A Study of the Onset and Offset of Antiplatelet Effects Comparing Ticagrelor, Clopidogrel, and Placebo With Aspirin

Study Overview
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Brief Summary
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The purpose of this study is to see how Ticagrelor, a new oral reversible anti-platelet medication, affects platelets. Anti-platelet agents are medications that block the formation of blood clots by preventing the clumping of platelets. Blood clots prevent us from bleeding, but when they form inside the arteries their formation is linked to a risk of medical problems such as heart attack and stroke. This study investigated how long it takes for Ticagrelor to begin working and how long it takes for it to stop working after the last dose of drug. Ticagrelor will be compared to clopidogrel, an established anti-platelet treatment for preventing blood clots, and placebo plus Aspirin.

Official Title
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A Multi-centre Randomised, Double-blind, Double-dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of Ticagrelor Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease (CAD)

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Ticagrelor Tablets
* Drug: Clopidogrel (over encapsulated) capsule
* Drug: Aspirin Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented stable Coronary Artery Disease (stable angina, previous MI history, previous history of revascularization); Females of child bearing potential must have a negative pregnancy test prior to receiving study drug and be willing to use a hormonal contraceptive in addition to double barrier contraception Exclusion Criteria: History of Acute Coronary Syndromes within 12 months of screening or need for revascularization (angioplasty or Coronary Artery Bypass Graft (CABG)) History of liver or kidney disease Have increased bleeding risk, eg, recent gastrointestinal bleed, uncontrolled high blood pressure, low platelet count, recent major trauma History of intolerance or allergy to Aspirin or clopidogrel

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Aspirin + Placebo | Drug: Aspirin Tablets<br>* Oral, 75 mg to 100 mg once daily. Aspirin obtained locally by the investigator, according to local practice. The dose remained constant throughout the study.<br>* Other names: ASA;|
| Active Comparator: 2<br>Aspirin + clopidogrel | Drug: Clopidogrel (over encapsulated) capsule<br>* Oral 75 mg; 600 mg loading dose followed by 75 mg once daily (ODD)<br>* Other names: Clopidogrel Bisulfate;Drug: Aspirin Tablets<br>* Oral, 75 mg to 100 mg once daily. Aspirin obtained locally by the investigator, according to local practice. The dose remained constant throughout the study.<br>* Other names: ASA;|
| Experimental: 3<br>Aspirin + Ticagrelor | Drug: Ticagrelor Tablets<br>* Oral, 90 mg; 180 mg loading dose followed by 90 mg twice daily (BD)<br>Drug: Aspirin Tablets<br>* Oral, 75 mg to 100 mg once daily. Aspirin obtained locally by the investigator, according to local practice. The dose remained constant throughout the study.<br>* Other names: ASA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final Extent Inhibition of Platelet Aggregation (IPA) Induced by 20 µM Adenosine Diphosphate (ADP) at 2 Hours After First Dose | IPA(%)=(PAb-PAt)/PAb*100.The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | At 2 hours after first dose of study drug | 
| Slope of Extent IPA Offset Curve 4 to 72 Hours After Last Dose of Study Drug | IPA(%)=(PAb-PAt)/PAb*100.The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. The unit for the slope of IPA curve is percent/hour. | 4 to 72 Hours after last dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final Extent IPA Induced by 20 µM ADP at 0.5 Hours After First Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 0.5 hours after first dose | 
| Final Extent IPA Induced by 20 µM ADP at 1 Hour After First Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 1 hour after first dose | 
| Final Extent IPA Induced by 20 µM ADP at 4 Hours After First Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 4 hours after first dose | 
| Final Extent IPA Induced by 20 µM ADP at 8 Hours After First Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 8 hours after first dose | 
| Final Extent IPA Induced by 20 µM ADP at 24 Hours After First Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 24 hours after first dose | 
| Final Extent IPA Induced by 20 µM ADP at 0 Hour Before Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 0 hour before last dose | 
| Final Extent IPA Induced by 20 µM ADP at 2 Hours After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 2 hours after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 4 Hours After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 4 hours after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 8 Hours After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 8 hours after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 24 Hours After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 24 hours after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 48 Hours After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 48 hours after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 72 Hours After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 72 hours after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 120 Hours - Day 5 After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 120 hours - Day 5 after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 168 Hours - Day 7 After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference of baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 168 hours - Day 7 after last dose | 
| Final Extent IPA Induced by 20 µM ADP at 240 Hours - Day 10 After Last Dose | IPA(%)=(PAb-PAt)/PAb*100. The unit % is the percentage of difference for baseline versus post baseline value relative to baseline value of platelet aggregation. PA (platelet aggregation) is measured by LTA (Light Transmittance Aggregometry). PAb is the response at baseline (last measurement before study drug) and PAt is a response at post-treatment. IPA=0% means no PA inhibition and 100% means 100% PA inhibition. | 240 hours - Day 10 after last dose | 
| Cardiopulmonary Parameters at Baseline: Forced Expiratory Volume in 1 Second (FEV1) | FEV1 is measured by Spirometry, the unit is Liter. | Baseline | 
| Cardiopulmonary Parameters at Post 6-week Treatment: FEV1 | FEV1 is measured by Spirometry, the unit is Liter. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Forced Vital Capacity (FVC) | FVC is measured by Spirometry, the unit is Liter. | Baseline | 
| Cardiopulmonary Parameters at Post 6-week Treatment: FVC | FVC is measured by Spirometry, the unit is Liter. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Ratio of Forced Expiratory Volume in 1 Second Over Forced Vital Capacity (FEV1/FVC Ratio) | FEV1/FVC Ratio is measured by Spirometry, the unit is Ratio. | Baseline | 
| Cardiopulmonary Parameters at Post 6-week Treatment: FEV1/FVC Ratio | FEV1/FVC Ratio is measured by Spirometry, the unit is Ratio. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Mean Forced Expiratory Flow Between 25% and 75% of the FVC (FEF25-75) | FEF25-75 is measured by Spirometry, the unit is Liter/Second. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: FEF25-75 | FEF25-75 is measured by Spirometry, the unit is Liter/Second. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Functional Residual Capacity (FRC) | FRC is measured by Body Box Plethysmography, the unit is Liter. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: FRC | FRC is measured by Body Box Plethysmography, the unit is Liter. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Total Lung Capacity (TLC) | TLC is measured by Body Box Plethysmography, the unit is Liter. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: TLC | TLC is measured by Body Box Plethysmography, the unit is Liter. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Residual Volume (RV) | RV is measured by Body Box Plethysmography, the unit is Liter. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: RV | RV is measured by Body Box Plethysmography, the unit is Liter. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Minute Ventilation (VE) | VE is measured by Spirometry and Body Box Plethysmography, the unit is Liter/Minute | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: VE | VE is measured by Spirometry and Body Box Plethysmography, the unit is Liter/Minute | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Respiratory Rate (RR) | RR is measured by Spirometry and Body Box Plethysmography, the unit is Breaths/Minute. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: RR | RR is measured by Spirometry and Body Box Plethysmography, the unit is Breaths/Minute. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Tidal Volume (VT) | VT is measured by Body Box Plethysmography, the unit is Liter/Minute. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: VT | VT is measured by Body Box Plethysmography, the unit is Liter/Minute. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Single Breath Diffusing Capacity for the Lungs Using Carbon Monoxide (DLCOSB) | DLCOSB is measured by Body Box Plethysmography, the unit is Percent. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: DLCOSB | DLCOSB is measured by Body Box Plethysmography, the unit is Percent. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Ejection Fraction (EF) | EF is measured by Echocardiogram, the unit is Percent. The ejection fraction is defined by: (LV diastolic volume - LV systolic volume)/LV diastolic volume. The unit % is the percentage change of left ventricular diastolic versus systolic volume relative to the diastolic volume. LV is the left ventricle. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: EF | EF is measured by Echocardiogram, the unit is Percent. The ejection fraction is defined by: (LV diastolic volume - LV systolic volume)/LV diastolic volume. The unit % is the percentage change of left ventricular diastolic versus systolic volume relative to the diastolic volume. LV is the left ventricle. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP is measured by clinical lab, the unit is pg/mL. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: NT-proBNP | NT-proBNP is measured by clinical lab, the unit is pg/mL. | 6-week post treatment | 
| Cardiopulmonary Parameters at Baseline: Blood Oxygen Saturation Measured by Pulse Oximetry (SpO2) | SpO2 is measured by pulse oximetry, the unit is Percent. The unit % is the percentage of oxygen attached hemoglobin relative to the total hemoglobin. | Baseline | 
| Cardiopulmonary Parameters Post 6-week Treatment: SpO2 | SpO2 is measured by pulse oximetry, the unit is Percent. The unit % is the percentage of oxygen attached hemoglobin relative to the total hemoglobin. | 6-week post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary artery disease, CAD, heart attack, stable angina, Stable coronary artery disease