Low Maintenance Dose Ticagrelor Versus Clopidogrel in Diabetes Patients Undergoing PCI (OPTIMUS-6)

Study Description

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Brief Summary:

To date there is very little PD and pharmacokinetic (PK) data on the ticagrelor 60 mg bid dosing regimen. In particular, there is no prospective PK/PD study on this dosing regimen in patients with DM who are known to have impaired response to clopidogrel therapy. Since DM patients frequently require elective PCI due to chronic progression of CAD (and not solely because of an acute thrombotic complication), and clopidogrel remains the guideline recommended P2Y12 inhibiting therapy for these patients, understanding the PD effects of the ticagrelor 60 mg bid regimen in this setting is an unmet clinical need. This is also in light of the ongoing THEMIS trial which is specifically evaluating the impact of the ticagrelor 60 mg bid dosing regimen in type 2 DM patients without a prior major CV event.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2; Coronary Artery Disease	Drug: Ticagrelor; Drug: Clopidogrel	Phase 4

Detailed Description:

Patients with diabetes mellitus (DM) are characterized by platelet hyperreactivity and reduced pharmacodynamic (PD) effects to several oral antiplatelet agents, including clopidogrel. In addition to the hyperreactive platelet phenotype, impaired drug metabolism as well as increased platelet turnover rates may contributed to impaired clopidogrel-induced antiplatelet effects in DM patients. These observations may contribute to the higher ischemic event rates, including stent thrombosis, observed in DM patients compared with non-DM patients treated with clopidogrel.

Ticagrelor is characterized by more prompt, potent and predictable antiplatelet effects compared with clopidogrel and lower ischemic events in patients with an acute coronary syndrome (ACS) on a background of aspirin therapy. In patients who experienced a prior (1-3 years) myocardial infarction (MI), compared with placebo, ticagrelor 60 mg bid on a background of aspirin therapy also reduced long-term ischemic events, with a mortality benefit observed in DM patients.

To date the PD effects of ticagrelor versus clopidogrel in DM largely derive from post-hoc assessments or in stabilized patients (e.g. >30 days after PCI), and have not been prospectively evaluated in the context of elective PCI procedures. Moreover, PD studies with the ticagrelor 60 mg bid regimen are limited. Therefore, the aim of this investigation will be to compare the PD effects of a ticagrelor 60 mg bid versus clopidogrel 75 mg od MD regimen in DM patients without a prior major CV event undergoing elective PCI.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	42 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Prospective randomized
Masking:	None (Open Label)
Masking Description:	Staff performing PK/PD assessments will remain blinded to treatment assignment.
Primary Purpose:	Treatment
Official Title:	A Randomized Comparison of Platelet Inhibition Using a Low Maintenance Dose Ticagrelor Regimen Versus Standard Dose Clopidogrel in Diabetes Mellitus Patients Without Prior Major Cardiovascular Events Undergoing Elective Percutaneous Coronary Intervention: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-6 Study
Actual Study Start Date :	March 14, 2018
Estimated Primary Completion Date :	March 2019
Estimated Study Completion Date :	July 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ticagrelor; 180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD	Drug: Ticagrelor; After providing written informed consent and following diagnostic angiography, patients meeting study entry criteria undergoing PCI will be randomly assigned in a 1:1 ratio to treatment with either ticagrelor or clopidogrel. Randomized treatment will be maintained for 30±3 days.; Other Name: Brilinta
Active Comparator: Clopidogrel; 600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD	Drug: Clopidogrel; After providing written informed consent and following diagnostic angiography, patients meeting study entry criteria undergoing PCI will be randomly assigned in a 1:1 ratio to treatment with either ticagrelor or clopidogrel. Randomized treatment will be maintained for 30±3 days.; Other Name: Plavix

Outcome Measures

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Primary Outcome Measures :

1. P2Y12 reaction units (PRU) [ Time Frame: 30 days ]
   The primary endpoint of our study will be platelet reactivity, measured as PRU level using VerifyNow PRU, of ticagrelor versus clopidogrel MD at 30 days after PCI, immediately pre-dosing dosing (trough levels).

Secondary Outcome Measures :

1. Platelet reactivity index (PRI) [ Time Frame: 30 days ]
   Platelet reactivity measured as PRI% using whole blood vasodilator-stimulated phosphoprotein (VASP), of ticagrelor versus clopidogrel MD at 30 days after PCI, immediately pre-dosing dosing (trough levels).

Eligibility Criteria

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

Criteria

Inclusion criteria:

1. Provision of informed consent prior to any study specific procedures
2. Men or women ≥18 years of age
3. Diagnosed with type 2 DM defined by ongoing glucose lowering drug (oral medications and / or insulin) treatment for at least 1 month
4. Presence of CAD undergoing elective PCI* * Patients will need to be cardiac enzyme-negative prior to undergoing coronary angiography. Patient will need to be on a background of aspirin therapy (treated with a 325 mg LD prior to coronary angiography unless already on chronic low-dose aspirin therapy). Patients on maintenance clopidogrel 75 mg therapy for at least 1 week due to a prior vascular intervention will also be eligible. However, patients on clopidogrel, ticagrelor or prasugrel due to a prior acute major cardiovascular event (MI or stroke) will not be eligible.

Exclusion criteria:

1. Previous MI (with the exception of definite non-type 1 MI [eg, due to coronary revascularization procedure, profound hypotension, hypertensive emergency, tachycardia, or profound anemia])
2. Previous stroke (transient ischemic attack [TIA] is not included in the stroke definition)
3. Use of an intravenous antiplatelet therapy (i.e., cangrelor or GPI) during PCI
4. On treatment with clopidogrel, prasugrel, or ticagrelor due to a prior acute major CV event (MI or stroke) (on treatment with clopidogrel due to prior vascular intervention not secondary to a major CV event is allowed)
5. Planned use of aspirin treatment at doses >100 mg od

6. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study:

   • Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir
   • CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily
7. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses)
8. Patients with known bleeding diathesis or coagulation disorder
9. History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months prior to randomization, or major surgery within 30 days prior to randomization
10. Active pathological bleeding
11. Hypersensitivity to ticagrelor and clopidogrel or any of the excipients
12. Increased risk of bradycardic events (eg, known sick sinus syndrome, second or third degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker
13. Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy)
14. Renal failure requiring dialysis
15. Known platelet count <80x106/mL
16. Known hemoglobin <9 g/dL
17. Women of child-bearing potential (ie, those who are not chemically or surgically sterilized or who are not post-menopause) who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator OR who have a positive pregnancy test at enrolment or randomization OR women who are breast-feeding. If a subject becomes pregnant during the course of the study the investigational product should be discontinued immediately [the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) will be followed up and documented even if the subject was discontinued from the study].
18. Inability of the patient to understand and/or comply with study procedures and/or follow up, in the opinion of the investigator, OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study
19. Life expectancy of less than 1 month based on investigator's judgement
20. Participation in another clinical study with an investigational (defined as non-FDA approved) product within 28 days prior to enrolment
21. Previous randomization in the present study

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Dominick J Angiolillo, MD,PhD	+1-904-244-3378	dominick.angiolillo@jax.ufl.edu
Contact: Andrea Goosen, MPH, CCRP	904-244-5617	Andrea.Goosen@jax.ufl.edu

Locations

United States, Florida
University of Florida	Recruiting
Jacksonville, Florida, United States, 32209
Contact: Dominick J Angiolillo, MD, PhD dominick.angiolillo@jax.ufl.edu
Principal Investigator: Dominick J Angiolillo, MD, PhD

Sponsors and Collaborators

University of Florida

AstraZeneca

Investigators

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

More Information

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Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT03437044 History of Changes
Other Study ID Numbers:	ESR 13396
First Posted:	February 19, 2018
Last Update Posted:	March 16, 2018
Last Verified:	March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		No
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:

diabetes mellitus; percutaneous coronary intervention; ticagrelor; clopidogrel; coronary artery disease

Additional relevant MeSH terms:

Coronary Artery Disease; Coronary Disease; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Diseases; Cardiovascular Diseases; Arterial Occlusive Diseases; Vascular Diseases; Diabetes Mellitus; Myocardial Ischemia; Diabetes Mellitus, Type 2; Arteriosclerosis; Clopidogrel; Ticlopidine

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; Fibrinolytic Agents; Fibrin Modulating Agents; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors