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 Hispanic 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 Hispanic 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 Hispanic
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 requiring dialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inhibition of the P2Y12 Receptor as Measured by P2Y12 Reactions Units (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose | At 2 hours after the loading dose | Participants with low (\<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose | At 0.5 and 8 hours after the loading dose | Participants with low (\<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value |
| Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 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 the end of dosing interval on Day 8 | The end of dosing interval was approximately 12 hours after the last evening dose of ticagrelor and approximately 24 hours after the last morning dose of clopidogrel. Participants with low (\<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value |
| Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | Predose, 0.5, 2, 8 hours from loading dose; 0, 2, 8 and 12 hours from last dose | The standard deviation (SD) is a statistic using the log-transformed data and is not the geometric SD. |
| AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | Predose, 0.5, 2, 8 hours from loading dose; 0, 2, 8 and 12 hours from last dose | The SD is a statistic using the log-transformed data and is not the geometric SD. |
Countries
United States
Participant flow
Recruitment details
Patients recruited from 6 centers in the United States from April 2012 until May 2013.
Pre-assignment details
53 patients screened; 40 patients randomized; 38 patients completed the study (7, 8, or 9 days of both treatment sequences), and 39 completed follow-up.
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor (Period 1) Then Clopidogrel (Period 2) Sequence Ticagrelor 180 milligrams (mg) loading dose followed by 90 mg twice daily (bd) for 7,8 or 9 days (Period 1), and then clopidogrel 600 mg loading dose followed by 75 mg once daily (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), then ticagrelor 180 mg loading dose followed by 90 mg bd for 7,8 or 9 days (Period 2) | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Withdrawal by Subject | 1 | 0 |
| Treatment Period 2 | Not completed at least 7 days treatment | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Clopidogrel (Period 1) Then Ticagrelor (Period 2) Sequence | Ticagrelor (Period 1) Then Clopidogrel (Period 2) Sequence |
|---|---|---|---|
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >=65 years | 18 Participants | 8 Participants | 10 Participants |
| Age, Customized Between 18 and 65 years | 22 Participants | 12 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 40 Participants | 20 Participants | 20 Participants |
| Race/Ethnicity, Customized Not Reported | 5 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 35 Participants | 18 Participants | 17 Participants |
| Region of Enrollment United States | 40 Participants | 20 Participants | 20 Participants |
| Sex: Female, Male Female | 12 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 28 Participants | 14 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 40 | 6 / 39 |
| serious Total, serious adverse events | 0 / 40 | 0 / 39 |
Outcome results
Primary
Inhibition of the P2Y12 Receptor as Measured by P2Y12 Reactions Units (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose
Participants with low (\<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value
Time frame: At 2 hours after the loading dose
Population: Pharmacodynamic (PD) Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ticagrelor Arm | Inhibition of the P2Y12 Receptor as Measured by P2Y12 Reactions Units (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose | 34.2 PRU |
| Clopidogrel Arm | Inhibition of the P2Y12 Receptor as Measured by P2Y12 Reactions Units (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose | 201.4 PRU |
p-value: <0.00195% CI: [-197, -137.4]Mixed Models Analysis
Secondary
AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses
The SD is a statistic using the log-transformed data and is not the geometric SD.
