In Vitro Pharmacodynamic Effects of Cangrelor in Ticagrelor Treated Patients

• ClinicalTrials.gov Identifier: NCT02081443
• Recruitment Status: Completed
• First Posted: March 7, 2014
• Results First Posted: March 3, 2017
• Last Update Posted: April 4, 2017
• Sponsor: University of Florida
• Collaborator: The Medicines Company
• Information provided by (Responsible Party): University of Florida

Study Description

Brief Summary:

Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events, including stent thrombosis, in patients undergoing stent procedures who have not been pretreated with clopidogrel. In vitro investigations have shown cangrelor to be associated with more rapid, potent, and consistent platelet inhibition in patients on maintenance prasugrel therapy exposed to a re-loading dose of prasugrel. However, if cangrelor exerts similar effects in ticagrelor treated patients remain unknown. The aim of the present study is to evaluate the effects on platelet function achieved after in vitro incubation with cangrelor in patients on ticagrelor maintenance dose who receive a loading dose of ticagrelor.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Drug: Ticagrelor 180mg; Drug: Ticagrelor 90mg	Not Applicable

Detailed Description:

A higher degree of platelet inhibition remains the goal in the peri-interventional period in patients undergoing percutaneous coronary interventions (PCI) as this is associated with a lower rate of adverse ischemic events. Ticagrelor and prasugrel are novel and potent generation oral P2Y12 receptor inhibitors associated with a greater reduction in ischemic events compared with clopidogrel. However, both prasugrel and ticagrelor have recently showed variability in pharmacodynamic (PD) response, particularly in patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI, exposing these patients to an increased risk of thrombotic complications. These findings support the need for intravenous agents with more rapid platelet inhibiting effects. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events, including stent thrombosis, in patients undergoing PCI who have not been pretreated with clopidogrel. In vitro PD investigations have shown cangrelor to be associated with more rapid, potent, and consistent platelet inhibition in patients on maintenance prasugrel therapy exposed to a re-loading dose of prasugrel. However, if cangrelor exerts similar effects in ticagrelor treated patients remain unknown. The aim of the present study is to evaluate the PD effects achieved after in vitro incubation with cangrelor in patients on ticagrelor maintenance dose who receive a loading dose of ticagrelor. The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. PD assessments will be done before and after incubation with cangrelor at 3 time-points. The study hypothesis is that in vitro incubation with cangrelor will lead to incremental P2Y12 receptor blockade, the extent of which will be inversely related to dose of ticagrelor.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: In Vitro Pharmacodynamic Effects of Cangrelor on Platelet P2Y12 Receptor Mediated Signaling in Ticagrelor Treated Patients
• Study Start Date: April 2014
• Actual Primary Completion Date: October 2015
• Actual Study Completion Date: October 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ticagrelor 180mg; The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.	Drug: Ticagrelor 90mg; The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.; Other Name: Brilinta
Active Comparator: Ticagrelor 90mg; The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.	Drug: Ticagrelor 180mg; The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.; Other Name: Brilinta

Outcome Measures

Primary Outcome Measures :

1. Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP) [ Time Frame: Baseline ]
   PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment

Secondary Outcome Measures :

1. PRI Measured by VASP [ Time Frame: 1 hour ]
   PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment
2. PRI Measured by VASP [ Time Frame: 4 hours ]
   PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Patients with angiographically documented coronary artery disease.
2. Age between 18 to 80 years
3. On treatment per standard of care with ticagrelor 90mg/b.i.d. and aspirin <100mg/day for at least 14 days.

Exclusion criteria

1. History of intracranial bleeding
2. Known severe hepatic dysfunction
3. Known hypersensitivy
4. Active bleeding or propensity to bleed
5. Platelet count <80x106/mL
6. Hemodynamic instability
7. Serum creatinine <30 mL/min
8. Use of oral anticoagulants (Vitamin K antagonist, dabigatran, rivaroxaban, apixaban)
9. Recent (<14 days) antiplatelet treatment with a glycoprotein IIb/IIIa inhibitor
10. Blood dyscrasia
11. Patients with sick sinus syndrome (SSS) or II or III degree AV block without pacemaker
12. Drugs interfering CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromicin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromizycin
13. Hemoglobin < 10g/dL
14. Pregnant females [women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study].

Contacts and Locations

Locations

United States, Florida

Dominick Angiolillo

Jacksonville, Florida, United States, 32209

Sponsors and Collaborators

University of Florida

The Medicines Company

Investigators

• Principal Investigator: Dominick Angiolillo; University of Florida

More Information

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02081443
• Other Study ID Numbers: CIT
• First Posted: March 7, 2014
• Results First Posted: March 3, 2017
• Last Update Posted: April 4, 2017
• Last Verified: March 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by University of Florida:

coronary artery disease; platelet function; ticagrelor; cangrelor

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs