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Effect of Primidone on Platelet Responsiveness in Patients Determined to be Clopidogrel Resistant

Primary Purpose

Clopidogrel Resistance, Secondary Stroke Prevention

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Primidone
Sponsored by
Dent Neuroscience Research Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clopidogrel Resistance focused on measuring Clopidogrel, Clopidogrel Resistance, Primidone, Secondary Stroke Prevention

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Males and females aged 18 - 90 years who are clopidogrel resistant as determined by whole blood aggregometry
  • Patients with a low risk of new cerebrovascular ischemic events as indicated by an Essen Stroke Risk Score of less than three

Exclusion Criteria:

  • Any history of allergy or intolerance to either Plavix or clopidogrel
  • Any history of allergy or intolerance to either Mysoline or primidone
  • Any clinically significant abnormalities in complete blood count as determined by the investigator
  • Use of any acute medications within the last two weeks or initiation of any non-study medications during the study period that would effect CYP enzymes or platelet function
  • Use of tobacco products from 2 weeks prior to enrollment in the study and throughout the duration of the study
  • Any planned surgical procedures during the study or 5 days after the study has ended
  • History of alcoholism or alcohol abuse
  • Participants who have had any alcohol consumption within 24 hours of a blood draw
  • Previous stroke in past 3 months
  • Participants who are or are planning to become pregnant
  • Participants who of reproductive potential must agree to use a method of contraception for the duration of the study as well as 4 weeks after participation is complete
  • Change in any medications that could affect liver enzymes or platelet aggregation throughout the study
  • Compliance less than 80 % based on pill counts on two different study visits

Sites / Locations

  • Dent Neurologic Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Primidone

Arm Description

Participants will receive primidone in addition to their clopidogrel regimen. For the first 3 days of the study, participants will take 125 mg of primidone (one-half tablet). After 3 days of 125 mg, the primidone dose will be increased to 250 mg (1 tablet) taken at bedtime for the next 17-25 days. The participant will then be asked to return and be retested.

Outcomes

Primary Outcome Measures

Platelet Aggregometry
Platelet Aggregometry will be used to assess platelet responsiveness to clopidogrel following treatment with investigational medication. Blood will be placed in plastic cuvettes and probes will be inserted. Wires on the probes measure platelet aggregation in electrical impedance. A baseline is obtained and then adenosine diphosphate (ADP) is added to cause aggregation. Clopidogrel prevents platelet aggregation through irreversible binding of its active metabolite to the ADP receptors on the platelet surface. The change in impedance from baseline is directly proportional to the extent of platelet aggregation and is expressed in ohms of resistance.

Secondary Outcome Measures

Area Under the Curve of Clopidogrel Metabolite Levels
Whole blood from the subjects will be drawn 30 minutes, 1 hour, 2 hours, 3 hours and 4 hours post clopidogrel dose. Once the blood is drawn, the metabolite will be derivatized to keep the metabolite stable in blood. Derivatization of the metabolite, involves spiking blood samples with 2-bromo-3'methoxyacetophenone contained in an acetonitrile solution. Once derivatization has been done, metabolite levels will be analyzed using liquid chromatography mass spectrometry (LCMS). Once concentration levels of the active metabolite are known, the area under the curve will be calculated under trapezoid rule (linear up, log down).

Full Information

First Posted
December 6, 2013
Last Updated
August 1, 2016
Sponsor
Dent Neuroscience Research Center
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1. Study Identification

Unique Protocol Identification Number
NCT02008123
Brief Title
Effect of Primidone on Platelet Responsiveness in Patients Determined to be Clopidogrel Resistant
Official Title
Effect of Primidone on Platelet Responsiveness in Patients Determined to be Clopidogrel Resistant
Study Type
Interventional

2. Study Status

Record Verification Date
August 2016
Overall Recruitment Status
Withdrawn
Why Stopped
Inclusion/Exclusion criteria was too stringent to enroll patients at this site.
Study Start Date
August 2013 (undefined)
Primary Completion Date
December 2017 (Anticipated)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dent Neuroscience Research Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine whether adding primidone will improve the metabolism of clopidogrel thereby increasing metabolite levels within the blood stream and platelet response to clopidogrel in patients who were previously found to lack adequate response to clopidogrel. This information could help overcome clopidogrel resistance in patients who are at risk for stroke or transient ischemic attack (TIA).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clopidogrel Resistance, Secondary Stroke Prevention
Keywords
Clopidogrel, Clopidogrel Resistance, Primidone, Secondary Stroke Prevention

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Primidone
Arm Type
Experimental
Arm Description
Participants will receive primidone in addition to their clopidogrel regimen. For the first 3 days of the study, participants will take 125 mg of primidone (one-half tablet). After 3 days of 125 mg, the primidone dose will be increased to 250 mg (1 tablet) taken at bedtime for the next 17-25 days. The participant will then be asked to return and be retested.
Intervention Type
Drug
Intervention Name(s)
Primidone
Other Intervention Name(s)
Mysoline (brand)
Intervention Description
Primidone is an antiepileptic used for the management of generalized tonic-clonic seizures and for the management of complex partial seizures. One of primidone's active metabolite is phenobarbital, which is a potent cytochrome P450 inducer. In this study, primidone will be used to induce CYP 1A2 in order to provide more efficient metabolism of clopidogrel to its active form
Primary Outcome Measure Information:
Title
Platelet Aggregometry
Description
Platelet Aggregometry will be used to assess platelet responsiveness to clopidogrel following treatment with investigational medication. Blood will be placed in plastic cuvettes and probes will be inserted. Wires on the probes measure platelet aggregation in electrical impedance. A baseline is obtained and then adenosine diphosphate (ADP) is added to cause aggregation. Clopidogrel prevents platelet aggregation through irreversible binding of its active metabolite to the ADP receptors on the platelet surface. The change in impedance from baseline is directly proportional to the extent of platelet aggregation and is expressed in ohms of resistance.
Time Frame
Platelet aggregometry will be performed at Visit 1 and Visit 2 which will be 20-28 days following Visit 1.
Secondary Outcome Measure Information:
Title
Area Under the Curve of Clopidogrel Metabolite Levels
Description
Whole blood from the subjects will be drawn 30 minutes, 1 hour, 2 hours, 3 hours and 4 hours post clopidogrel dose. Once the blood is drawn, the metabolite will be derivatized to keep the metabolite stable in blood. Derivatization of the metabolite, involves spiking blood samples with 2-bromo-3'methoxyacetophenone contained in an acetonitrile solution. Once derivatization has been done, metabolite levels will be analyzed using liquid chromatography mass spectrometry (LCMS). Once concentration levels of the active metabolite are known, the area under the curve will be calculated under trapezoid rule (linear up, log down).
Time Frame
Metabolite Levels Drawn 30 minutes, 1 hour, 2 hours, 3 hours and 4 hours post clopidogrel dose at Visit 1 and Visit 2 which will be 20-28 days following Visit 1.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females aged 18 - 90 years who are clopidogrel resistant as determined by whole blood aggregometry Patients with a low risk of new cerebrovascular ischemic events as indicated by an Essen Stroke Risk Score of less than three Exclusion Criteria: Any history of allergy or intolerance to either Plavix or clopidogrel Any history of allergy or intolerance to either Mysoline or primidone Any clinically significant abnormalities in complete blood count as determined by the investigator Use of any acute medications within the last two weeks or initiation of any non-study medications during the study period that would effect CYP enzymes or platelet function Use of tobacco products from 2 weeks prior to enrollment in the study and throughout the duration of the study Any planned surgical procedures during the study or 5 days after the study has ended History of alcoholism or alcohol abuse Participants who have had any alcohol consumption within 24 hours of a blood draw Previous stroke in past 3 months Participants who are or are planning to become pregnant Participants who of reproductive potential must agree to use a method of contraception for the duration of the study as well as 4 weeks after participation is complete Change in any medications that could affect liver enzymes or platelet aggregation throughout the study Compliance less than 80 % based on pill counts on two different study visits
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vernice Bates, M.D.
Organizational Affiliation
Dent Neurologic Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dent Neurologic Institute
City
Amherst
State/Province
New York
ZIP/Postal Code
14226
Country
United States

12. IPD Sharing Statement

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Effect of Primidone on Platelet Responsiveness in Patients Determined to be Clopidogrel Resistant

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