Clopidogrel Response and CYP2C19 Genotype in Ischemic Stroke Patients (CLOGIS)

Personalized therapy as prophylaxis in ischemic stroke patients is not yet an option. From patients with ischemic heart disease, we know that patients with in vitro high on treatment platelet reactivity (HTPR) have an increased risk of stent thrombosis following per-cutaneous coronary intervention. Other studies have shown association of CYP2C19 genotypes with different responses to the anti platelet drug Clopidogrel. We measure HTPR in ischemic stroke patients on increasing doses of clopidogrel and investigate the CYP2C19 genotype for each patient.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: Clopidogrel

Detailed Description

Background: Clopidogrel (CLO) is a pro-drug metabolized in the liver by the Cytochrom-P450 system to its active component. Studies in acute ischemic stroke (IS) patients have proven that genetic differences in coding of an enzyme responsible for the metabolism of CLO (CYP2C19) results in different response to CLO when tested in the blood. An American study in cardiac patients have shown an association between the genotype and the CLO-response to different dosages of CLO, meaning that patients who are non-responders to low dosages of CLO may be responders to higher CLO dosages. Furthermore, the study showed that patients with a distinct genotype does not gain CLO response even at high CLO dosages (300 mg/day).

Perspective: The study will have an impact on the patient, the relatives and the social economy. The project answers if it is possible to give personalized therapy to IS patients securing the best possible prophylactic treatment for each single patient. Hereby reducing the risk of early death, disability and dependency. The project determines the genetic distribution of CYP2C19 alleles in the Danish IS population and determine the association between genotype and CLO-response in clinically relevant dosages in a Caucasian population of IS patients.

Objective: To determine the correlation between genotype and Clopidogrel response to different CLO dosage and to determine the distribution of different alleles of CYP2C19 genotypes in a Danish IS population.

Hypothesis: CLO response is determined by CYP2C19 genotype, and there is a correlation between drug-response and CYP2C19 genotype.

Method: Systematic recording of data on 103 IS patients receiving prophylactic treatment with CLO 75 mg/day.

Genotype is determined in collaboration with Division of Clinical Biochemistry, Dept. of Diagnostics, Glostrup Hospital determining the CYP2C19 genotype *1(wild-type), *2(Loss Of Function=LOF) and *17(Gain Of Function=GOF). CLO responder status is determined using the VerifyNow P2Y12 assays.

Patients receiving CLO 75 mg/day who are non-responders when testing with VerifyNow P2Y12 assays have a blood sample for genetic testing. Patients carrying the *2 genotype on one or both alleles are CLO responder status tested on increasing doses of CLO, rising 75 mg/day every 14 days (150/225/300 mg) until maximum CLO 300 mg/day. Responder status is tested at the end of every second week, before increasing dosage. If the patient is CLO responder on the tested dose (150/225/300 mg) or non-responder on CLO 300 mg/day, the patient is ended in the study and switched to treatment with ASA in combination with Dipyramidole.

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Roskilde, Denmark, 4000
    • Zealand University Hospital, dept of neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ischemic stroke diagnosis
• treatment with clopidogrel 75 mg/day

Exclusion Criteria:

• increased risk of bleeding
• treatment with NOAC, vitamin K antagonist or other antiplatelet drug than clopidogrel
• unable to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clopidogrel non-responders; Increasing doses og Clopidogrel depending on PRU values measured on VerifyNow	Drug: Clopidogrel; increasing doses of clopidogrel depending on PRU values (75-300 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who has clopidogrel HTPR	Clopidogrel responder status measured with VerifyNow	7 days
Number of patients who are carriers of CYP2C19 loss-of-function alleles	Genotyping patients for different loss-of-function CYP2C19 alleeles (*2, *3)	1 day
Number of patients who are carriers of P2Y12-receptor loss-of-function alleles	genotyping patients for different loss-of-function P2Y12 receptor alleeles	1 day

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Investigators: Principal Investigator: Charlotte Rath, MD, Zealand University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): July 30, 2017
• Study Completion (Actual): July 30, 2017

Study Registration Dates

• First Submitted: August 21, 2017
• First Submitted That Met QC Criteria: December 20, 2017
• First Posted (Actual): December 28, 2017

Study Record Updates

• Last Update Posted (Actual): December 28, 2017
• Last Update Submitted That Met QC Criteria: December 20, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: 2015-003548-38

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No