Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3)

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00642174
• Collaborator: Daiichi Sankyo, Inc. (Industry)
• Enrollment: 35
• Locations: 4
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 8.8
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This trial is designed as a phase 2 randomized, double-blind double dummy, active comparator controlled, two-period two-arm crossover study to enroll 40 patients across multiple centers. The study will compare platelet function following a prasugrel loading dose and 1 week of prasugrel maintenance therapy with high-dose clopidogrel loading dose and 1 week of high-dose clopidogrel maintenance therapy in patients with drug treated type 2 diabetes mellitus who have coronary artery disease. Various assays of platelet function will be used in this study. Platelet function will be studied using the following assays: Accumetrics VerifyNowTM P2Y12, Light Transmittance Aggregometry (LTA), Vasodilator-associated stimulated phosphoprotein (VASP), and Thromboelastography (TEG)-platelet mapping.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus; Coronary Artery Disease	Drug: prasugrel; Drug: Clopidogrel	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Pharmacodynamic Comparison of Prasugrel (LY640315) Versus High Dose Clopidogrel in Subjects With Type 2 Diabetes Mellitus and Coronary Artery Disease.
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prasugrel Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Drug: prasugrel; Oral prasugrel 60-mg loading dose, followed by 6-9 days of oral prasugrel 10-mg/day tablet maintenance dose.; Other Names: LY640315 Effient Efient
Active Comparator: Clopidogrel Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.	Drug: Clopidogrel; Oral clopidogrel 600-mg loading dose, followed by 6-9 days of oral clopidogrel 150-mg/day tablet maintenance dose.

Outcome Measures

Primary Outcome Measures

1. Inhibition of Platelet Aggregation (IPA) 4 Hours After Loading Dose Assessed by Accumetrics VerifyNow™ P2Y12 Assay [4 hours after loading dose]

   The inhibition of platelet aggregation 4 hours after the loading dose was administered was assessed using the Accumetrics VerifyNow™ P2Y12 assay. Percentage inhibition, as reported by VerifyNow™ P2Y12, was calculated from P2Y12 Reaction Unit (PRU) (rate and extent of adenosine diphosphate [ADP]-stimulated platelet aggregation) and BASE (estimate of baseline platelet reactivity independent of P2Y12 receptor inhibition [reference values]: rate and extent of Thrombin Receptor-Activated Peptide-stimulated platelet aggregation) values as follows: Percentage (%) inhibition = (1-PRU/BASE) x 100.

Secondary Outcome Measures

1. Inhibition of Platelet Aggregation at 1- and 24-Hours After Loading Dose (LD) and 24-Hours After Last Maintenance Dose (LMD) Assessed by Accumetrics VerifyNow™ P2Y12 Assay [1 hour and 24 hours after the loading dose (LD) and 24 hours after the last maintenance dose (LMD)]

   Inhibition of platelet aggregation 1- and 24-hours after loading dose and 24-hours after last maintenance dose was administered was assessed using Accumetrics VerifyNow™ P2Y12 assay. Percentage inhibition, as reported by VerifyNow™ P2Y12, was calculated from PRU (rate and extent of ADP-stimulated platelet aggregation) and BASE (estimate of baseline platelet reactivity independent of P2Y12 receptor inhibition [reference values]: rate and extent of Thrombin Receptor-Activated Peptide-stimulated platelet aggregation) values as follows: Percentage (%) inhibition = (1-PRU/BASE) x 100.

2. Maximum Platelet Aggregation (MPA) as Assessed by Light Transmittance Aggregometry (LTA) [Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose]

   Mean platelet aggregation (MPA) to 5 and 20 µM adenosine diphosphate (ADP) was assessed by light transmittance aggregometry (LTA). Platelet aggregation was monitored for a total of 7 minutes after addition of ADP. Maximum platelet aggregation was the maximal aggregation value achieved during the 7-minute observation period following addition of agonists.

3. Platelet Reactivity Index (PRI) [Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose]

   Data from the Vasodilator-associated stimulated phosphoprotein assay were reported as the platelet reactivity index (PRI) which was calculated from corrected mean fluorescence intensity (cMFI) following incubation of platelets with either prostaglandin E1 (PGE1) alone or PGE1 plus ADP: Platelet Reactivity Index (%) = [1-(cMFI PGEI+ADP/cMFI PGEI)] x 100. Lower PRI values indicate greater platelet P2Y12 inhibition.

4. Inhibition of Platelet Function as Measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate [Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose]

   Thromboelastography (TEG) platelet mapping (MP) maximum amplitude (MA) - Adenosine Diphosphate (ADP) millimeters (mm) at each time point. The TEG-MP MA measures strength of clot formation in whole blood. MA-ADP is the maximal amplitude resulting from fibrin and platelets not blocked by ADP-receptor inhibiting drugs. Fibrin strands in blood sample link a rotating sample cup with a stationary pin suspended by a torsion wire. The degree of platelet contribution to the MA through platelet-fibrin bonding directly influences the magnitude of pin movement and ultimately the amplitude of the tracing.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 Diabetes Mellitus and on oral or parenteral hypoglycemic therapy for at least 1 month.

• History of Coronary Artery Disease with or without other types of vascular disease (such as peripheral vascular disease).

• Taking Aspirin 75-325 mg/day for at least 1 week prior to randomization.

• Between the ages of 18-74 years old.

• If a woman of child bearing age, must not be pregnant and must agree to use reliable method of birth control during the duration of the study.

Exclusion Criteria:

• Thienopyridine therapy within 30 days or have a defined need for thienopyridine treatment.

• Coronary Artery Bypass Graft (CABG) or Percutaneous Coronary Intervention (PCI) with no stent placed within 30 days.

• Planned coronary revascularization

• Hemoglobin A1c (HbA1c) > or equal to 10 mg/dL within the last 3 months.

• Received fibrolytic therapy <24 hours prior to randomization.

• Received non-fibrin-specific fibrinolytic therapy <48 hours prior to randomization.

• At risk of bleeding.

• History of ischemic stroke, transient ischemic attack (TIA), intercranial neoplasm, arteriovenous malformation, or aneurysm.

• Body weight <60 kilograms (kg).

• International Normalized Ratio (INR) >1.5, platelet count <100,000/mm3, or anemia (hemoglobin <10 gm/dL) within 1 week of study entry.

• Are receiving or will receive oral anticoagulation or antiplatelet treatment therapy.

• Are being treated with daily non-steroidal anti-inflammatory drugs (NSAIDS).

• Are pregnant, breast-feeding or plan to become pregnant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Jacksonville	Florida	United States	32209
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Worcester	Massachusetts	United States	01655
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	New York	New York	United States	10029
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Oklahoma City	Oklahoma	United States	73104

Sponsors and Collaborators

• Eli Lilly and Company
• Daiichi Sankyo, Inc.

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9am-5pm Eastern time (UTC/GMT-5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00642174
• Other Study ID Numbers: 11241; H7T-MC-TACA
• First Posted: Mar 24, 2008
• Last Update Posted: Feb 23, 2010
• Last Verified: Feb 1, 2010

• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Clopidogrel; Prasugrel Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Prasugrel Then Clopidogrel	Clopidogrel Then Prasugrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose. Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose. Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.
Period Title: Period 1 - Initial Drug
STARTED	18	17
COMPLETED	18	16
NOT COMPLETED	0	1
Period Title: Period 1 - Initial Drug
STARTED	18	16
COMPLETED	18	16
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Prasugrel Then Clopidogrel	Clopidogrel Then Prasugrel	Total
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose. Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose. Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Total of all reporting groups
Overall Participants	18	17	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.3 (9.43)	62.4 (8.14)	61.3 (8.76)
Sex: Female, Male (Count of Participants)
Female	4 22.2%	7 41.2%	11 31.4%
Male	14 77.8%	10 58.8%	24 68.6%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	8 44.4%	7 41.2%	15 42.9%
African	3 16.7%	4 23.5%	7 20%
Hispanic	4 22.2%	4 23.5%	8 22.9%
Native American	0 0%	1 5.9%	1 2.9%
East Asian	1 5.6%	0 0%	1 2.9%
West Asian	2 11.1%	1 5.9%	3 8.6%
Region of Enrollment (participants) [Number]
United States	18 100%	17 100%	35 100%

