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

NCT02539160 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: ESR-15-10953
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

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 pharmacodynamic (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 coronary artery disease) 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.

Conditions

Coronary Artery Disease; Diabetes Mellitus

Keywords

coronary artery disease; diabetes mellitus; chronic kidney disease; ticagrelor

Outcome Measures

Primary Outcomes (1)

• Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %)

  The primary end point of the study was platelet reactivity assessed by VASP-PRI following treatment with ticagrelor 90mg between DM-CKD and DM-non-CKD cohorts. PRI % is a measure of platelet reactivity, where higher PRI levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRI greater than 50% represents inadequate response to antiplatelet medications.

  7 days

Secondary Outcomes (1)

• Platelet Reactivity Measured by VerifyNow P2Y12

  7 days

Study Arms (4)

CKD - Ticagrelor 90

ACTIVE COMPARATOR

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

CKD - Ticagrelor 60

EXPERIMENTAL

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

Non-CKD - Ticagrelor 90

ACTIVE COMPARATOR

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

Non-CKD - Ticagrelor 60

EXPERIMENTAL

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

Interventions

ticagrelor DRUG

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).

Also known as: brilinta

CKD - Ticagrelor 60; CKD - Ticagrelor 90; Non-CKD - Ticagrelor 60; Non-CKD - Ticagrelor 90

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead

Study Sites (1)

University of Florida

Jacksonville, Florida, 32209, United States

Location

Related Publications (1)

• Franchi F, Rollini F, Been L, Maaliki N, Abou Jaoude P, Rivas A, Zhou X, Jia S, Briceno M, Lee CH, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Bass TA, Angiolillo DJ. Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic effects of ticagrelor in patients with diabetes mellitus and coronary artery disease. Eur Heart J Cardiovasc Pharmacother. 2022 Aug 11;8(5):452-461. doi: 10.1093/ehjcvp/pvab042.

  PMID: 34114623 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease; Diabetes Mellitus; Renal Insufficiency, Chronic

Interventions

Ticagrelor

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Dominick J. Angiolillo, MD, PhD
• Organization: University of Florida College of Medicine Jacksonville

dominick.angiolillo@jax.ufl.edu

+1-904-244-3378

Study Officials

• Dominick J Angiolillo, MD, PhD

  University of Florida College of Medicine-Jacksonville

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2015
• First Posted: September 2, 2015
• Study Start: February 1, 2016
• Primary Completion: November 14, 2019
• Study Completion: June 17, 2020
• Last Updated: January 28, 2022
• Results First Posted: January 28, 2022

Record last verified: 2022-01

Locations

US (1)