients will undergo platelet function testing and the study medication will be discontinued.

Eligibility criteria: Inclusion Criteria:

* Patients age 18 or older
* Patients with a history of ACS and/or who receive PCI with stent placement at Lancaster General Hospital requiring dual antiplatelet therapy with aspirin and clopidogrel.

Exclusion Criteria:

* Patients with active or any known history of bleeding such as gastrointestinal, intracranial, or any other bleeding diathesis
* History of major surgery in the last year (any surgical procedure that involves general anesthesia or respiratory assistance)
* Clinical findings associated with an increased risk of bleeding at the judgment of the investigator
* Patients actively receiving anticoagulation therapy
* Hemoglobin \< 10 g/dL
* Platelets \< 150,000/mm3
* Known hepatic dysfunction
* History of intracranial malignancy or stroke
* Patients receiving thienopyridines chronically prior to PCI
* Concurrent use of CYP P450 2C19 substrates, or inhibiting/ inducing medications with the exception of proton pump inhibitors
* Illicit drug or alcohol abuse
* Daily treatment with nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors
* Allergy to St. Johns wort or lactose
* Patients expected to discontinue dual antiplatelet therapy prior to completion of the study protocol
* Patients unable to adhere to the study protocol

Primary outcomes:
measure: Mean platelet reactivity (as measured in platelet reactivity units) on day 7 and day 21
timeFrame: Day 7 and Day 21
Secondary outcomes:
Other outcomes:
Locations:
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
Study officials:
affiliation: Lancaster General Hospital
name: Kathy M Makkar, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lancaster General Hospital
name: Roy S Small, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lancaster General Hospital
name: Rupal P Dumasia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lancaster General Hospital
name: Jill A Rebuck, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lancaster General Research Institute
name: Michael A Horst, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lancaster General Hospital
name: Yee M Lee, PharmD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lancaster General Hospital
name: Richard D Paoletti, RPh
role: PRINCIPAL_INVESTIGATOR
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