OPTIMUS-5: Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT02548650
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 66
• Location: 1
• Arms: 2
• Actual Duration (Months): 34.7
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor, more frequently clopidogrel, represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI) or peripheral arterial disease (PAD). However, rates of ischemic recurrences remain high. Vorapaxar is a protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. Patients with diabetes mellitus (DM) are known to be at increased risk of recurrent atherothrombotic events, which translates into worse outcomes, despite the use of standard of care therapy. This is in part due to the hyperreactive platelet phenotype, which characterizes DM patients, and to inadequate response to oral antiplatelet agents, including clopidogrel. Therefore, vorapaxar is an attractive treatment option for DM patients with a prior MI. The pharmacodynamic (PD) effects of vorapaxar in DM patients and how these may differentiate from non-DM patients has not been explored. Further, the role of vorapaxar as part of a dual antithrombotic treatment regimen combined with clopidogrel (and stopping aspirin) represents another important area of clinical interest. The proposed prospective, parallel-design study conducted in patients post-MI or with PAD with and without DM will aim the assess the pharmacodynamic effects of vorapaxar in addition to standard DAPT with aspirin and clopidogrel as well as in combination with clopidogrel only following aspirin withdrawal.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Infarction; Diabetes Mellitus; Peripheral Arterial Disease	Drug: Vorapaxar; Drug: Clopidogrel; Drug: Aspirin	Phase 4

Detailed Description

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor, more frequently clopidogrel, represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI) or peripheral arterial disease (PAD). However, rates of ischemic recurrences remain high, in part due to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, continue to be activated. Vorapaxar is a novel, orally active, competitive and slowly reversible protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral arterial disease. Patients with DM are known to be at increased risk of recurrent atherothrombotic events, which translates into worse outcomes, despite the use of standard of care therapy. This is in part due to the hyperreactive platelet phenotype, which characterizes DM patients, and to inadequate response to oral antiplatelet agents, including clopidogrel. Importantly, in DM patients with prior MI included in the TRA 2P trial, vorapaxar reduced the primary composite end point at 3 years by 27% and led to a greater absolute risk reduction compared with those without DM. Therefore, vorapaxar is an attractive treatment option for DM patients with a prior MI. However, to date the PD effects of vorapaxar in DM patients and how these may differentiate from non-DM patients has not been explored. Further, current trends in clinical practice are seeing many patients discontinue aspirin and maintain clopidogrel. Hence, the role of vorapaxar as part of a dual antithrombotic treatment regimen combined with clopidogrel (and stopping aspirin) represents another important area of clinical interest, in order to maximize ischemic protection while reducing the risk of bleeding. The proposed prospective, parallel-design study conducted in patients post-MI or with PAD with and without DM will aim the assess the pharmacodynamic effects of vorapaxar in addition to standard DAPT with aspirin and clopidogrel as well as in combination with clopidogrel only following aspirin withdrawal. Pharmacodynamic assessments will be performed at multiple time point, with different assays exploring multiple pathways of platelet aggregation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacodynamic Effects of Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus: The Optimizing Anti-Platelet Therapy In Diabetes MellitUS (OPTIMUS)-5 Study
• Actual Study Start Date: Mar 25, 2016
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Feb 14, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patients with diabetes Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.	Drug: Vorapaxar; Triple therapy with DAPT plus vorapaxar (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days; Other Names: Zontivity ; Drug: Clopidogrel; Triple therapy with DAPT plus vorapaxar (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days; Other Names: Plavix ; Drug: Aspirin; Triple therapy with DAPT plus vorapaxar(vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days; Other Names: ASA
Active Comparator: Patients without diabetes Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.	Drug: Vorapaxar; Triple therapy with DAPT plus vorapaxar (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days; Other Names: Zontivity ; Drug: Clopidogrel; Triple therapy with DAPT plus vorapaxar (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days; Other Names: Plavix ; Drug: Aspirin; Triple therapy with DAPT plus vorapaxar(vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days; Other Names: ASA

Outcome Measures

Primary Outcome Measures

1. Maximal Platelet Aggregation in DM [30 days]

   Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy in diabetic patients

Secondary Outcome Measures

1. Maximal Platelet Aggregation in Non-DM [30 days]

   Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy in non-diabetic patients

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Patients with a prior MI between 2 weeks and 24 months or with PAD.

2. On DAPT with low-dose aspirin (81mg od) and clopidogrel (75mg od) as per standard-of-care for at least 14 days.

3. Age ≥ 18 years old.

Exclusion criteria:

1. History of acute coronary syndrome in the previous 2 weeks.

2. History of stroke, transient ischemic attack, or intracranial hemorrhage.

3. Active pathological bleeding, history of bleeding events or increased risk of bleeding.

4. Known severe hepatic impairment.

5. Use of strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) or inducers (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin).

6. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban).

7. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the past 14 days.

8. Creatinine clearance <30 mL/minute.

9. Platelet count <80x106/mL

10. Hemoglobin <10g/dL

11. Hemodynamic instability

12. Pregnant 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
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Dominick J Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 2, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02548650
• Other Study ID Numbers: IIS 53377
• First Posted: Sep 14, 2015
• Last Update Posted: Feb 12, 2020
• Last Verified: Jan 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
• Keywords provided by University of Florida: myocardial infarction; diabetes mellitus; vorapaxar; peripheral arterial disease
• Additional relevant MeSH terms: Myocardial Infarction; Peripheral Arterial Disease; Peripheral Vascular Diseases; Diabetes Mellitus; Infarction; Aspirin; Clopidogrel; Vorapaxar

Study Results

Participant Flow

Pre-assignment Detail	Between March 2016 and October 2018, 71 patients agreed to participate in the study; 5 patients were not eligible for randomization due to the presence of an exclusion criteria. 66 patients (DM, n=30; non-DM, n=36) were exposed to at least one dose of study medication, representing the safety population.

Arm/Group Title	Patients With Diabetes	Patients Without Diabetes
Arm/Group Description	Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.	Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.
Period Title: Triple Therapy
STARTED	30	36
COMPLETED	29	32
NOT COMPLETED	1	4
Period Title: Triple Therapy
STARTED	29	32
COMPLETED	28	30
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Patients With Diabetes	Patients Without Diabetes	Total
Arm/Group Description	Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.	Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.	Total of all reporting groups
Overall Participants	30	34	64
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (8)	56 (9)	58 (10)
Sex: Female, Male (Count of Participants)
Female	7 23.3%	11 32.4%	18 28.1%
Male	23 76.7%	23 67.6%	46 71.9%
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	14 46.7%	11 32.4%	25 39.1%
White	15 50%	22 64.7%	37 57.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.3%	1 2.9%	2 3.1%
chronic kidney disease (Count of Participants)
Count of Participants [Participants]	2 6.7%	2 5.9%	4 6.3%

Outcome Measures

1. Primary Outcome

Title	Maximal Platelet Aggregation in DM
Description	Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy in diabetic patients
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

The PD population included all patients with PD data and without a major protocol deviation thought to affect the PD effects of vorapaxar, aspirin and clopidogrel. Two patients were not compliant with medications and therefore excluded from the PD analysis. Some patients did not have primary end point data but were considered for other analyses.

Arm/Group Title	Triple Therapy	Dual Therapy
Arm/Group Description	vorapaxar plus DAPT	(vorapaxar plus clopidogrel)
Measure Participants	30	30
Mean (Standard Deviation) [percentage of aggregation]	65 (20)	78 (20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Triple Therapy, Dual Therapy
	Comments	The primary end point of our study was the comparison of CAT-induced MPA measured by LTA between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy. We hypothesized that dual therapy would be non-inferior to triple therapy after 30±5 days of treatment
	Type of Statistical Test	Non-Inferiority
	Comments	Under the null hypothesis that the mean aggregation between dual and triple therapy is not equal to 0 and a common standard deviation of 13%, a sample size of 28 patients per group with a valid primary end point time point allowed for the 95% confidence interval (CI) to stay within ± 10% with a 80% power and a two-sided alpha=0.05.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	12
	Confidence Interval	(2-Sided) 95%; 3 to 21
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Maximal Platelet Aggregation in Non-DM
Description	Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy in non-diabetic patients
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Triple Therapy	Dual Therapy
Arm/Group Description	vorapaxar plus DAPT	(vorapaxar plus clopidogrel)
Measure Participants	34	34
Mean (Standard Deviation) [percentage of aggregation]	60 (15)	70 (20)

Adverse Events

Time Frame	Study duration (60 days)
Arm/Group Title	Patients With Diabetes		Patients Without Diabetes
Arm/Group Description	Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.		Triple therapy (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days.
All Cause Mortality
	Patients With Diabetes		Patients Without Diabetes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/36 (0%)
Serious Adverse Events
	Patients With Diabetes		Patients Without Diabetes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Patients With Diabetes		Patients Without Diabetes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		2/36 (5.6%)
Blood and lymphatic system disorders
minor bleeding	1/30 (3.3%)	1	0/36 (0%)	0
Cardiac disorders
Chest pain	1/30 (3.3%)	1	2/36 (5.6%)	2

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.