Pharmacodynamic Study on Efficacy of Clopidogrel With St. John's Wort

Acute Coronary Syndrome Clinical Trial

— INDUCE-it  

Official title:

The Effect of Inducing the Cytochrome P450 System on the Pharmacodynamic Efficacy of Clopidogrel

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01330589
• Other study ID #: 2010-56-LGH
• Status: Withdrawn
• Phase: N/A
• First received: March 28, 2011
• Last updated: October 3, 2017
• Start date: April 2011
• Est. completion date: March 2015

Study information

• Verified date: October 2017
• Source: Lancaster General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Coronary Syndrome

Intervention

Drug:
• Placebo
Non-active placebo for 7 days: PO/TID
• St. Johns Wort
For 7 days: 300mg PO/TID

Locations

Country	Name	City	State
United States	Lancaster General Hospital	Lancaster	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Lancaster General Hospital	H. G. Barsumian Memorial Fund, Louise von Hess Medical Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. doi: 10.1161/CIRCULATIONAHA.109.903955. Epub 2010 Jun 21. — View Citation

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).

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. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22. — View Citation

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. — View Citation

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. doi: 10.1056/NEJMoa0808227. Epub 2008 Dec 22. — View Citation

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.. — View Citation

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. — View Citation

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. — View Citation

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 Nov 15;345(20):1506. N Engl J Med 2001 Dec 6;345(23):1716. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean platelet reactivity (as measured in platelet reactivity units) on day 7 and day 21	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).	Day 7 and Day 21