Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-function: a Validation Study

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT03489863
• Collaborator: Scott R. MacKenzie Foundation (Other)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Months): 9.7
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons between these agents among patients with different CYP2C19 genetic polymorphisms, which is currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations require external validation cohorts to support the study findings. Therefore, the present randomized study is designed to serve as an external validation cohort conducted in patients with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Prasugrel; Drug: Ticagrelor	Phase 4

Detailed Description

Therapeutic inhibition of platelet activation is essential for the management of ischemic cardiovascular disease. The use of platelet adenosine diphosphate (ADP) P2Y12 receptor antagonists (clopidogrel, prasugrel, and ticagrelor) in addition to aspirin are associated with a decrease in cardiovascular events in high-risk coronary artery disease (CAD) patients. Clopidogrel is the most broadly utilized P2Y12 receptor antagonist. However, among clopidogrel treated patients, there is broad variability in antiplatelet drug response which is known carry prognostic implications. Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons between these agents among patients with different CYP2C19 genetic polymorphisms which is currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations require external validation cohorts to support the study findings. Therefore, the present randomized study is designed to serve as an external validation cohort conducted in patients with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective randomizedProspective randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-function Genotype: a Validation Study in Patients With Stable Coronary Artery Disease
• Actual Study Start Date: May 30, 2018
• Actual Primary Completion Date: Mar 20, 2019
• Actual Study Completion Date: Mar 20, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Prasugrel Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).	Drug: Prasugrel; Maintenance dose will be maintained for 10±3 days.; Other Names: Effient
Active Comparator: Ticagrelor Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).	Drug: Ticagrelor; Maintenance dose will be maintained for 10±3 days.; Other Names: Brilinta

Outcome Measures

Primary Outcome Measures

1. P2Y12 Reaction Unit (PRU) [at 24 hours post loading dose]

   Platelet reactivity measured by VerifyNow and reported as PRU

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Patients with CAD [defined as the presence of at least a 50% stenosis in a major epicardial vessel or major branch, or any prior coronary revascularization (PCI or coronary bypass graft surgery)] on treatment with either aspirin (81mg/day) or aspirin and clopidogrel (75m/day) for at least 30 days as per standard of care

• Participated in UFJ 2016-14 study with genetic buccal swab test and have at least one CYP 2C19 LOF allele (CYP2C192 and CYP2C193)

• Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.

Exclusion criteria:

• Known allergies to prasugrel or ticagrelor

• Weight <60kg

• Considered at high risk for bleeding

• Currently active bleeding

• History of ischemic or hemorrhagic stroke or transient ischemic attack, or intracranial hemorrhage

• Known severe hepatic dysfunction

• On treatment with oral anticoagulant therapy (Vitamin K antagonists, dabigatran, apixaban, rivaroxaban)

• Platelet count <80x106/mL

• Hemoglobin <10 g/dL.

• Creatinine Clearance <30 mL/minute

• Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.

• Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with ticagrelor): CYP3A Inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin ) and CYP3A Inducers (rifampin, phenytoin, carbamazepine, and phenobarbital)

• Pregnant or breastfeeding females

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Jacksonville	Florida	United States	32209

Sponsors and Collaborators

• University of Florida
• Scott R. MacKenzie Foundation

Investigators

• Principal Investigator: Dominick J Angiolillo, MD,PhD, University of Florida

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 25, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03489863
• Other Study ID Numbers: IRB201703338 -A
• First Posted: Apr 6, 2018
• Last Update Posted: Sep 16, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of Florida: clopidogrel; prasugrel; ticagrelor
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ticagrelor; Prasugrel Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Prasugrel	Ticagrelor
Arm/Group Description	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Prasugrel: Maintenance dose will be maintained for 10±3 days.	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Ticagrelor: Maintenance dose will be maintained for 10±3 days.
Period Title: Overall Study
STARTED	7	7
COMPLETED	7	6
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Prasugrel	Ticagrelor	Total
Arm/Group Description	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Prasugrel: Maintenance dose will be maintained for 10±3 days.	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Ticagrelor: Maintenance dose will be maintained for 10±3 days.	Total of all reporting groups
Overall Participants	7	7	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (8)	60 (8)	59 (8)
Sex: Female, Male (Count of Participants)
Female	2 28.6%	2 28.6%	4 28.6%
Male	5 71.4%	5 71.4%	10 71.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 42.9%	4 57.1%	7 50%
White	4 57.1%	3 42.9%	7 50%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
diabetes mellitus (Count of Participants)
Count of Participants [Participants]	4 57.1%	2 28.6%	6 42.9%

Outcome Measures

1. Primary Outcome

Title	P2Y12 Reaction Unit (PRU)
Description	Platelet reactivity measured by VerifyNow and reported as PRU
Time Frame	at 24 hours post loading dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prasugrel	Ticagrelor
Arm/Group Description	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Prasugrel: Maintenance dose will be maintained for 10±3 days.	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Ticagrelor: Maintenance dose will be maintained for 10±3 days.
Measure Participants	7	6
Mean (Standard Deviation) [PRU]	5 (10)	24 (22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prasugrel, Ticagrelor
	Comments	The primary endpoint is non-inferiority in PRU, at 24 hours of prasugrel versus ticagrelor. Under the assumption of 0 difference at 24 hours in mean PRU between ticagrelor and prasugrel and a common standard deviation of 50 PRU, a sample size of 22 patients per group allows for the 95% CI to stay within ± 45 PRU with a 90% power and alpha = 0.05.
	Type of Statistical Test	Non-Inferiority
	Comments	see above
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-18
	Confidence Interval	(2-Sided) 95%; -38 to 2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	10 days
Arm/Group Title	Prasugrel		Ticagrelor
Arm/Group Description	Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Prasugrel: Maintenance dose will be maintained for 10±3 days.		Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose). Ticagrelor: Maintenance dose will be maintained for 10±3 days.
All Cause Mortality
	Prasugrel		Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Prasugrel		Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Prasugrel		Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.