Pharmacokinetics of Antiplatelet Drugs in Diabetic pAtients

NCT ID: NCT02302508

Last Updated: 2019-07-24

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-01
• Study Completion Date: 2021-12-31

Brief Summary

Clopidogrel efficacy appears diminished in patients with type 2 diabetes (T2D) who continue to show an increased risk of adverse cardiovascular events and mortality compared to those without T2D.The aim of the first project is to describe the pharmacokinetic (PK) profile of three antiplatelet drugs in 4 groups of patients according to their diabetic or non-diabetic status. To this end, PK profiles will be determined after a single oral dose of 300 mg clopidogrel, 60 mg prasugrel and 180 mg ticagrelor in patients (n=108); 1) with T2D and good glycemic control; 2) with T2D and poor glycemic control; 3) with insulin-treated diabetes; and 4) non-diabetic subjects.

Detailed Description

Clopidogrel efficacy appears diminished in patients with T2D who continue to show an increased risk of adverse cardiovascular events and mortality compared to those without T2D. To the contrary, response to prasugrel and ticagrelor appears conserved in ACS patients with diabetes. There are several mechanisms that may be contributing to the blunted response to clopidogrel but a postulated decreased concentration of clopidogrel active metabolite is worth pursuing further.

The overall objective of this proposal is to describe the pharmacokinetic profiles of three antiplatelet drugs namely, clopidogrel, prasugrel and ticagrelor in four groups of patients according to their diabetic or non-diabetic status.

Patients (n=108) will be recruited to constitute 4 groups: Group I, 27 confirmed T2D with A1C ≤7; Group II, 27 patients with poor glycemic control A1C Patients (n=108) will be recruited to constitute 4 groups: Group I, 27 confirmed T2D with A1C <7.0; Group II, 27 patients with poor glycemic control A1C >7.5; Group III, 27 patients with insulin-treated T2D; and Group IV, 27 sex-matched non-diabetic healthy subjects. Subjects with type 2 diabetes according to the Canadian Clinical Guidelines will be recruited at the CHUM outpatient clinic. After an overnight fast, participants will be admitted to the CRCHUM's Clinical Research Unit (they will not be hospitalized). A crossover randomized study design with 3 phases (washout period of 12 days between phases) will be conducted. Subjects will receive a single oral dose of clopidogrel 300 mg or prasugrel 60 mg or ticagrelor 180 mg in a randomized fashion on 3 different occasions. Serial blood samples will be drawn and urine collected over 10 hours (PK and PD analysis).

A blood sample will be taken for pharmacogenetic analyses. Additional blood samples will be collected just before the administration of antiplatelet drugs to measure fasting insulin, glycaemia levels to determine the HOMA-IR. In addition, the following covariates namely, gender, age, weight, duration of diabetes and drug profile will be also recorded.

Their regular medication will be administered 4 hours after the administration of the antiplatelet drug.

Conditions

Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

T2D patients with A1C ≤7.0

Clopidogrel, Prasugrel, Ticagrelor A single oral dose of clopidogrel 300 mg or prasugrel 60 mg or ticagrelor 180 mg in a randomized fashion on 3 different occasions (washout period of 12 days or more)

Group Type: EXPERIMENTAL

Clopidogrel, Prasugrel, Ticagrelor

Intervention Type: DRUG

PK and PD parameters will be compared between groups and comparison will be performed between antiplatelet agents

T2D patients with A1C>7.5

Clopidogrel, Prasugrel, Ticagrelor A single oral dose of clopidogrel 300 mg or prasugrel 60 mg or ticagrelor 180 mg in a randomized fashion on 3 different occasions (washout period of 12 days or more)

Group Type: EXPERIMENTAL

Clopidogrel, Prasugrel, Ticagrelor

Intervention Type: DRUG

PK and PD parameters will be compared between groups and comparison will be performed between antiplatelet agents

Insulino-treated

Clopidogrel, Prasugrel, Ticagrelor A single oral dose of clopidogrel 300 mg or prasugrel 60 mg or ticagrelor 180 mg in a randomized fashion on 3 different occasions (washout period of 12 days or more)

Group Type: EXPERIMENTAL

Clopidogrel, Prasugrel, Ticagrelor

Intervention Type: DRUG

PK and PD parameters will be compared between groups and comparison will be performed between antiplatelet agents

Non-diabetic healthy subjects

Clopidogrel, Prasugrel, Ticagrelor A single oral dose of clopidogrel 300 mg or prasugrel 60 mg or ticagrelor 180 mg in a randomized fashion on 3 different occasions (washout period of 12 days or more)

Group Type: ACTIVE_COMPARATOR

Clopidogrel, Prasugrel, Ticagrelor

Intervention Type: DRUG

PK and PD parameters will be compared between groups and comparison will be performed between antiplatelet agents

Interventions

Clopidogrel, Prasugrel, Ticagrelor

PK and PD parameters will be compared between groups and comparison will be performed between antiplatelet agents

Intervention Type: DRUG

Other Intervention Names

Plavix; Brilinta; Effient

Eligibility Criteria

Inclusion Criteria

• Participants will be ≥18 years old
• Non-smokers (>3 months)
• T2D with good glycemic control A1C<7.0
• T2D with poor glycemic control A1C >7.5
• Insulin-treated T2D
• Non-diabetic healthy subjects

Exclusion Criteria

• Subjects with estimated glomerular filtration (MDRD) <50 mL/min/1.73m2
• ALT and AST 3 times above the upper limit of normal
• Organ transplant recipients
• Inflammatory illnesses (i.e., polyarthritis, hepatitis, cirrhosis, active infectious diseases)
• Active cancer (except non-melanoma skin cancer)
• Uncontrolled thyroid functions
• Inflammatory bowel diseases (ulcerous colitis and Crohn's disease), bariatric surgery
• Pregnancy
• History of drug or alcohol abuse
• Platelet function disorder,
• One of the following therapies : P2Y12 inhibitors, antithrombotics, antibiotics, anticoagulant, antivirals, CYP450 inducers (carbamazepine, phenobarbital, phenytoin, rifampin, St-John's worth), CYP450 inhibitors (amiodarone, fluoxetine, verapamil), immunosuppressors, INFs, or grapefruit juice (<4 weeks) or an investigational drug
• Intolerance or hypersensitivity to antiplatelet drugs or their excipients

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Centre de Recherche du Centre Hospitalier de l'Université de Montréal

OTHER

Sponsor Role: collaborator

Centre hospitalier de l'Université de Montréal (CHUM)

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Veronique Michaud, BPharm. PhD

Role: PRINCIPAL_INVESTIGATOR

Centre de recherche du Centre Hospitalier de l'université de Montréal (CHUM)

Locations

Centre hospitalier de l'Université de Montréal (CHUM)

Montreal, Quebec, Canada

Countries

Canada

Other Identifiers

14.143

Identifier Type: -

Identifier Source: org_study_id