Comparison of TIcagrelor and Clopidogrel in Patients With Coronary Artery diseaSe and Type 2 Diabetes Mellitus (TICS-DM) (TICS-DM)

Comparison of TIcagrelor and Clopidogrel in Patients With Coronary Artery diseaSe and Type 2 Diabetes Mellitus (TICS-DM): a Randomized Pharmacodynamic Study

Patients with type 2 diabetes mellitus (T2DM), have a high prevalence of suboptimal response to clopidogrel (up to 40%). This impaired response to antiplatelet drugs has been consistently associated with a higher risk of adverse ischemic outcomes. Different strategies have been suggested to overcome variability in response to clopidogrel and improve clinical outcomes in diabetic patients. One of these strategies is the use of newer P2Y12 inhibitors, such as ticagrelor, with more potent and consistent platelet inhibitory effects compared to clopidogrel. In summary, since patients with T2DM continue to have enhanced platelet reactivity despite the administration of commonly used dual antiplatelet therapy with aspirin and standard doses of clopidogrel, newer and more potent antiplatelet treatment strategies are warranted in this high-risk population. The purpose of the present study is to compare platelet inhibitory effects achieved with ticagrelor versus clopidogrel, both on top of aspirin therapy, in patients with type 2 DM and stable coronary artery disease.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease; Diabetes Mellitus. Type 2
• Intervention / Treatment: Drug: Ticagrelor; Drug: Clopidogrel

Detailed Description

Despite the clinical benefit associated with dual therapy consisting in aspirin and clopidogrel, there are still a considerable number of patients who continue to have atherothrombotic events. Several studies have shown a wide interindividual variability in response to clopidogrel treatment and patients with poor response have an increased risk of recurrent ischemic events. In particular, patients with type 2 diabetes mellitus (T2DM), have a high prevalence of suboptimal response to clopidogrel (up to 40%). This impaired response to antiplatelet drugs has been consistently associated with a higher risk of adverse ischemic outcomes. Different strategies have been suggested to overcome variability in response to clopidogrel and improve clinical outcomes in diabetic patients. One of these strategies is the use of newer P2Y12 inhibitors, such as ticagrelor, with more potent and consistent platelet inhibitory effects compared to clopidogrel. In summary, since patients with T2DM continue to have enhanced platelet reactivity despite the administration of commonly used dual antiplatelet therapy with aspirin and standard doses of clopidogrel, newer and more potent antiplatelet treatment strategies are warranted in this high-risk population. The purpose of the present study is to compare platelet inhibitory effects achieved with ticagrelor versus clopidogrel, both on top of aspirin therapy, in patients with type 2 DM and stable coronary artery disease (CAD).

This is a multi-center prospective, open-label, two-sequence, two-period, randomized crossover study conducted in T2DM patients between the ages of 18 and 75 years with known CAD. Subjects will be randomized in a 1:1 fashion to take ticagrelor (180-mg loading dose the first day followed by 90-mg maintenance dose) or clopidogrel (600-mg loading dose the first day followed by 75-mg daily maintenance dose) for one-week on a background of aspirin therapy (100 mg daily). After a 2-4 week washout period, subjects will cross-over treatment regimen. The washout periods are included to minimize carryover effects between treatment regimens. Patient compliance will be assessed by interview and pill counting.

Platelet function testing will be performed at the following time-points (repeated in the two periods of treatment): baseline, 2 and 24 hours after taking loading dose of the assigned drug, and 1 week after initiating the assigned drug.

All statistical comparisons of platelet function for the primary and secondary endpoints will be conducted using linear mixed-effect models with treatment, sequence, period and treatment*period (treatment by period interaction in order to test for carryover effects) as fixed effects, subject as a random effect and baseline value of the corresponding platelet function test as a covariate. A two-tailed p value of less than 0.05 will be considered to indicate a statistically significant difference for all the analyses performed.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: José Luis Ferreiro; Email: jlferreiro@bellvitgehospital.cat

Study Locations

• Spain
  • Madrid, Spain, 28040
    • Not yet recruiting
    • Hospital Clinico San Carlos
    • Principal Investigator: David Vivas, PhD
  • Murcia, Spain, 30120
    • Not yet recruiting
    • Hospital Clínico Universitario Virgen de la Arrixaca
    • Principal Investigator: Antonio Tello-Montoliu, PhD
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Recruiting
      • Hospital Universitari de Bellvitge - IDIBELL
      • Principal Investigator: José Luis Ferreiro, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures
• Age between 18 and 75 years
• Type 2 DM according to ADA criteria
• Angiographically documented CAD
• Chronic treatment (>1 month) with aspirin (100mg/day)

Exclusion Criteria:

• Known allergies to aspirin, clopidogrel, or ticagrelor
• Blood dyscrasia
• Any recent acute coronary syndrome (<30 days) or hemodinamic instability
• Recent antiplatelet therapy (<14 days), with the exception of ASA, including: thienopyridines, cilostazol, dipiridamol, glycoprotein IIb/IIIa inhibitors
• Oral anticoagulation with a coumarin derivative
• Concomitant treatment with a potent CYP3A4 inhibitor (e.g. ketoconazole, claritromicine, nefazodone, ritonavir, atazanavir)
• Any active bleeding
• Recent history of stroke, TIA or intracranial bleeding (<6 months prior to inclusion)
• Platelet count <100x106/microl
• Severe chronic kidney disease (creatinine clearance measured with Cockcroft-Gault formula <30ml/min)
• Any active neoplasm
• Baseline ALT >2.5 times the upper limit of normality
• Pregnant or childbearing females

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A; After providing written informed consent, eligible subjects will be randomized in a 1:1 fashion to group A or B. Ticagrelor (180-mg loading dose the first day followed by 90-mg b.i.d. maintenance dose) for one week; washout period of 2-4 weeks; crossover to clopidogrel (600-mg loading dose the first day followed by 75-mg daily maintenance dose) for one-week.	Drug: Ticagrelor; Other Names: Brilinta; Drug: Clopidogrel; Other Names: Plavix
Experimental: Group B; After providing written informed consent, eligible subjects will be randomized in a 1:1 fashion to group A or B. Clopidogrel (600-mg loading dose the first day followed by 75-mg daily maintenance dose) for one-week; washout period of 2-4 weeks; crossover to ticagrelor (180-mg loading dose the first day followed by 90-mg b.i.d. maintenance dose) for one week.	Drug: Ticagrelor; Other Names: Brilinta; Drug: Clopidogrel; Other Names: Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet reactivity	maximal platelet aggregation, measured with light transmittance aggregometry (using 20 μM ADP as agonist), achieved after 1 week of treatment with ticagrelor or clopidogrel	7 days

Collaborators and Investigators

• Sponsor: Spanish Society of Cardiology
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: José Luis Ferreiro, Hospital Universitari de Bellvitge - IDIBELL

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): February 1, 2017

Study Registration Dates

• First Submitted: May 27, 2015
• First Submitted That Met QC Criteria: May 27, 2015
• First Posted (Estimate): May 29, 2015

Study Record Updates

• Last Update Posted (Estimate): April 14, 2016
• Last Update Submitted That Met QC Criteria: April 13, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: ISSBRIL0162