Salts of Clopidogrel: Investigation to ENsure Clinical Equivalence (SCIENCE)

November 27, 2023 updated by: Alexandros Tselepis, University of Ioannina

Comparative Study of Clinical Efficacy and Safety of Different Clopidogrel Salts in Patients With Cardiovascular Disease. A Multi-center Non-interventional Clinical Trial.

Clopidogrel besylate (CB) is not differentiated relative to the orignal clopidogrel hydrogen sulfate (CHS) in the pharmacokinetics and in antiplatelet potency in healthy volunteers. In addition,CB exhibits similar pharmacodynamic properties compared to CHS in patients with a history of acute coronary syndrome (ACS) and in patients with ACS undergoing percutaneous coronary intervention (PCI). However, there is a lack of data on the clinical efficacy and safety of this salt to the original salt in patients with cardiovascular disease. The aim of this study is to investigate the clinical efficacy and safety of CB in relation to that of CHS in patients eligible to receive clopidogrel.

Study Overview

Status

Completed

Conditions

Detailed Description

It is now well documented that platelets play an important role in the pathogenesis of acute coronary syndromes. This phenomenon has significantly strengthened the position of antiplatelet drugs in treatment, and prevention of these syndromes. In terms of administration, antiplatelet drugs are divided into two categories, the oral and intravenous medications. Of these, oral medications are the choice for long-term or prophylactic treatment of patients with acute coronary syndrome. Among them, is clopidogrel, which together with aspirin is now the cornerstone of antiplatelet therapy. Indeed, clopidogrel is a widely used antiplatelet drug. It is second in sales worldwide after atorvastatin and has been prescribed to more than 100 million patients worldwide. Clopidogrel can be used as monotherapy or in combination with aspirin. The efficacy in reducing ischemic events in patients with ACS has been shown in more than 15 major clinical studies involving more than 200,000 patients. These studies also proved the safety of clopidogrel to the bleeding complications (only 1-2% per year).Clopidogrel is a second generation thienopyridine that inhibits the binding of ADP to purinergic receptors of platelet membrane. The ADP activates platelets through different receptors coupled to G-proteins. The main receptor for platelet activation by ADP is P2Y12, associated with the adenyl cyclase and cause deactivation of the resulting reduction in the levels of c-AMP. The identification of this receptor led to the complete elucidation of the mechanism of action of clopidogrel, which proved to be an irreversible antagonist P2Y12.

Clopidogrel is a prodrug that, once granted, is absorbed in the intestine by a process in which an important role is played by the protein carrier ABCB1/MDR1. Then clopidogrel is converted in the liver to the pharmacologically active metabolite by the action of cytochrome P450 (CYP450) and mainly isoform CYP2C19 and isoforms CYP3A4, CYP3A5, CYP1A2, CYP2B6 and CYP2C9. It should be noted that 85% of clopidogrel absorbed, hydrolyzed by esterases in the intestinal mucosa and blood to form biologically inactive products while only 15% of the administered drug is converted to its active metabolite, which is a potent, irreversible, selective inhibitor of receptor P2Y12 ADP resulting in the inhibition of the activation of receptor GPIIb / IIIa and thereby preventing platelet aggregation.

Currently, clopidogrel generic forms are available in the market. Indeed, in 2010 and after 10 years of circulation of the original formulation (clopidogrel bisulfate) under the trade names Plavix or Iscover, released new generic formulations of clopidogrel (generic) due to expiration of the period of exclusive marketing using the original formulation. Main difference of generic forms of clopidogrel to the original formulation (clopidogrel bisulfate) is pharmacochemical recommendation salt of clopidogrel, which in the case of generic formulations is benzenesulfonic (besylate) or hydrochloride salt. Generic formulations of clopidogrel have received marketing approval from the health authorities of the European Union. Bioequivalence comparative studies of clopidogrel generic formulations in healthy volunteers for generic clopidogrel bisulfate, clopidogrel besylate and clopidogrel hydrochloride have proven same pharmacodynamic and pharmacokinetic profile. Considering the wide variability of platelet response to clopidogrel treatment and the high incidence of atherothrombotic events in clopidogrel hyporesponsive patients, studies comparing the pharmacodynamic properties of various generic clopidogrel formulations with those of original clopidogrel bisulfate in CAD patients are essential.

Therefore, given the numerous generic clopidogrel salts that are commercially available today, it is of importance to note that any clinical data or research results arising from the use of these formulations in patients with cardiovascular disease should be related to the specific product used and not generally to the generic clopidogrel.

Our group has performed two prospective pharmacodynamic studies comparing the antiplatelet effectiveness of clopidogrel besylate with that of clopidogrel bisulfate in patients with a history of an ACS, and in ACS patients undergoing PCI. In both studies we showed pharmacodynamic bioequivalence in all platelet function tests performed.

There is a strong need of conducting further clinical studies with adequate number of patients with each clopidogrel generic formulation commercially available in order to confirm its therapeutic equivalence with the innovator product.

Study Type

Observational

Enrollment (Actual)

1500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Greece
    • Epirus
      • Ioannina, Epirus, Greece, 45110
        • Atherothrombosis Research Centre / Laboratory of Biochemistry, University of Ioannina

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Suitable for the study will be every patient eligible to receive clopidogrel based on the international guidelines. In particular, in the study will participate patients with an acute coronary syndrome (ACS) or having a stable coronary artery disease (CAD). Patients who have experienced an acute ischemic stroke or a transient ischemic attack (TIA) during the previous 6 months or having a history of peripheral artery disease (PAD) or carotid artery disease, will be also eligible for enrollment. Finally, patients with atrial fibrillation (AF) who will refuse or will not be eligible to use of any oral anticoagulant will be included in the study. The study will include at least 1,500 patients (at least 750 will receive clopidogrel hydrogen sulfate and at least 750 clopidogrel besylate).

Description

Inclusion Criteria:

  • Both sexes
  • age >18 years
  • age <85 years
  • Patients with an ACS with or without percutaneous coronary intervention, stable CAD, history of an ischemic stroke/TIA, PAD, carotid artery disease or atrial fibrillation
  • agree on study participation
  • will comply with all required study procedures

Exclusion Criteria:

  • >85 years
  • <18 years

Patients with

  • hypersensitivity reaction or contraindication to clopidogrel,
  • active bleeding or history of severe bleeding (peptic ulcer, trauma or intracranial hemorrhage),
  • blood coagulation disorders,
  • uncontrolled severe hypertension,
  • history of drug or alcohol abuse,
  • pregnancy or breastfeeding,
  • liver disease
  • chronic kidney disease,
  • malignancy,
  • disagree on study participation,
  • evidence for poor compliance with all required study procedures

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Clopidogrel hydrogen sulfate (CHS)
Clopidogrel hydrogen sulfate, 75 mg / day
Clopidogrel Besylate (CB)
Clopidogrel Besylate , 75 mg / day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Efficacy End Point
Time Frame: 12 months
Composite of death from vascular causes (cardiovascular causes or cerebrovascular causes), MI, or stroke for the entire follow-up period.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary Efficacy End Point
Time Frame: up to 6 and 12 months
Composite of death from any cause, MI, or stroke (ischemic or hemorrhagic), stent thrombosis and PCI during the entire follow-up period
up to 6 and 12 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Safety End Point
Time Frame: up to 6 and 12 months
The rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria
up to 6 and 12 months
Secondary Safety End Point
Time Frame: up to 6 and 12 months
Urticaria, temporary or permanent interruption of clopidogrel due to urticaria, temporary interruption due to surgery, dental procedures, patient's desire or bleeding, transient thrombocytopenia
up to 6 and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Ioannina

Collaborators

University Hospital, Ioannina

Investigators

  • Study Chair: Alexandros Tselepis, MD, PhD Professor, University of Ioannina

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Actual)

May 1, 2014

Study Completion (Actual)

November 1, 2014

Study Registration Dates

First Submitted

April 28, 2014

First Submitted That Met QC Criteria

April 29, 2014

First Posted (Estimated)

April 30, 2014

Study Record Updates

Last Update Posted (Actual)

November 28, 2023

Last Update Submitted That Met QC Criteria

November 27, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012-Clo-U-Io-01

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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