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

• ClinicalTrials.gov Identifier: NCT00528411
• Recruitment Status: Completed
• First Posted: September 12, 2007
• Results First Posted: January 11, 2012
• Last Update Posted: January 13, 2012
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Drug: Ticagrelor Tablets; Drug: Clopidogrel (over encapsulated) capsule; Drug: Aspirin Tablets	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 123 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: October 2007
• Actual Primary Completion Date: March 2009
• Actual Study Completion Date: March 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Final Extent Inhibition of Platelet Aggregation (IPA) Induced by 20 µM Adenosine Diphosphate (ADP) at 2 Hours After First Dose [ Time Frame: At 2 hours after first 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.
2. Slope of Extent IPA Offset Curve 4 to 72 Hours After Last Dose of Study Drug [ Time Frame: 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.

Secondary Outcome Measures :

1. Final Extent IPA Induced by 20 µM ADP at 0.5 Hours After First Dose [ Time Frame: 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.
2. Final Extent IPA Induced by 20 µM ADP at 1 Hour After First Dose [ Time Frame: 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.
3. Final Extent IPA Induced by 20 µM ADP at 4 Hours After First Dose [ Time Frame: 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. Final Extent IPA Induced by 20 µM ADP at 8 Hours After First Dose [ Time Frame: 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.
5. Final Extent IPA Induced by 20 µM ADP at 24 Hours After First Dose [ Time Frame: 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.
6. Final Extent IPA Induced by 20 µM ADP at 0 Hour Before Last Dose [ Time Frame: 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.
7. Final Extent IPA Induced by 20 µM ADP at 2 Hours After Last Dose [ Time Frame: 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.
8. Final Extent IPA Induced by 20 µM ADP at 4 Hours After Last Dose [ Time Frame: 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.
9. Final Extent IPA Induced by 20 µM ADP at 8 Hours After Last Dose [ Time Frame: 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.
10. Final Extent IPA Induced by 20 µM ADP at 24 Hours After Last Dose [ Time Frame: 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.
11. Final Extent IPA Induced by 20 µM ADP at 48 Hours After Last Dose [ Time Frame: 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.
12. Final Extent IPA Induced by 20 µM ADP at 72 Hours After Last Dose [ Time Frame: 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.
13. Final Extent IPA Induced by 20 µM ADP at 120 Hours - Day 5 After Last Dose [ Time Frame: 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.
14. Final Extent IPA Induced by 20 µM ADP at 168 Hours - Day 7 After Last Dose [ Time Frame: 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.
15. Final Extent IPA Induced by 20 µM ADP at 240 Hours - Day 10 After Last Dose [ Time Frame: 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.
16. Cardiopulmonary Parameters at Baseline: Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Baseline ]
    FEV1 is measured by Spirometry, the unit is Liter.
17. Cardiopulmonary Parameters at Post 6-week Treatment: FEV1 [ Time Frame: 6-week post treatment ]
    FEV1 is measured by Spirometry, the unit is Liter.
18. Cardiopulmonary Parameters at Baseline: Forced Vital Capacity (FVC) [ Time Frame: Baseline ]
    FVC is measured by Spirometry, the unit is Liter.
19. Cardiopulmonary Parameters at Post 6-week Treatment: FVC [ Time Frame: 6-week post treatment ]
    FVC is measured by Spirometry, the unit is Liter.
20. Cardiopulmonary Parameters at Baseline: Ratio of Forced Expiratory Volume in 1 Second Over Forced Vital Capacity (FEV1/FVC Ratio) [ Time Frame: Baseline ]
    FEV1/FVC Ratio is measured by Spirometry, the unit is Ratio.
21. Cardiopulmonary Parameters at Post 6-week Treatment: FEV1/FVC Ratio [ Time Frame: 6-week post treatment ]
    FEV1/FVC Ratio is measured by Spirometry, the unit is Ratio.
22. Cardiopulmonary Parameters at Baseline: Mean Forced Expiratory Flow Between 25% and 75% of the FVC (FEF25-75) [ Time Frame: Baseline ]
    FEF25-75 is measured by Spirometry, the unit is Liter/Second.
23. Cardiopulmonary Parameters Post 6-week Treatment: FEF25-75 [ Time Frame: 6-week post treatment ]
    FEF25-75 is measured by Spirometry, the unit is Liter/Second.
24. Cardiopulmonary Parameters at Baseline: Functional Residual Capacity (FRC) [ Time Frame: Baseline ]
    FRC is measured by Body Box Plethysmography, the unit is Liter.
