Ticagrelor China Pharmacokinetic/Pharmacodynamic Study

Phase 4CompletedNCT02064985

AstraZeneca61 enrolled

Overview

open label, single centre, randomised, Phase IV, pharmacokinetic, pharmacodynamic, and safety study to evaluate single and multiple doses of 45, 60, and 90 mg of ticagrelor in Chinese patients with stable coronary heart disease

Up to 36 patients will be randomized in order to ensure 10 patients per treatment are evaluable.Ticagrelor will be supplied as 45 mg, 60mg, and 90mg tablets. Following an 8 hour fast on single dose on Day 1 and Day 7; on multiple doses from Day 3 to Day 6. Prior to the first dose of study drug there will be a screening period of maximum of 19 days. Patients will report to the clinical pharmacology unit (CPU) on Day -2 and will remain confined there until completion of study procedures on Day 7, the patients will be discharged on Day 8. In addition, patients will return to the CPU for a follow up visit 2 to 5 days after the last dose. Each patients participation, including the screening period, will take approximately 33 days.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Stable Coronary Heart Disease (CHD)

Interventions

Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor)DRUG

To determine the Inhibition of Platelet Aggregation (IPA) profiles of single and multiple doses of ticagrelor 45, 60, and 90 mg in Chinese patients with stable coronary heart disease (CHD) on chronic low dose ASA (75-100mg daily).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Provision of signed and dated written informed consent prior to any study specific procedures. 2. Female or male Chinese (as defined by Chinese Regulatory) patients aged 18 years or older with suitable veins for cannulations or repeated venipunctures. 3. Documented stable coronary heart disease (CHD) fulfilling all of the following, and taking 75-100 mg ASA daily treatment: Diagnosed stable angina pectoris per the guidance of Chinese Society of Cardiology published in 2007, patients with angina severity classified as I and II of Canadian Cardiovascular Society grading of angina pectoris. 4. Female patients without pregnant potential Exclusion Criteria: 1. Any indication for oral anticoagulant or dual antiplatelet treatment and chronic ASA with doses greater than 100 mg/day. 2. Concomitant therapy with strong CYP3A inhibitors, CYP3A substrates with narrow therapeutic index, or strong CYP3A inducers within 14 days preceding the first dose of study medication and during study treatment. 3. Increased bleeding risk. 4. Contraindication or other reason that ASA or ticagrelor should not be administered 5. Patients that are scheduled for revascularization (eg, PCI, CABG) during the study period

Locations (1)

Research Site

Beijing, China

Outcomes

Primary Outcomes

IPA on Day 1

The Inhibition of Platelet Aggregation (IPA) profiles of single and multiple doses of ticagrelor 45, 60, and 90 mg in Chinese patients with stable coronary heart disease (CHD) on chronic low dose ASA (75-100mg daily). Primary variable: IPA (final extent) induced by 20µM ADP at each assessment point after single and multiple doses of ticagrelor measured by Light-Transmittance Aggregometry (LTA).

Time frame: Baseline and at 0.5 hour, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours,48 hours after dose intake on Day 1

IPA on Day 7

The inhibition of Platelet Aggregation (IPA) profiles of single and multiple doses of ticagrelor 45, 60, and 90 mg in Chinese patients with stable coronary heart disease (CHD) on chronic low dose ASA (75-100mg daily). Primary variable: IPA (final extent) induced by 20µM ADP at each assessment point after single and multiple doses of ticagrelor measured by Light-Transmittance Aggregometry (LTA).

Time frame: Baseline and at 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours after dose intake on Day 7

Secondary Outcomes

Percent Change From Baseline in PRU on Day 1

Percent Change from baseline in Platelet P2Y12 Reaction Units (PRU)(measured by VerifyNow) profiles of multiple doses of ticagrelor 45, 60, and 90 mg in Chinese patients with stable coronary heart disease on chronic low dose ASA.

Time frame: Baseline and at 0.5 hour, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours,48 hours after dose intake on Day 1

Pharmacokinetics Parameters of Ticagrelor on Day 7(1)

Pharmacokinetics parameters of Ticagrelor on Day 7---Cmax

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Safety---Vital Signs Over Time---Blood Pressure

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Vital signs (seated blood pressure \[BP\])

Data from ClinicalTrials.gov

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Time frame: Baseline, Day 1 to Day 7 and 2 to 5 days after last dose

Percent Change From Baseline in PRU on Day 7

Time frame: Baseline and at 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours after dose intake on Day 7

TIPA(Max)---Day 1

The time to peak IPA (TIPAmax) was estimated for ADP-induced final extent IPA.

Time frame: Day 1

TIPA(Max)---Day 7

The time to peak IPA (TIPAmax) was estimated for ADP-induced final extent IPA.

Time frame: Day 7

AUEC(Final Extent) on Day 1

The area-under-the-effect curve (AUEC) was estimated for ADP-induced final extent IPA.

Time frame: IPA was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

AUEC(Final Extent) on Day 7

The area-under-the-effect curve (AUEC) was estimated for ADP-induced final extent IPA.

Time frame: IPA was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Pharmacokinetics Parameters of Ticagrelor on Day 1(3)

The pharmacokinetics parameter of ticagrelor on Day 1---tmax and t1/2

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

Pharmacokinetics Parameters of Ticagrelor on Day 1(2)

The pharmacokinetics parameters of Ticagrelor on Day 1---AUC(0-inf), AUC(0-12h) and AUC(0-t).

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

Pharmacokinetics Parameters of Ticagrelor on Day 7(2)

The pharmacokinetics parameters of ticagrelor on Day 7---tmax

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 1(1)

Pharmacokinetics parameters of AR-C124910XX (active metabolite) on Day 1---Cmax

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 1(3)

Pharmacokinetics parameters of AR-C124910XX (active metabolite) on Day 1: tmax and t1/2

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(1)

Pharmacokinetics parameters of Metabolite (AR-C124910XX) on Day 7---Cmax

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(4)

Pharmacokinetics parameters of AR-C124910XX (active metabolite) on Day 7---tmax

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Pharmacokinetics Parameters of Metabolite : Parent on Day 1--Cmax

To determine Cmax ratio for the metabolite to that of the parent compound on Day 1

Time frame: Day 1

Pharmacokinetics Parameters of Metabolite : Parent on Day 7---Cmax

To determine Cmax ratio of metabolite to that of the parent compound on Day 7

Time frame: Day 7

Safety---Physical Examination, Summary of Abnormalities

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Physical examination

Time frame: 2 to 5 days after last dose

Safety---Hematology Laboratory Variables Over Time---hematocrit

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---hematocrit

Time frame: 2 to 5 days after last dose

Safety---All Allowed Concomitant Medications During Study Treatment

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Concomitant medications

Time frame: All allowed concomitant medications during study treatment(up to 2-5 days after last dose), includes medications that began prior to randomization but were ongoing after randomization.

Safety---Causally Related Adverse Events by System Organ Class and Preferred Term

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Assessment of adverse events

Time frame: Includes adverse events with an onset date on or after the date of first dose and up to and including the last study visit (up to 2-5 days after last dose).

Pharmacokinetics Parameters of Ticagrelor on Day 1(1)

The pharmacokinetics parameters of Ticagrelor on Day 1---Cmax

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

Pharmacokinetics Parameters of Ticagrelor on Day 7(3)

Pharmacokinetics parameters of Ticagrelor on Day 7---AUC(0-12h)

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Pharmacokinetics Parameters of Ticagrelor on Day 7(4)

Pharmacokinetics parameters of Ticagrelor on Day 7---Accumulation ratio(ratio of Day 7 AUC(0-12h) to Day 1 AUC(0-12h))

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Safety---Vital Signs Over Time---Height

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Vital signs (Height)

Time frame: Baseline

Safety---Vital Signs Over Time---Weight

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Vital signs (Weight)

Time frame: Baseline

Safety---Vital Signs Over Time---Pulse Rate

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Vital signs (Pulse Rate)

Time frame: Baseline, Day 1 to Day 7 and 2 to 5 days after last dose

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 1(2)

Pharmacokinetics parameters of AR-C124910XX (active metabolite) on Day 1---AUC(0-12h), AUC(0-t) and AUC(0-inf)

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(2)

Pharmacokinetics parameters of Metabolite (AR-C124910XX) on Day 7---AUC(0-12h)

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(3)

Pharmacokinetics parameters of Metabolite (AR-C124910XX) on Day 7---Accumulation ratio(ratio of Day 7 AUC(0-12h) to Day 1 AUC(0-12h))

Time frame: Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7

Safety---Hematology Laboratory Variables Over Time---Erythrocytes

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Erythrocytes

Time frame: 2 to 5 days after last dose

Safety---Hematology Laboratory Variables Over Time---Hemoglobin

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Hemoglobin

Time frame: 2 to 5 days after last dose

Safety---Hematology Laboratory Variables Over Time---Leukocytes

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Leukocytes

Time frame: 2 to 5 days after last dose

Safety---Hematology Laboratory Variables Over Time---Platelets

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Platelets

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Glucose

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Glucose

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Alanine Aminotransferase

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Alanine Aminotransferase

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Aspartate Aminotransferase

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Aspartate Aminotransferase

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Alkaline Phosphatase

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Alkaline Phosphatase

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Creatinine

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Creatinine

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Total Bilirubin

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Total Bilirubin

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Sodium

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Sodium

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Potassium

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Potassium

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Chloride

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Chloride

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Phosphate

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Phosphate

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Albumin

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Albumin

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Protein

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Protein

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Blood Urea Nitrogen

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Blood Urea Nitrogen

Time frame: 2 to 5 days after last dose

Safety---Clinical Chemistry Variables Over Time---Bicarbonate

The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Clinical Chemistry---Bicarbonate

Time frame: 2 to 5 days after last dose

Pharmacokinetics Parameters of Metabolite : Parent on Day 1--AUC(0-inf)

To determine AUC(0-inf) ratio for the metabolite to that of the parent compound on Day 1

Time frame: Day 1

Pharmacokinetics Parameters of Metabolite : Parent on Day 7---AUC(0-12h)

To determine AUC(0-12h) ratio of metabolite to that of the parent compound on Day 7.

Time frame: Day 7