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

• ClinicalTrials.gov Identifier: NCT02548650
• Recruitment Status: Completed
• First Posted: September 14, 2015
• Results First Posted: January 27, 2020
• Last Update Posted: February 12, 2020
• Sponsor: University of Florida
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): University of Florida

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 (Clinical Trial)
• 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: March 25, 2016
• Actual Primary Completion Date: December 2018
• Actual Study Completion Date: February 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: ASA

Outcome Measures

Primary Outcome Measures :

1. Maximal Platelet Aggregation in DM [ Time Frame: 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 [ Time Frame: 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

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

Criteria

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

United States, Florida

University of Florida

Jacksonville, Florida, United States, 32209

Sponsors and Collaborators

University of Florida

Merck Sharp & Dohme Corp.

Investigators

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

  Study Documents (Full-Text)

Documents provided by University of Florida:

Study Protocol and Statistical Analysis Plan  [PDF] October 2, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Franchi F, Rollini F, Kairouz V, Rivas Rios J, Rivas A, Agarwal M, Briceno M, Wali M, Nawaz A, Silva G, Shaikh Z, Maaliki N, Been L, Piraino J, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Jennings LK, Bass TA, Angiolillo DJ. Pharmacodynamic Effects of Vorapaxar in Patients With and Without Diabetes Mellitus: Results of the OPTIMUS-5 Study. JACC Basic Transl Sci. 2019 Sep 1;4(7):763-775. doi: 10.1016/j.jacbts.2019.07.011. eCollection 2019 Nov.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02548650
• Other Study ID Numbers: IIS 53377
• First Posted: September 14, 2015
• Results First Posted: January 27, 2020
• Last Update Posted: February 12, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• 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; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Aspirin; Clopidogrel; Vorapaxar; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents