Pharmacodynamic Study on Efficacy of Clopidogrel With St. John's Wort - Full Text View

Purpose

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

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

Condition	Intervention
Acute Coronary Syndrome	Drug: Placebo Drug: St. Johns Wort

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	The Effect of Inducing the Cytochrome P450 System on the Pharmacodynamic Efficacy of Clopidogrel

Resource links provided by NLM:

Drug Information available for: St. John's Wort Clopidogrel bisulfate

U.S. FDA Resources

Further study details as provided by Lancaster General Hospital:

Primary Outcome Measures:

Mean platelet reactivity (as measured in platelet reactivity units) on day 7 and day 21 [ Time Frame: Day 7 and Day 21 ] [ Designated as safety issue: No ]
The investigators are comparing the mean platelet reactivity (as measured in platelet reactivity units) within subjects (treatment effect) between placebo and St. Johns Wort. In addition we will be assessing the period effect (difference between those getting treatment AB - placebo/St. Johns Wort and those getting treatment BA - St. Johns Wort/placebo).

Estimated Enrollment:	84
Study Start Date:	April 2011
Estimated Study Completion Date:	September 2013
Estimated Primary Completion Date:	September 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: AB: Placebo (A); St. Johns Wort (B) Receive placebo for 7 days, 7 days washout and 7 days of St. Johns Wort	Drug: Placebo Non-active placebo for 7 days: PO/TID Drug: St. Johns Wort For 7 days: 300mg PO/TID
Experimental: BA: St. Johns Wort (B); Placebo (A) Receive St. Johns Wort for 7 days, 7 days washout and 7 days of placebo	Drug: Placebo Non-active placebo for 7 days: PO/TID Drug: St. Johns Wort For 7 days: 300mg PO/TID

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

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

Hypothesis

Reduced platelet reactivity is present in patients receiving St. John's wort as compared to placebo when utilized in combination with clopidogrel
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

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01330589

Contacts

Contact: Kathy M Makkar, Pharm.D.

717-544-7416

kamakkar@lghealth.org

Locations

United States, Pennsylvania
Lancaster General Hospital	Recruiting
Lancaster, Pennsylvania, United States, 17604

Sponsors and Collaborators

Lancaster General Hospital

H. G. Barsumian Memorial Fund

Louise von Hess Medical Research Institute

Investigators

Principal Investigator:	Kathy M Makkar, PharmD	Lancaster General Hospital
Principal Investigator:	Roy S Small, MD	Lancaster General Hospital
Principal Investigator:	Rupal P Dumasia, MD	Lancaster General Hospital
Principal Investigator:	Jill A Rebuck, PharmD	Lancaster General Hospital
Principal Investigator:	Michael A Horst, PhD	Lancaster General Research Institute
Principal Investigator:	Yee M Lee, PharmD	Lancaster General Hospital
Principal Investigator:	Richard D Paoletti, RPh	Lancaster General Hospital

More Information

Publications:

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. Erratum in: N Engl J Med 2001 Dec 6;345(23):1716. N Engl J Med 2001 Nov 15;345(20):1506.

Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2411-20. Erratum in: JAMA. 2003 Feb 26;289(8):987.

Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006 Apr 20;354(16):1706-17. Epub 2006 Mar 12.

Kimura T, Morimoto T, Kozuma K, Honda Y, Kume T, Aizawa T, Mitsudo K, Miyazaki S, Yamaguchi T, Hiyoshi E, Nishimura E, Isshiki T; RESTART Investigators. Comparisons of baseline demographics, clinical presentation, and long-term outcome among patients with early, late, and very late stent thrombosis of sirolimus-eluting stents: Observations from the Registry of Stent Thrombosis for Review and Reevaluation (RESTART). Circulation. 2010 Jul 6;122(1):52-61. Epub 2010 Jun 21.

Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J, Defreyn G, Maffrand JP. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol. 1992 Aug 4;44(3):527-32.

Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. Epub 2008 Dec 22.

Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360(4):363-75. Epub 2008 Dec 22.

Wang LS, Zhu B, Abd El-Aty AM, Zhou G, Li Z, Wu J, Chen GL, Liu J, Tang ZR, An W, Li Q, Wang D, Zhou HH. The influence of St John's Wort on CYP2C19 activity with respect to genotype. J Clin Pharmacol. 2004 Jun;44(6):577-81.

Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data. 2004 May 27;(343):1-19.

Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM, Li T, Liu J, Yang TL, Wang D, Zhong XY, Zhou HH. St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther. 2004 Mar;75(3):191-7.

Lau W, Carville D, Guyer K, Neer C. St. John's wort enhances the platelet inhibitor effect of clopidogrel in clopidogrel "resistant" healthy volunteers. J Am Coll Cardiol 2005;4:382A(abstract).

Lau WC, Welch TD, Shields TA, Rubenfire M, Gurbel PA. The effect of St. John's wort on the pharmacodynamic efficacy of clopidogrel in hyporesponsive volunteers. J Am Coll Cardiol 2010;55:A171(abstract).

Responsible Party:	Michael A. Horst, PhD, MPHS, MS, Director of Research, Lancaster General Hospital
ClinicalTrials.gov Identifier:	NCT01330589 History of Changes
Other Study ID Numbers:	2010-56-LGH
Study First Received:	March 28, 2011
Last Updated:	January 16, 2013
Health Authority:	United States: Institutional Review Board

Keywords provided by Lancaster General Hospital:

Percutaneous coronary intervention
Clopidogrel
St. John's Wort
CYP 2C19 loss-of-function allele

Additional relevant MeSH terms:

Acute Coronary Syndrome
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Angina Pectoris
Vascular Diseases
Chest Pain
Pain
Signs and Symptoms
Clopidogrel
Platelet Aggregation Inhibitors

Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 22, 2013

Pharmacodynamic Study on Efficacy of Clopidogrel With St. John's Wort (INDUCE-it)