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

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT03437044
• Collaborator: AstraZeneca (Industry)
• Enrollment: 40
• Location: 1
• Arms: 2
• Actual Duration (Months): 27.5
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective randomizedProspective 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: Mar 14, 2018
• Actual Primary Completion Date: Jun 27, 2019
• Actual Study Completion Date: Jun 27, 2020

Arms and Interventions

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 Names: 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 Names: Plavix

Outcome Measures

Primary Outcome Measures

1. P2Y12 Reaction Units (PRU) [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). PRU is a marker of platelet reactivity. Higher PRU values correspond to higher aggregation and lower response to antiplatelet therapy.

Secondary Outcome Measures

1. Platelet Reactivity Index (PRI) [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). PRI% is a marker of platelet reactivity. Higher PRI values correspond to higher aggregation and lower response to antiplatelet therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses)

2. Patients with known bleeding diathesis or coagulation disorder

3. 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

4. Active pathological bleeding

5. Hypersensitivity to ticagrelor and clopidogrel or any of the excipients

6. 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

7. Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy)

8. Renal failure requiring dialysis

9. Known platelet count <80x106/mL

10. Known hemoglobin <9 g/dL

11. 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].

12. 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

13. Life expectancy of less than 1 month based on investigator's judgement

14. Participation in another clinical study with an investigational (defined as non-FDA approved) product within 28 days prior to enrolment

15. Previous randomization in the present 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
• AstraZeneca

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 4, 2018
• Informed Consent Form - Feb 15, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03437044
• Other Study ID Numbers: ESR 13396
• First Posted: Feb 19, 2018
• Last Update Posted: Nov 30, 2021
• Last Verified: Nov 1, 2021

• 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: diabetes mellitus; percutaneous coronary intervention; ticagrelor; clopidogrel; coronary artery disease
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Clopidogrel; Ticagrelor

Study Results

Participant Flow

Arm/Group Title	Ticagrelor	Clopidogrel
Arm/Group Description	180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD 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.	600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD 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.
Period Title: Overall Study
STARTED	20	20
COMPLETED	17	18
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Ticagrelor	Clopidogrel	Total
Arm/Group Description	180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD 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.	600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD 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.	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (7)	66 (9)	66 (8)
Sex: Female, Male (Count of Participants)
Female	8 40%	3 15%	11 27.5%
Male	12 60%	17 85%	29 72.5%
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	6 30%	7 35%	13 32.5%
White	14 70%	12 60%	26 65%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 5%	1 2.5%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	P2Y12 Reaction Units (PRU)
Description	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). PRU is a marker of platelet reactivity. Higher PRU values correspond to higher aggregation and lower response to antiplatelet therapy.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ticagrelor	Clopidogrel
Arm/Group Description	180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD 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.	600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD 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.
Measure Participants	17	18
Mean (95% Confidence Interval) [PRU]	60	146

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments	the corresponding baseline value of platelet reactivity was used as covariate

2. Secondary Outcome

Title	Platelet Reactivity Index (PRI)
Description	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). PRI% is a marker of platelet reactivity. Higher PRI values correspond to higher aggregation and lower response to antiplatelet therapy.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ticagrelor	Clopidogrel
Arm/Group Description	180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD 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.	600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD 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.
Measure Participants	17	18
Mean (95% Confidence Interval) [PRI %]	25	65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	the corresponding baseline value of platelet reactivity was used as covariate

Adverse Events

Time Frame	30 days
Arm/Group Title	Ticagrelor		Clopidogrel
Arm/Group Description	180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD 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.		600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD 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.
All Cause Mortality
	Ticagrelor		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Ticagrelor		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Ticagrelor		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/20 (30%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/20 (30%)	6	0/20 (0%)	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.