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Impact of Chronic Kidney Disease on the Effects of Ticagrelor in Patients With Diabetes and Coronary Artery Disease

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ClinicalTrials.gov Identifier: NCT02539160
Recruitment Status : Recruiting
First Posted : September 2, 2015
Last Update Posted : February 7, 2019
Sponsor:
Information provided by (Responsible Party):
University of Florida

Brief Summary:
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. To date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although PD studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Diabetes Mellitus Drug: ticagrelor Phase 4

Detailed Description:

Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. These observations underscore the importance of antiplatelet therapy for prevention of atherothrombotic recurrences in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. This may be in part due to the impaired pharmacokinetic (PK) and pharmacodynamic (PD) effects of clopidogrel in patients with DM and CKD. Since both DM and CKD represent pandemic public health problems, the prevalence of which will double over the next 20 years, identifying antiplatelet agents with more favorable PK/PD profiles is of key importance.

Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. In patients with CKD, ticagrelor led to an even greater relative risk reduction of ischemic events, including cardiovascular mortality, compared to patients without CKD. However, to date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although PD studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 82 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Impact of Chronic Kidney Disease on the Pharmacodynamic and Pharmacokinetic Effects of Ticagrelor in Patients With Diabetes Mellitus and Coronary Artery Disease
Study Start Date : February 2016
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Ticagrelor

Arm Intervention/treatment
Active Comparator: CKD - Ticagrelor 90
Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.
Drug: ticagrelor
Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).
Other Name: brilinta

Experimental: CKD - Ticagrelor 60
Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.
Drug: ticagrelor
Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).
Other Name: brilinta

Active Comparator: Non-CKD - Ticagrelor 90
Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.
Drug: ticagrelor
Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).
Other Name: brilinta

Experimental: Non-CKD - Ticagrelor 60
Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.
Drug: ticagrelor
Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).
Other Name: brilinta




Primary Outcome Measures :
  1. Platelet reactivity measured by vasodilator stimulated phosphoprotein (VASP) platelet reactivity index (PRI) [ Time Frame: 7-10 days ]

Secondary Outcome Measures :
  1. Platelet reactivity measured by VerifyNow P2Y12 [ Time Frame: 7-10 days ]


Information from the National Library of Medicine

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

Inclusion Criteria:

  • Age >18 years.
  • Type 2 DM, defined according to World Health Organization (WHO) definition, on treatment with oral hypoglycemic agents and/or insulin for at least 2 months without any changes in treatment regimen;
  • Angiographically documented CAD.
  • On treatment with low-dose aspirin (81mg/day) and clopidogrel (75mg/day) for at least 30 days as part of standard of care.

Exclusion Criteria:

  • Patients with end-stage renal disease on hemodialysis.
  • Use of any antiplatelet therapy (except aspirin and clopidogrel) in past 30 days.
  • Use of parenteral or oral anticoagulation in past 30 day.
  • Active pathological bleeding.
  • History of intracranial hemorrhage with prior hemorrhage stroke.
  • Blood dyscrasia or bleeding diathesis.
  • Any active malignancy.
  • Platelet count < 80x106/µl.
  • Hemoglobin <10 g/dl.
  • Known hepatic dysfunction (known moderate and severe hepatic dysfunction).
  • Hemodynamic instability.
  • Known allergy or hypersensitivity to ticagrelor or any excipients.
  • Pregnant / lactating females (women of childbearing age must use reliable birth control while in the study).
  • Strong inhibitors of cytochrome CYP3A4 and potent inducers of cytochrome CYP3A4 (to avoid interaction with ticagrelor): ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin.
  • Patients with sick sinus syndrome (SSS) or high degree atrio-ventricular block without pacemaker protection.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02539160


Contacts
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Contact: Dominick J Angiolillo, MD, PhD +1-904-244-3378 dominick.angiolillo@jax.ufl.edu

Locations
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United States, Florida
University of Florida Recruiting
Jacksonville, Florida, United States, 32209
Contact: Dominick Angiolillo       dominick.angiolillo@jax.ufl.edu   
Sponsors and Collaborators
University of Florida
Investigators
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Principal Investigator: Dominick J Angiolillo, MD, PhD University of Florida College of Medicine-Jacksonville

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02539160     History of Changes
Other Study ID Numbers: ESR-15-10953
First Posted: September 2, 2015    Key Record Dates
Last Update Posted: February 7, 2019
Last Verified: February 2019

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

Keywords provided by University of Florida:
coronary artery disease
diabetes mellitus
chronic kidney disease
ticagrelor

Additional relevant MeSH terms:
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Platelet Aggregation Inhibitors
Diabetes Mellitus
Kidney Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Renal Insufficiency, Chronic
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Renal Insufficiency
Ticagrelor
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs