A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function:

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT02065479
• Collaborator: (none)
• Enrollment: 65
• Location: 1
• Arms: 2
• Duration (Months): 61.7
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability, including genetic variations of the cytochrome P450 (CYP) 2C19 enzyme. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

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

Detailed Description

Clopidogrel is the most broadly utilized platelet P2Y12 receptor inhibitor. However, numerous studies have shown that pharmacodynamics (PD) response profiles vary among clopidogrel treated patients and that individuals with reduced response have an increased risk of recurrent ischemic events. There are multiple factors contributing to clopidogrel response variability. Among these, genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key contributor to clopidogrel metabolism, have been involved. In particular, loss-of-function (LOF) alleles of the CYP2C19 enzyme reduce transformation of clopidogrel pro-drug into its active metabolite. Thus, patients carrying LOF alleles have lower levels of clopidogrel's active metabolite as well as diminished platelet inhibition, which translates into an increased rate of adverse cardiovascular events, particularly in the setting of percutaneous coronary intervention (PCI). Because of these findings, drug regulating authorities have provided a boxed warning on the product label of clopidogrel on the potential for reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggested considering alternative antiplatelet therapies for these individuals. Prasugrel and ticagrelor are novel generation P2Y12 receptor inhibitors characterized by greater PD potency and reduced ischemic event rates compared with clopidogrel, and are not affected by CYP2C19 LOF polymorphisms. However, to date there are limited head-to-head PD comparisons between these two new P2Y12 receptors blockers, and there are no studies assessing on how these agents behave among CYP2C19 LOF carriers. Tailoring antiplatelet therapy according to results of genetic testing has been limited in real world clinical practice because of not having readily accessible results of individual's genetic makeup. The aim of the present study is to compare the PD effects of prasugrel versus ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles using the novel point-of-care genetic testing Spartan RX-CYP2C19 which permits accurate and rapid identification of CYP2C19 genetic status.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients With Coronary Artery Disease Undergoing PCI With CYP2C19 Loss-of-function Genotypes: A Feasibility Study With Point-of-care Pharmacodynamic and Genetic Testing
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Apr 22, 2019
• Actual Study Completion Date: Apr 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ticagrelor The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers.	Drug: Prasugrel; Comparison of platelet reactivity between prasugrel and ticagrelor; Other Names: Effient
Experimental: Prasugrel The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers.	Drug: Ticagrelor; Comparison of platelet reactivity between prasugrel and ticagrelor; Other Names: Brilinta

Outcome Measures

Primary Outcome Measures

1. Platelet Reactivity [24 hours post loading dose]

   The primary endpoint is P2Y12 reaction unit (PRU) measured by the Verify Now P2Y12 assay 24hours/hospital discharge post randomization to prasugrel vs ticagrelor. PRU is is an arbitrary unit of measure to assess ADP-induced platelet aggregation.

Eligibility Criteria

Criteria

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

• Inclusion criteria:

1. Patients scheduled for left heart catheterization and undergoing PCI

2. Age 18-75 years

3. On aspirin (81mg) or aspirin (81mg) and clopidogrel (75mg/day)

4. Presence of at least one 2C19 LOF allele

• Exclusion criteria:

1. Known allergies to aspirin, prasugrel, ticagrelor, or clopidogrel

2. Age >75 years

3. Weight <60kg

4. Considered at high risk for bleeding

5. History of ischemic or hemorrhagic stroke or transient ischemic attack

6. Known severe hepatic dysfunction

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

8. Use of glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)

9. Blood dyscrasia or bleeding diathesis

10. Platelet count <80x106/mL

11. Hemoglobin <10 g/dL.

12. Active bleeding or hemodynamic instability

13. Creatinine Clearance <30 mL/minute

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

15. Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin.

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

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

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 19, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02065479
• Other Study ID Numbers: UFJ 2014-12; IRB201702750
• First Posted: Feb 19, 2014
• Last Update Posted: Sep 16, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Florida: Coronary Artery Disease; Percutaneous Coronary Intervention; Genetic Polymorphism; Pharmacodynamic
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ticagrelor; Prasugrel Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Ticagrelor	Prasugrel
Arm/Group Description	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Prasugrel: Comparison of platelet reactivity between prasugrel and ticagrelor	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Ticagrelor: Comparison of platelet reactivity between prasugrel and ticagrelor
Period Title: Overall Study
STARTED	33	32
COMPLETED	33	32
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ticagrelor	Prasugrel	Total
Arm/Group Description	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Prasugrel: Comparison of platelet reactivity between prasugrel and ticagrelor	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Ticagrelor: Comparison of platelet reactivity between prasugrel and ticagrelor	Total of all reporting groups
Overall Participants	33	32	65
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (8)	60 (9)	59 (9)
Sex: Female, Male (Count of Participants)
Female	7 21.2%	7 21.9%	14 21.5%
Male	26 78.8%	25 78.1%	51 78.5%
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	8 24.2%	9 28.1%	17 26.2%
White	23 69.7%	21 65.6%	44 67.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 6.1%	2 6.3%	4 6.2%
Region of Enrollment (Count of Participants)
United States	33 100%	32 100%	65 100%
Diabetes Mellitus (Count of Participants)
Count of Participants [Participants]	10 30.3%	14 43.8%	24 36.9%

Outcome Measures

1. Primary Outcome

Title	Platelet Reactivity
Description	The primary endpoint is P2Y12 reaction unit (PRU) measured by the Verify Now P2Y12 assay 24hours/hospital discharge post randomization to prasugrel vs ticagrelor. PRU is is an arbitrary unit of measure to assess ADP-induced platelet aggregation.
Time Frame	24 hours post loading dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ticagrelor	Prasugrel
Arm/Group Description	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Prasugrel: Comparison of platelet reactivity between prasugrel and ticagrelor	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Ticagrelor: Comparison of platelet reactivity between prasugrel and ticagrelor
Measure Participants	33	32
Mean (Standard Deviation) [PRU]	36 (41)	33 (56)

Adverse Events

Time Frame	4 weeks
Arm/Group Title	Ticagrelor		Prasugrel
Arm/Group Description	The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Prasugrel: Comparison of platelet reactivity between prasugrel and ticagrelor		The primary endpoint is the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 loss of function allele carriers. Ticagrelor: Comparison of platelet reactivity between prasugrel and ticagrelor
All Cause Mortality
	Ticagrelor		Prasugrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/33 (100%)		32/32 (100%)
Serious Adverse Events
	Ticagrelor		Prasugrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		1/32 (3.1%)
Vascular disorders
Stroke	0/33 (0%)	0	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Ticagrelor		Prasugrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/33 (9.1%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Dypnea	3/33 (9.1%)	3	0/32 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.