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

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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:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Florida

Tracking Information
First Submitted Date  ICMJE September 8, 2015
First Posted Date  ICMJE September 14, 2015
Results First Submitted Date  ICMJE January 10, 2020
Results First Posted Date  ICMJE January 27, 2020
Last Update Posted Date February 12, 2020
Actual Study Start Date  ICMJE March 25, 2016
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 10, 2020)
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
Original Primary Outcome Measures  ICMJE
 (submitted: September 11, 2015)
Maximal platelet aggregation [ Time Frame: 30 days ]
Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between vorapaxar plus DAPT and vorapaxar plus clopidogrel
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 10, 2020)
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
Original Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2015)
Maximal platelet aggregation achieved with vorapaxar plus DAPT [ Time Frame: 30 days ]
Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between diabetic and non diabetic patients treated with vorapaxar plus DAPT
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus
Official Title  ICMJE 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
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myocardial Infarction
  • Diabetes Mellitus
  • Peripheral Arterial Disease
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Vorapaxar
    • Drug: Clopidogrel
    • Drug: Aspirin
  • 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.
    Interventions:
    • Drug: Vorapaxar
    • Drug: Clopidogrel
    • Drug: Aspirin
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 10, 2020)
66
Original Estimated Enrollment  ICMJE
 (submitted: September 11, 2015)
64
Actual Study Completion Date  ICMJE February 14, 2019
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02548650
Other Study ID Numbers  ICMJE IIS 53377
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Florida
Study Sponsor  ICMJE University of Florida
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Dominick J Angiolillo, MD, PhD University of Florida College of Medicine-Jacksonville
PRS Account University of Florida
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP