Impact of Citalopharm and Fluvoxamine on Platelet Response to Clopidogrel

Sponsor

Hadassah Medical Organization (Other)

Overall Status

Completed

CT.gov ID

NCT01396720

Collaborator

(none)

Enrollment

Arms

Duration (Months)

Study Details

Study Description

Brief Summary

Clopidogrel is a platelets inhibitor that is widely used particularly during and after acute coronary events and coronary interventions. Several studies have shown that some patients are resistant to clopidogrel. The resistance mechanism is not entirely clear, but at least in part it is related to interactions between medications. Clopidogrel is a pro-drug converted in vivo to its active metabolite by CYP2C19 and CYP3A in the liver. Consequently drugs that inhibit the CYP2C19 can affect the production of the active metabolite and cause "clopidogrel resistance". Therefore the FDA has recently published a "safety alert" which recommends avoiding cross treatment with clopidogrel and drugs that are expected to inhibit CYP2C19 (including omeprazole, fluvoxamine, cimetidine, fluconazole and others). Nevertheless there no clear evidence in the literature for clinical relevance of such interactions.

Selective serotonin reuptake inhibitors (SSRIs) are group of antidepressant drugs that are widely used for treatment of depression and anxiety. SSRIs are considered to be very safe with favorable side effect profile, hence many patient after coronary events who suffers from behavioral and emotional disturbances are treated with those drugs. However there are several reports that SSRIs can inhibit platelet function and increase bleeding tendency particularly in concomitant administration with aspirin. The proposed mechanism is blocking of platelets serotonin reuptake that result in platelet dysfunction.

Fluvoxamine - is a member in the SSRI family and a potent inhibitor of the CYP2C19. Theoretically fluvoxamine should have two conflicting effects on the response to clopidogrel. Pharmacokinetically it is expected to decrease the clopidogrel responsiveness due to inhibition of CYP2C19 and reduction in the production of the active metabolite. On the other hand "pharmacodynamically" fluvoxamine may directly inhibit platelet aggregation due its effect on serotonin reuptake, thus increasing the effect of clopidogrel. Other SSRIs that do not interact with the CYP2C19 such as citalophram are expected to have only pharmocodynamic effect on platelet aggregation.

Although both clopidogrel and SSRIs are widely used in the last decade and concomitant treatment is quite common, no data is available about in influence of the interaction between those drugs on platelet function and on clinical events. The net effect of fluvoxamine and other SSRIs on platelet function in the presence of clopidogrel is not known.

The aim of the investigators study is to assess the effect of two SSRIs fluvoxamine and citalophram on platelet aggregation and to test the effect of these drugs on the laboratory response to clopidogrel, in healthy individuals.

Study design: randomized, double blinded, controlled crossover trial. Primary study end point: Change in % platelet aggregation and VASP phosphorylation after treatment with clopidogrel + fluvoxamine or clopidogrel + citalophram as compared to each drug alone.

Condition or Disease	Intervention/Treatment	Phase
Drug Interactions Between Clopidogrel and Serotonin Reuptake Inhibitors	Drug: fluvoxamine Drug: citalopharm	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Impact of Citalopharm and Fluvoxamine on Platelet Response to Clopidogrel, a Randomized, Double-blind, Crossover Trial

Study Start Date :

Sep 1, 2011

Actual Primary Completion Date :

Dec 1, 2012

Actual Study Completion Date :

Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: fluvoxamine	Drug: fluvoxamine Fluvoxamine 100mg daily, 7 days
Active Comparator: citalopharm	Drug: citalopharm Citalopharm 20mg daily, 7 days

Arm

Intervention/Treatment

Active Comparator: fluvoxamine

Drug: fluvoxamine

Fluvoxamine 100mg daily, 7 days

Active Comparator: citalopharm

Drug: citalopharm

Citalopharm 20mg daily, 7 days

Outcome Measures

Primary Outcome Measures

Platelet reactivity in response to clopidogrel [12 months]
We will assess response to clopidogrel by two methods: 1. % change in platelet aggregation using light transmission aggregometry with ADP as agonist. 2. % of change in VASP phosphorylation - measure of activation of the platelet P2Y12 receptor (targeted by clopidogrel). The response clopidogrel will be measured after administration of clopidogrel and after co-administration of clopidogrel and each of the study drugs (fluvoxamine and citalophram). Statistical analysis will be performed to assess differences in platelet function between the different drug treatments.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy volunteers

Exclusion Criteria:

Bleeding tendency
Hypersensitivity to study drugs

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Hadassah Medical Organization

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

RONNY ALCALAI, Director, Cardiac Care Unit, Mt. Scopus, Hadassah Medical Organization

ClinicalTrials.gov Identifier:

NCT01396720

Other Study ID Numbers:

0255-HMO-CTIL

First Posted:

Jul 19, 2011

Last Update Posted:

Jan 29, 2013

Last Verified:

Jan 1, 2013

Additional relevant MeSH terms:

Fluvoxamine

Study Results

No Results Posted as of Jan 29, 2013