Stable Coronary Artery Disease
Conditions
Keywords
Stable Coronary Artery Disease, CAD
Brief summary
The purpose of this study is to assess the pharmacodynamic effect of ticagrelor in African American patients with stable coronary artery disease.
Detailed description
A Randomized, Open-Label, Multiple Dose, Crossover, Multiple Center Study of the Antiplatelet Effects of Ticagrelor versus Clopidogrel in African American Patients with Stable Coronary Artery Disease
Interventions
DRUGTicagrelor
Min - 90mg/Max - 180mg tablets (loading dose)
DRUGClopidogrel
75mg (once daily)/Max - 600mg tablets (loading dose)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of signed and dated informed consent before initiation of any study-related procedures * Male or female patients aged 18 years or older * Documented stable CAD fulfilling and taking 75-100mg ASA daily treatment * Females must be post menopausal or surgically sterile Self-identified as African American
Exclusion criteria
* Any indication for oral anticoagulant (e.g., atrial fibrillation, mitral stenosis or prosthetic heart valve) or dual antiplatelet treatment (e.g., clopidogrel, prasugrel, ASA dose other than 75 to 100 mg daily) during study period * Patients who had ACS or stent placed within 12 months of screening Patients with a history of moderate or severe hepatic impairment * Current smokers, including the use of tobacco containing products in the past 1 month of randomization Patients required dialysis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Inhibition of the P2Y12 Receptor as Measured by Platelet Reaction Unit (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose | At 2 hours after the loading dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose | At 0.5 hour and 8 hours after the loading dose | — |
| Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | At 2 hours and 8 hours on Day 7 after multiple doses and at end of dosing interval on Day 8 | — |
| Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | Predose, 0.5 hour, 2 hours, 8 hours from loading dose; 0, 2 hours, 8 hours and 12 hours from last dose | The standard deviation (SD) is the geometric SD |
| AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | Predose, 0.5 hour, 2 hours, 8 hours from loading dose and 0, 2 hours, 8 hours and 12 hours from last dose | The standard deviation (SD) is the geometric SD |
Countries
United States
Participant flow
Recruitment details
Patients recruited from 8 participating centers in the United States from 28 March 2012 until 04 September 2013
Pre-assignment details
50 patients screened; 34 patients randomized; 30 patients completed the study (7, 8, or 9 days of both treatments), and 31 completed follow-up
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor (Period 1) Then Clopidogrel (Period 2) Sequence Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days (Period 1), and then clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days (Period 2) | 20 |
| Clopidogrel (Period 1) Then Ticagrelor (Period 2) Sequence Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days (Period 1), and then ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days (Period 2) | 14 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Did not complete 7-9 days of treatment. | 1 | 0 |
| Treatment Period 1 | Withdrawal by Subject | 2 | 0 |
| Washout Period - 10 to 14 Days | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Ticagrelor (Period 1) Then Clopidogrel (Period 2) Sequence | Clopidogrel (Period 1) Then Ticagrelor (Period 2) Sequence | Total |
|---|---|---|---|
| Age, Customized >=18 to <65 years | 12 Participants | 10 Participants | 22 Participants |
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >= 65 years | 8 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants | 14 Participants | 34 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 20 Participants | 14 Participants | 34 Participants |
| Region of Enrollment United States | 20 Participants | 14 Participants | 34 Participants |
| Sex: Female, Male Female | 8 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 34 | 2 / 31 |
| serious Total, serious adverse events | 1 / 34 | 0 / 31 |
Outcome results
Primary
Inhibition of the P2Y12 Receptor as Measured by Platelet Reaction Unit (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose
Time frame: At 2 hours after the loading dose
Population: Pharmacodynamic (PD) Analysis Set (N=32) - included all participants for whom PD data was available with no major protocol deviations thought to significantly affect the PD of ticagrelor or clopidogrel
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ticagrelor | Inhibition of the P2Y12 Receptor as Measured by Platelet Reaction Unit (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose | 27.6 PRU |
| Clopidogrel | Inhibition of the P2Y12 Receptor as Measured by Platelet Reaction Unit (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose | 211.2 PRU |
p-value: <0.00195% CI: [-213.9, -153.3]Mixed Models Analysis
Secondary
AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses
The standard deviation (SD) is the geometric SD
Time frame: Predose, 0.5 hour, 2 hours, 8 hours from loading dose and 0, 2 hours, 8 hours and 12 hours from last dose
Population: Pharmacokinetic (PK) Analysis Set - included all patients for whom at least one valid PK reading was available
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 pre-dose hours) | 1.0 ng/mL | Standard Deviation 1 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0.5 hours after the loading dose | 9.8 ng/mL | Standard Deviation 4.9 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose | 222.6 ng/mL | Standard Deviation 2.7 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose - Period 1 N=19 | 119.0 ng/mL | Standard Deviation 1.7 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses - Period 1 N=18 | 93.2 ng/mL | Standard Deviation 5.8 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses - Period 1 N=18 | 136.7 ng/mL | Standard Deviation 6.3 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses - Period 1 N=18 | 89.8 ng/mL | Standard Deviation 5.6 |
| Ticagrelor | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | End of dosing interval on Day 8 - Period 1 N=18 | 140.8 ng/mL | Standard Deviation 1.9 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | End of dosing interval on Day 8 - Period 1 N=18 | 110.3 ng/mL | Standard Deviation 1.4 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 pre-dose hours) | 1.0 ng/mL | Standard Deviation 1 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses - Period 1 N=18 | 74.5 ng/mL | Standard Deviation 2 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0.5 hours after the loading dose | 2.3 ng/mL | Standard Deviation 3.2 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses - Period 1 N=18 | 112.6 ng/mL | Standard Deviation 1.3 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose | 150.9 ng/mL | Standard Deviation 2.5 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses - Period 1 N=18 | 172.3 ng/mL | Standard Deviation 1.7 |
| Clopidogrel | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose - Period 1 N=19 | 54.8 ng/mL | Standard Deviation 7.5 |
Secondary
Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose
Time frame: At 0.5 hour and 8 hours after the loading dose
Population: PD Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ticagrelor | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose | 0.5 hours | 166.3 PRU |
| Ticagrelor | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose | 8 hours (N=28 ticagrelor, N=27 clopidogrel) | 27.2 PRU |
| Clopidogrel | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose | 0.5 hours | 270.1 PRU |
| Clopidogrel | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose | 8 hours (N=28 ticagrelor, N=27 clopidogrel) | 192.6 PRU |
Comparison: Analysis at 0.5 hours after loading dosep-value: <0.00195% CI: [-142.5, -65]Mixed Models Analysis
Comparison: Analysis at 8 hours after loading dosep-value: <0.00195% CI: [-197.4, -133.3]Mixed Models Analysis
Secondary
Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8
Time frame: At 2 hours and 8 hours on Day 7 after multiple doses and at end of dosing interval on Day 8
Population: PD Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ticagrelor | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 2 hours on Day 7 (N=27 for clopidogrel) | 22.9 PRU |
| Ticagrelor | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 8 hours on Day 7 | 28.5 PRU |
| Ticagrelor | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | End of dosing interval on Day 8 | 39.3 PRU |
| Clopidogrel | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 2 hours on Day 7 (N=27 for clopidogrel) | 157.8 PRU |
| Clopidogrel | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 8 hours on Day 7 | 146.5 PRU |
| Clopidogrel | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | End of dosing interval on Day 8 | 172.7 PRU |
Comparison: Analysis at 2 hours on Day 7 after multiple dosesp-value: <0.00195% CI: [-160.4, -109.5]Mixed Models Analysis
Comparison: Analysis at 8 hours on Day 7 after multiple dosesp-value: <0.00195% CI: [-143.9, -92.2]Mixed Models Analysis
Comparison: Analysis at end of dosing interval on Day 8p-value: <0.00195% CI: [-159.7, -107.1]Mixed Models Analysis
Secondary
Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses
The standard deviation (SD) is the geometric SD
Time frame: Predose, 0.5 hour, 2 hours, 8 hours from loading dose; 0, 2 hours, 8 hours and 12 hours from last dose
Population: Pharmacokinetic (PK) Analysis Set - included all patients for whom at least one valid PK reading was available
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 pre-dose hours) | 1.0 ng/mL | Standard Deviation 1 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0.5 hours after the loading dose | 206.6 ng/mL | Standard Deviation 5.2 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose | 1167.3 ng/mL | Standard Deviation 1.8 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose - Period 1 N=19 | 395.9 ng/mL | Standard Deviation 1.5 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses - Period 1 N=18 | 168.4 ng/mL | Standard Deviation 7.3 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses - Period 1 N=18 | 324.6 ng/mL | Standard Deviation 8.9 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses - Period 1 N=18 | 179.2 ng/mL | Standard Deviation 7.4 |
| Ticagrelor | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | End of dosing interval on Day 8 - Period 1 N=18 | 284.9 ng/mL | Standard Deviation 2.2 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | End of dosing interval on Day 8 - Period 1 N=18 | 295.7 ng/mL | Standard Deviation 1.9 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 pre-dose hours) | 1.2 ng/mL | Standard Deviation 1.8 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses - Period 1 N=18 | 187.4 ng/mL | Standard Deviation 2.1 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0.5 hours after the loading dose | 33.7 ng/mL | Standard Deviation 8.2 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses - Period 1 N=18 | 311.3 ng/mL | Standard Deviation 1.7 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose | 756.9 ng/mL | Standard Deviation 1.9 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses - Period 1 N=18 | 608.8 ng/mL | Standard Deviation 1.9 |
| Clopidogrel | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose - Period 1 N=19 | 141.9 ng/mL | Standard Deviation 12.1 |