Time frame: Predose, 0.5, 2, 8 hours from loading dose; 0, 2, 8 and 12 hours from last dose
Population: PK Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 hours - pre-dose) | 1.1 ng/mL | Standard Deviation 2.3 |
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0,.5 hours after the loading dose | 13.6 ng/mL | Standard Deviation 66.3 |
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose - Period 2 N=18 | 153.2 ng/mL | Standard Deviation 128.6 |
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose | 113.8 ng/mL | Standard Deviation 54.6 |
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses | 113.3 ng/mL | Standard Deviation 102.1 |
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses | 183.4 ng/mL | Standard Deviation 120.8 |
| Ticagrelor Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses | 132.8 ng/mL | Standard Deviation 61.9 |
| Ticagrelor Arm | 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=17 | 124.8 ng/mL | Standard Deviation 56.6 |
| Clopidogrel Arm | 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=17 | 57.7 ng/mL | Standard Deviation 83.5 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 hours - pre-dose) | 1.0 ng/mL | Standard Deviation 0 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses | 62.7 ng/mL | Standard Deviation 76.7 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 0,.5 hours after the loading dose | 9.3 ng/mL | Standard Deviation 26.9 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses | 83.5 ng/mL | Standard Deviation 71.4 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose - Period 2 N=18 | 170.8 ng/mL | Standard Deviation 156.5 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses | 97.4 ng/mL | Standard Deviation 147.9 |
| Clopidogrel Arm | AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose | 97.7 ng/mL | Standard Deviation 61.9 |
Secondary
Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose
Participants with low (\<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value
Time frame: At 0.5 and 8 hours after the loading dose
Population: PD Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ticagrelor Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose | 0.5 hours | 134.6 PRU |
| Ticagrelor Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose | 8 hours | 34.0 PRU |
| Clopidogrel Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose | 0.5 hours | 269.8 PRU |
| Clopidogrel Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose | 8 hours | 202.8 PRU |
Comparison: Analysis at 0.5 hours after the loading dosep-value: <0.00195% CI: [-172.3, -98]Mixed Models Analysis
Comparison: Analysis at 8 hours after the loading dosep-value: <0.00195% CI: [-204, -133.7]Mixed Models Analysis
Secondary
Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8
The end of dosing interval was approximately 12 hours after the last evening dose of ticagrelor and approximately 24 hours after the last morning dose of clopidogrel. Participants with low (\<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value
Time frame: At 2 hours and 8 hours on Day 7 after multiple doses, and at the end of dosing interval on Day 8
Population: PD Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ticagrelor Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 2 hours on day 7 | 28.5 PRU |
| Ticagrelor Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 8 hours on Day 7 -ticagrelor N=36 clopidogrel N=33 | 38.7 PRU |
| Ticagrelor Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 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 - N's per 8 hours | 51.5 PRU |
| Clopidogrel Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 2 hours on day 7 | 179.0 PRU |
| Clopidogrel Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 | 8 hours on Day 7 -ticagrelor N=36 clopidogrel N=33 | 178.9 PRU |
| Clopidogrel Arm | Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 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 - N's per 8 hours | 182.1 PRU |
Comparison: Analysis at 2 hours on Day 7 after multiple dosesp-value: <0.00195% CI: [-176.9, -124.1]Mixed Models Analysis
Comparison: Analysis at 8 hours on Day 7 after multiple dosesp-value: <0.00195% CI: [-168.4, -111.9]Mixed Models Analysis
Comparison: Analysis at end of dosing interval on Day 8p-value: <0.00195% CI: [-158, -103.2]Mixed Models Analysis
Secondary
Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses
The standard deviation (SD) is a statistic using the log-transformed data and is not the geometric SD.
Time frame: Predose, 0.5, 2, 8 hours from loading dose; 0, 2, 8 and 12 hours from last dose
Population: Pharmacokinetic (PK) Analysis Set, defined as all participants for whom at least one valid PK reading was available
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 hours - pre-dose) | 1.2 ng/mL | Standard Deviation 7.5 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0,.5 hours after the loading dose | 206.7 ng/mL | Standard Deviation 413.1 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose - Period 2 N=18 | 665.4 ng/mL | Standard Deviation 566.2 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose | 376.9 ng/mL | Standard Deviation 378.8 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses | 248.8 ng/mL | Standard Deviation 238.9 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses | 609.3 ng/mL | Standard Deviation 271.3 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses | 340.4 ng/mL | Standard Deviation 283.8 |
| Ticagrelor Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | End of dosing interval on Day 8 - Period 1 N=17 | 283.3 ng/mL | Standard Deviation 438.1 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | End of dosing interval on Day 8 - Period 1 N=17 | 200.7 ng/mL | Standard Deviation 268.4 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | Baseline (0 hours - pre-dose) | 1.1 ng/mL | Standard Deviation 1.8 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0 hours after multiple doses | 220.1 ng/mL | Standard Deviation 295.8 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 0,.5 hours after the loading dose | 118.6 ng/mL | Standard Deviation 352 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after multiple doses | 305.2 ng/mL | Standard Deviation 301.6 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after the loading dose - Period 2 N=18 | 758.5 ng/mL | Standard Deviation 716.6 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 2 hours after multiple doses | 466.5 ng/mL | Standard Deviation 534.5 |
| Clopidogrel Arm | Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses | 8 hours after the loading dose | 479.6 ng/mL | Standard Deviation 210.7 |