Outcome Measures

1. Primary Outcome

Title	Inhibition of Platelet Aggregation (IPA) 4 Hours After Loading Dose Assessed by Accumetrics VerifyNow™ P2Y12 Assay
Description	The inhibition of platelet aggregation 4 hours after the loading dose was administered was assessed using the Accumetrics VerifyNow™ P2Y12 assay. Percentage inhibition, as reported by VerifyNow™ P2Y12, was calculated from P2Y12 Reaction Unit (PRU) (rate and extent of adenosine diphosphate [ADP]-stimulated platelet aggregation) and BASE (estimate of baseline platelet reactivity independent of P2Y12 receptor inhibition [reference values]: rate and extent of Thrombin Receptor-Activated Peptide-stimulated platelet aggregation) values as follows: Percentage (%) inhibition = (1-PRU/BASE) x 100.
Time Frame	4 hours after loading dose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Population, which included all randomized participants who had blood draws for IPA at 4 hours, who met compliance criteria, and who had last dose of study drug prior to the blood draw for IPA.

Arm/Group Title	Prasugrel	Clopidogrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.
Measure Participants	34	35
Baseline	9.4 (10.23)	9.3 (11.46)
4 Hours After Loading Dose	89.3 (9.40)	27.7 (23.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: there is no difference between prasugrel and clopidogrel in IPA assessed by Accumetrics VerifyNow™ P2Y12 4 hours after administration of loading dose. Assuming 90% power, 2-sided alpha of 0.05, and a 17.5% difference in IPA between treatment groups with a standard deviation of 20, a total of 15 completed subjects per sequence group (i.e., 15 subject who receive prasugrel first, then clopidogrel; and 15 subjects who receive clopidogrel first, then prasugrel) was determined.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value is for 4 Hours After Loading Dose.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (i.e. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (Net)
	Estimated Value	61.6
	Confidence Interval	() 95%; 53.83 to 69.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

2. Secondary Outcome

Title	Inhibition of Platelet Aggregation at 1- and 24-Hours After Loading Dose (LD) and 24-Hours After Last Maintenance Dose (LMD) Assessed by Accumetrics VerifyNow™ P2Y12 Assay
Description	Inhibition of platelet aggregation 1- and 24-hours after loading dose and 24-hours after last maintenance dose was administered was assessed using Accumetrics VerifyNow™ P2Y12 assay. Percentage inhibition, as reported by VerifyNow™ P2Y12, was calculated from PRU (rate and extent of ADP-stimulated platelet aggregation) and BASE (estimate of baseline platelet reactivity independent of P2Y12 receptor inhibition [reference values]: rate and extent of Thrombin Receptor-Activated Peptide-stimulated platelet aggregation) values as follows: Percentage (%) inhibition = (1-PRU/BASE) x 100.
Time Frame	1 hour and 24 hours after the loading dose (LD) and 24 hours after the last maintenance dose (LMD)

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Population, which included all randomized participants who had blood draws for IPA, who met compliance criteria, and who had last dose of study drug prior to the blood draw for IPA.

Arm/Group Title	Prasugrel	Clopidogrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.
Measure Participants	34	35
1 Hour After Loading Dose	49.9	13.4
24 Hours After Loading Dose	87.1	29.3
24 Hours After Last Maintenance Dose	61.8	44.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: there was no difference between prasugrel and clopidogrel in IPA assessed by Accumetrics VerifyNow™ P2Y12 1 hour after administration of the loading dose.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 1 Hour After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	36.5
	Confidence Interval	() 95%; 27.43 to 45.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: there was no difference between prasugrel and clopidogrel in IPA assessed by Accumetrics VerifyNow™ P2Y12 24 hours after administration of the loading dose.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hour After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	57.9
	Confidence Interval	() 95%; 49.56 to 66.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: there was no difference between prasugrel and clopidogrel in IPA assessed by Accumetrics VerifyNow™ P2Y12 24 hours post-Last Maintenance Dose (LMD).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hours After Last Maintenance Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	17.7
	Confidence Interval	() 95%; 10.27 to 25.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

3. Secondary Outcome

Title	Maximum Platelet Aggregation (MPA) as Assessed by Light Transmittance Aggregometry (LTA)
Description	Mean platelet aggregation (MPA) to 5 and 20 µM adenosine diphosphate (ADP) was assessed by light transmittance aggregometry (LTA). Platelet aggregation was monitored for a total of 7 minutes after addition of ADP. Maximum platelet aggregation was the maximal aggregation value achieved during the 7-minute observation period following addition of agonists.
Time Frame	Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Population, which included all randomized participants who had blood draws for MPA, who met compliance criteria, and who had last dose of study drug prior to the blood draw for MPA.

Arm/Group Title	Prasugrel	Clopidogrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.
Measure Participants	34	35
Baseline (5 μM ADP)	64.9	65.7
1 Hour After Loading Dose (5 μM ADP)	33.7	56.7
4 Hours After Loading Dose (5 μM ADP)	18.0	44.6
24 Hours After Loading Dose (5 μM ADP)	22.3	45.6
24 Hours After Last Maintenance Dose (5 μM ADP)	29.6	38.3
Baseline (20 μM ADP)	77.1	76.9
1 Hour After Loading Dose (20 μM ADP)	44.7	69.8
4 Hours After Loading Dose (20 μM ADP)	22.4	57.5
24 Hours After Loading Dose (20 μM ADP)	27.4	58.4
24 Hours After Last Maintenance Dose (20 μM ADP)	38.3	50.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5466
	Comments	P-value for Baseline (5 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.8
	Confidence Interval	() 95%; -3.66 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 1 After Post Loading Dose (5 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-23.0
	Confidence Interval	() 95%; -28.45 to -17.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 4 Hour After Loading Dose (5 uM ADP). A priori threshold for statisitical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-26.6
	Confidence Interval	() 95%; -31.18 to -22.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hour After Loading Dose (5 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-23.3
	Confidence Interval	() 95%; -27.42 to -19.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	P-value for 24 Hour After Last Maintenance Dose (5 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.7
	Confidence Interval	() 95%; -12.78 to -4.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8779
	Comments	P-value for Baseline (20 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	() 95%; -2.80 to 3.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 1 Hour After Loading Dose (20 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-25.2
	Confidence Interval	() 95%; -32.43 to -17.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 4 Hour After Loading Dose (20 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-35.1
	Confidence Interval	() 95%; -40.32 to -29.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hour After Loading Dose (20 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-31.0
	Confidence Interval	() 95%; -36.32 to -25.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in MPA assessed by Light Transmittance Aggregometry (LTA).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hour After Last Maintenance Dose (20 uM ADP). A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.4
	Confidence Interval	() 95%; -17.19 to -7.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

4. Secondary Outcome

Title	Platelet Reactivity Index (PRI)
Description	Data from the Vasodilator-associated stimulated phosphoprotein assay were reported as the platelet reactivity index (PRI) which was calculated from corrected mean fluorescence intensity (cMFI) following incubation of platelets with either prostaglandin E1 (PGE1) alone or PGE1 plus ADP: Platelet Reactivity Index (%) = [1-(cMFI PGEI+ADP/cMFI PGEI)] x 100. Lower PRI values indicate greater platelet P2Y12 inhibition.
Time Frame	Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Population, which included all randomized participants who had blood draws for Vasodilator-Associated Stimulated Phosphoprotein (VASP), who met compliance criteria, and who had last dose of study drug prior to the blood draw for inhibition of platelet function as assessed by VASP.

Arm/Group Title	Prasugrel	Clopidogrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.
Measure Participants	34	35
Baseline	83.5	80.6
1 Hour After Loading Dose	40.0	76.2
4 Hours After Loading Dose	14.5	67.5
24 Hours After Loading Dose	15.7	58.5
24 Hours After Last Maintenance Dose	27.4	42.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as assessed by VASP.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3692
	Comments	P-value for Baseline. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.9
	Confidence Interval	() 95%; -3.60 to 9.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as assessed by VASP.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 1 Hour After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-36.2
	Confidence Interval	() 95%; -47.43 to -24.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as assessed by VASP.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 4 Hours After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-53.0
	Confidence Interval	() 95%; -61.89 to -44.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as assessed by VASP.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hours After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-42.8
	Confidence Interval	() 95%; -50.03 to -35.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	The null hypothesis was that there was no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as assessed by VASP.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments	P-value for 24 Hours After Last Maintenance Dose. A priori threshold for statistical significance was set to p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-14.9
	Confidence Interval	() 95%; -23.42 to -6.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

5. Secondary Outcome

Title	Inhibition of Platelet Function as Measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate
Description	Thromboelastography (TEG) platelet mapping (MP) maximum amplitude (MA) - Adenosine Diphosphate (ADP) millimeters (mm) at each time point. The TEG-MP MA measures strength of clot formation in whole blood. MA-ADP is the maximal amplitude resulting from fibrin and platelets not blocked by ADP-receptor inhibiting drugs. Fibrin strands in blood sample link a rotating sample cup with a stationary pin suspended by a torsion wire. The degree of platelet contribution to the MA through platelet-fibrin bonding directly influences the magnitude of pin movement and ultimately the amplitude of the tracing.
Time Frame	Baseline, 1 Hour, 4 Hours, and 24 Hours after loading dose, and 24 Hours after last maintenance dose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Population, which included all randomized participants who had blood draws for Inhibition of Platelet Function (IPF) as measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate (ADP), who met compliance criteria, and who had last dose of study drug prior to blood draw for IPF.

Arm/Group Title	Prasugrel	Clopidogrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.	Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.
Measure Participants	34	35
Baseline	56.8	58.1
1 Hour After Loading Dose	38.5	54.8
4 Hours After Loading Dose	24.2	48.1
24 Hours After Loading Dose	29.3	49.2
24 Hours After Last Maintenance Dose	44.2	46.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate (ADP).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5238
	Comments	P-value for Baseline. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.3
	Confidence Interval	() 95%; -5.35 to 2.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate (ADP).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 1 Hour After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-16.2
	Confidence Interval	() 95%; -21.15 to -11.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate (ADP).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 4 Hours After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-23.9
	Confidence Interval	() 95%; -29.67 to -18.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate (ADP).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for 24 Hours After Loading Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-19.9
	Confidence Interval	() 95%; -24.97 to -14.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Clopidogrel
	Comments	Null hypothesis: no difference between prasugrel and clopidogrel in Inhibition of Platelet Function as measured by Thromboelastography (TEG)-Platelet Mapping Maximum Amplitude - Adenosine Diphosphate (ADP).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3725
	Comments	P-value for 24 Hours After Last Maintenance Dose. A priori threshold for statistical significance was set at p=0.05 level.
	Method	Mixed Models Analysis
	Comments	Linear mixed model with treatment, sequence and treatment by sequence (ie. period) as fixed effects and subject as random effect.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.6
	Confidence Interval	() 95%; -8.46 to 3.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least Squares Mean Difference = Prasugrel minus Clopidogrel.

Adverse Events

Arm/Group Title	Prasugrel		Clopidogrel
Arm/Group Description	Prasugrel: Oral prasugrel 60-mg loading dose, followed by 6 to 9 days of prasugrel 10-mg/day tablet maintenance dose.		Clopidogrel: Oral clopidogrel 600-mg loading dose, followed by 6 to 9 days of clopidogrel 150-mg/day tablet maintenance dose.
All Cause Mortality
	Prasugrel		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Prasugrel		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Prasugrel		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/34 (14.7%)		9/35 (25.7%)
Gastrointestinal disorders
Diarrhoea	0/34 (0%)	0	1/35 (2.9%)	1
Nausea	0/34 (0%)	0	1/35 (2.9%)	1
Vomiting	0/34 (0%)	0	1/35 (2.9%)	1
General disorders
Vessel puncture site haemorrhage	1/34 (2.9%)	1	0/35 (0%)	0
Infections and infestations
Sinusitis	0/34 (0%)	0	1/35 (2.9%)	3
Upper respiratory tract infection	1/34 (2.9%)	1	1/35 (2.9%)	1
Urinary tract infection	1/34 (2.9%)	1	0/35 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/34 (0%)	0	1/35 (2.9%)	2
Investigations
Haematocrit decreased	1/34 (2.9%)	1	0/35 (0%)	0
Haemoglobin decreased	1/34 (2.9%)	1	0/35 (0%)	0
Metabolism and nutrition disorders
Electrolyte imbalance	0/34 (0%)	0	1/35 (2.9%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	1/34 (2.9%)	2	0/35 (0%)	0
Nervous system disorders
Headache	1/34 (2.9%)	1	2/35 (5.7%)	2
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/34 (0%)	0	1/35 (2.9%)	1
Respiratory tract congestion	0/34 (0%)	0	1/35 (2.9%)	3
Rhinorrhoea	0/34 (0%)	0	1/35 (2.9%)	1
Surgical and medical procedures
Wart excision	0/34 (0%)	0	1/35 (2.9%)	1
Vascular disorders
Haemorrhage	0/34 (0%)	0	1/35 (2.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.