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

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)

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Aspirin Tablets; Drug: Clopidogrel (over encapsulated) capsule; Drug: Ticagrelor Tablets

• Study Type: Interventional
• Enrollment (Actual): 123
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Sheffield, United Kingdom
    • Research Site
• United States
  • Louisiana
    • Baton Rouge, Louisiana, United States
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States
      • Research Site
    • Towson, Maryland, United States
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Research Site
  • South Dakota
    • Rapid City, South Dakota, United States
      • Research Site
  • Texas
    • Houston, Texas, United States
      • Research Site

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Aspirin + Placebo	Drug: Aspirin Tablets; 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.; Other Names: ASA
Active Comparator: 2; Aspirin + clopidogrel	Drug: Aspirin Tablets; 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.; Other Names: ASA; Drug: Clopidogrel (over encapsulated) capsule; Oral 75 mg; 600 mg loading dose followed by 75 mg once daily (ODD); Other Names: Plavix; Clopidogrel Bisulfate
Experimental: 3; Aspirin + Ticagrelor	Drug: Aspirin Tablets; 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.; Other Names: ASA; Drug: Ticagrelor Tablets; Oral, 90 mg; 180 mg loading dose followed by 90 mg twice daily (BD)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Paul Gurbel, MD, Platelet & Thrombosis Research, LLC; Study Director: Philip Sager, MD, AstraZeneca

Publications and helpful links

General Publications

• Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J. 2012 Jul;164(1):35-42. doi: 10.1016/j.ahj.2012.03.022. Epub 2012 Jun 13.
• Jeong YH, Bliden KP, Tantry US, Gurbel PA. High on-treatment platelet reactivity assessed by various platelet function tests: is the consensus-defined cut-off of VASP-P platelet reactivity index too low? J Thromb Haemost. 2012 Mar;10(3):487-9. doi: 10.1111/j.1538-7836.2011.04604.x. No abstract available.
• Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, Gurbel PA. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet. 2010 Dec;3(6):556-66. doi: 10.1161/CIRCGENETICS.110.958561. Epub 2010 Nov 15.
• Storey RF, Bliden KP, Patil SB, Karunakaran A, Ecob R, Butler K, Teng R, Wei C, Tantry US, Gurbel PA; ONSET/OFFSET Investigators. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010 Jul 13;56(3):185-93. doi: 10.1016/j.jacc.2010.01.062.
• Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: September 10, 2007
• First Submitted That Met QC Criteria: September 11, 2007
• First Posted (Estimate): September 12, 2007

Study Record Updates

• Last Update Posted (Estimate): January 13, 2012
• Last Update Submitted That Met QC Criteria: January 12, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Coronary artery disease; stable angina; Stable coronary artery disease; CAD; heart attack
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Ticagrelor; Clopidogrel
• Other Study ID Numbers: D5130C00048