25. Cardiopulmonary Parameters Post 6-week Treatment: FRC [ Time Frame: 6-week post treatment ]
    FRC is measured by Body Box Plethysmography, the unit is Liter.
26. Cardiopulmonary Parameters at Baseline: Total Lung Capacity (TLC) [ Time Frame: Baseline ]
    TLC is measured by Body Box Plethysmography, the unit is Liter.
27. Cardiopulmonary Parameters Post 6-week Treatment: TLC [ Time Frame: 6-week post treatment ]
    TLC is measured by Body Box Plethysmography, the unit is Liter.
28. Cardiopulmonary Parameters at Baseline: Residual Volume (RV) [ Time Frame: Baseline ]
    RV is measured by Body Box Plethysmography, the unit is Liter.
29. Cardiopulmonary Parameters Post 6-week Treatment: RV [ Time Frame: 6-week post treatment ]
    RV is measured by Body Box Plethysmography, the unit is Liter.
30. Cardiopulmonary Parameters at Baseline: Minute Ventilation (VE) [ Time Frame: Baseline ]
    VE is measured by Spirometry and Body Box Plethysmography, the unit is Liter/Minute
31. Cardiopulmonary Parameters Post 6-week Treatment: VE [ Time Frame: 6-week post treatment ]
    VE is measured by Spirometry and Body Box Plethysmography, the unit is Liter/Minute
32. Cardiopulmonary Parameters at Baseline: Respiratory Rate (RR) [ Time Frame: Baseline ]
    RR is measured by Spirometry and Body Box Plethysmography, the unit is Breaths/Minute.
33. Cardiopulmonary Parameters Post 6-week Treatment: RR [ Time Frame: 6-week post treatment ]
    RR is measured by Spirometry and Body Box Plethysmography, the unit is Breaths/Minute.
34. Cardiopulmonary Parameters at Baseline: Tidal Volume (VT) [ Time Frame: Baseline ]
    VT is measured by Body Box Plethysmography, the unit is Liter/Minute.
35. Cardiopulmonary Parameters Post 6-week Treatment: VT [ Time Frame: 6-week post treatment ]
    VT is measured by Body Box Plethysmography, the unit is Liter/Minute.
36. Cardiopulmonary Parameters at Baseline: Single Breath Diffusing Capacity for the Lungs Using Carbon Monoxide (DLCOSB) [ Time Frame: Baseline ]
    DLCOSB is measured by Body Box Plethysmography, the unit is Percent.
37. Cardiopulmonary Parameters Post 6-week Treatment: DLCOSB [ Time Frame: 6-week post treatment ]
    DLCOSB is measured by Body Box Plethysmography, the unit is Percent.
38. Cardiopulmonary Parameters at Baseline: Ejection Fraction (EF) [ Time Frame: Baseline ]
    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.
39. Cardiopulmonary Parameters Post 6-week Treatment: EF [ Time Frame: 6-week post treatment ]
    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.
40. Cardiopulmonary Parameters at Baseline: N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) [ Time Frame: Baseline ]
    NT-proBNP is measured by clinical lab, the unit is pg/mL.
41. Cardiopulmonary Parameters Post 6-week Treatment: NT-proBNP [ Time Frame: 6-week post treatment ]
    NT-proBNP is measured by clinical lab, the unit is pg/mL.
42. Cardiopulmonary Parameters at Baseline: Blood Oxygen Saturation Measured by Pulse Oximetry (SpO2) [ Time Frame: Baseline ]
    SpO2 is measured by pulse oximetry, the unit is Percent. The unit % is the percentage of oxygen attached hemoglobin relative to the total hemoglobin.
43. Cardiopulmonary Parameters Post 6-week Treatment: SpO2 [ Time Frame: 6-week post treatment ]
    SpO2 is measured by pulse oximetry, the unit is Percent. The unit % is the percentage of oxygen attached hemoglobin relative to the total hemoglobin.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Louisiana

Research Site

Baton Rouge, Louisiana, United States

United States, Maryland

Research Site

Baltimore, Maryland, United States

Research Site

Towson, Maryland, United States

United States, Ohio

Research Site

Cincinnati, Ohio, United States

United States, Oklahoma

Research Site

Oklahoma City, Oklahoma, United States

United States, Pennsylvania

Research Site

Philadelphia, Pennsylvania, United States

United States, South Dakota

Research Site

Rapid City, South Dakota, United States

United States, Texas

Research Site

Houston, Texas, United States

United Kingdom

Research Site

Sheffield, United Kingdom

Sponsors and Collaborators

AstraZeneca

Investigators

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

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00528411
• Other Study ID Numbers: D5130C00048
• First Posted: September 12, 2007
• Results First Posted: January 11, 2012
• Last Update Posted: January 13, 2012
• Last Verified: January 2012

Keywords provided by AstraZeneca:

Coronary artery disease; CAD; heart attack; stable angina; Stable coronary artery disease

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Aspirin; Clopidogrel; Ticagrelor; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents