Pharmacodynamic Study on Efficacy of Clopidogrel With St. John's Wort (INDUCE-it)
3 ottobre 2017 aggiornato da: Michael A. Horst, PhD, MPHS, MS, Lancaster General Hospital
The Effect of Inducing the Cytochrome P450 System on the Pharmacodynamic Efficacy of Clopidogrel
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
Panoramica dello studio
Stato
Ritirato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
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.
Tipo di studio
Interventistico
Fase
- Non applicabile
Contatti e Sedi
Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.
Luoghi di studio
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Pennsylvania
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Lancaster, Pennsylvania, Stati Uniti, 17604
- Lancaster General Hospital
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Criteri di partecipazione
I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.
Criteri di ammissibilità
Età idonea allo studio
18 anni e precedenti (Adulto, Adulto più anziano)
Accetta volontari sani
No
Sessi ammissibili allo studio
Tutto
Descrizione
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
Piano di studio
Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione incrociata
- Mascheramento: Quadruplicare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
|---|---|
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Sperimentale: AB: Placebo (A); St. Johns Wort (B)
Receive placebo for 7 days, 7 days washout and 7 days of St. Johns Wort
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Non-active placebo for 7 days: PO/TID
For 7 days: 300mg PO/TID
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Sperimentale: BA: St. Johns Wort (B); Placebo (A)
Receive St. Johns Wort for 7 days, 7 days washout and 7 days of placebo
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Non-active placebo for 7 days: PO/TID
For 7 days: 300mg PO/TID
|
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Mean platelet reactivity (as measured in platelet reactivity units) on day 7 and day 21
Lasso di tempo: 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).
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Day 7 and Day 21
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Collaboratori e investigatori
Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.
Sponsor
Investigatori
- Investigatore principale: Kathy M Makkar, PharmD, Lancaster General Hospital
- Investigatore principale: Roy S Small, MD, Lancaster General Hospital
- Investigatore principale: Rupal P Dumasia, MD, Lancaster General Hospital
- Investigatore principale: Jill A Rebuck, PharmD, Lancaster General Hospital
- Investigatore principale: Michael A Horst, PhD, Lancaster General Research Institute
- Investigatore principale: Yee M Lee, PharmD, Lancaster General Hospital
- Investigatore principale: Richard D Paoletti, RPh, Lancaster General Hospital
Pubblicazioni e link utili
La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.
Pubblicazioni generali
- 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.
- Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres 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.
- 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. doi: 10.1001/jama.288.19.2411. Erratum In: JAMA. 2003 Feb 26;289(8):987.
- 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.
- 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. doi: 10.1056/NEJMoa060989. Epub 2006 Mar 12.
- 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. doi: 10.1056/NEJMoa010746. Erratum In: N Engl J Med 2001 Dec 6;345(23):1716. N Engl J Med 2001 Nov 15;345(20):1506.
- 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.
- 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. doi: 10.1016/0006-2952(92)90445-o.
- 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. doi: 10.1177/0091270004265642.
- 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. doi: 10.1016/j.clpt.2003.09.014.
- 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 T, Rubenfire M, Tantry US, Gurbel PA. The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol. 2011 Jan;57(1):86-93. doi: 10.1097/FJC.0b013e3181ffe8d0.
Studiare le date dei record
Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.
Studia le date principali
Inizio studio (Effettivo)
1 aprile 2011
Completamento primario (Effettivo)
1 marzo 2015
Completamento dello studio (Effettivo)
1 marzo 2015
Date di iscrizione allo studio
Primo inviato
28 marzo 2011
Primo inviato che soddisfa i criteri di controllo qualità
6 aprile 2011
Primo Inserito (Stima)
7 aprile 2011
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
5 ottobre 2017
Ultimo aggiornamento inviato che soddisfa i criteri QC
3 ottobre 2017
Ultimo verificato
1 ottobre 2017
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
Altri numeri di identificazione dello studio
- 2010-56-LGH
Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .