Ticagrelor China Pharmacokinetic/Pharmacodynamic Study

Phase 4

Completed

Conditions: Stable Coronary Heart Disease (CHD)

Interventions: Drug: Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor)

Registration Number: NCT02064985

Lead Sponsor: AstraZeneca

Brief Summary: 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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

Inclusion Criteria

Provision of signed and dated written informed consent prior to any study specific procedures.
Female or male Chinese (as defined by Chinese Regulatory) patients aged 18 years or older with suitable veins for cannulations or repeated venipunctures.
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.
Female patients without pregnant potential

Exclusion Criteria

Any indication for oral anticoagulant or dual antiplatelet treatment and chronic ASA with doses greater than 100 mg/day.
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.
Increased bleeding risk.
Contraindication or other reason that ASA or ticagrelor should not be administered
Patients that are scheduled for revascularization (eg, PCI, CABG) during the study period

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ticagrelor 45mg	Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor)	A single dose of ticagrelor 45 mg on Day 1 followed by 45 mg twice daily (bid) on Days 3-6 and a 45mg single dose on Day 7.
Ticagrelor 60mg	Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor)	A single dose of ticagrelor 60 mg on Day 1 followed by 60 mg twice daily (bid) on Days 3-6 and a 60mg single dose on Day 7.
Ticagrelor 90mg	Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor)	A single dose of ticagrelor 90 mg on Day 1 followed by 90 mg twice daily (bid) on Days 3-6 and a 90mg single dose on Day 7.

Primary Outcome Measures

Name	Time	Method
IPA on Day 1	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	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).
IPA on Day 7	Baseline and at 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours after dose intake 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).

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in PRU on Day 1	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	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.
Pharmacokinetics Parameters of Ticagrelor on Day 7(1)	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---Cmax
Safety---Vital Signs Over Time---Blood Pressure	Baseline, Day 1 to Day 7 and 2 to 5 days after last dose	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 \[BP\])
Percent Change From Baseline in PRU on Day 7	Baseline and at 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours after dose intake on Day 7	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.
TIPA(Max)---Day 1	Day 1	The time to peak IPA (TIPAmax) was estimated for ADP-induced final extent IPA.
Pharmacokinetics Parameters of Ticagrelor on Day 1(2)	Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1	The pharmacokinetics parameters of Ticagrelor on Day 1---AUC(0-inf), AUC(0-12h) and AUC(0-t).
Safety---Hematology Laboratory Variables Over Time---Erythrocytes	2 to 5 days after last dose	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Erythrocytes
TIPA(Max)---Day 7	Day 7	The time to peak IPA (TIPAmax) was estimated for ADP-induced final extent IPA.
AUEC(Final Extent) on Day 7	IPA was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7	The area-under-the-effect curve (AUEC) was estimated for ADP-induced final extent IPA.
Pharmacokinetics Parameters of Ticagrelor on Day 1(3)	Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1	The pharmacokinetics parameter of ticagrelor on Day 1---tmax and t1/2
AUEC(Final Extent) on Day 1	IPA was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1	The area-under-the-effect curve (AUEC) was estimated for ADP-induced final extent IPA.
Safety---Hematology Laboratory Variables Over Time---hematocrit	2 to 5 days after last dose	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---hematocrit
Safety---Clinical Chemistry Variables Over Time---Protein	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Blood Urea Nitrogen	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Bicarbonate	2 to 5 days after last dose	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
Pharmacokinetics Parameters of Ticagrelor on Day 1(1)	Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 36, and 48 hours post dose on Day 1	The pharmacokinetics parameters of Ticagrelor on Day 1---Cmax
Pharmacokinetics Parameters of Ticagrelor on Day 7(2)	Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7	The pharmacokinetics parameters of ticagrelor on Day 7---tmax
Pharmacokinetics Parameters of Metabolite : Parent on Day 1--Cmax	Day 1	To determine Cmax ratio for the metabolite to that of the parent compound on Day 1
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 1(1)	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 AR-C124910XX (active metabolite) on Day 1---Cmax
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 1(3)	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 AR-C124910XX (active metabolite) on Day 1: tmax and t1/2
Safety---Physical Examination, Summary of Abnormalities	2 to 5 days after last dose	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Physical examination
Safety---Causally Related Adverse Events by System Organ Class and Preferred Term	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).	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
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(1)	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---Cmax
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(4)	Plasma concentration was measured at Pre-dose, 0.5, 1, 2, 3, 6 and 12 hours post dose on Day 7	Pharmacokinetics parameters of AR-C124910XX (active metabolite) on Day 7---tmax
Pharmacokinetics Parameters of Metabolite : Parent on Day 7---Cmax	Day 7	To determine Cmax ratio of metabolite to that of the parent compound on Day 7
Safety---All Allowed Concomitant Medications During Study Treatment	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.	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Concomitant medications
Pharmacokinetics Parameters of Ticagrelor on Day 7(3)	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---AUC(0-12h)
Pharmacokinetics Parameters of Ticagrelor on Day 7(4)	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---Accumulation ratio(ratio of Day 7 AUC(0-12h) to Day 1 AUC(0-12h))
Safety---Vital Signs Over Time---Height	Baseline	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)
Safety---Vital Signs Over Time---Weight	Baseline	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)
Safety---Vital Signs Over Time---Pulse Rate	Baseline, Day 1 to Day 7 and 2 to 5 days after last dose	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)
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 1(2)	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 AR-C124910XX (active metabolite) on Day 1---AUC(0-12h), AUC(0-t) and AUC(0-inf)
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(2)	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---AUC(0-12h)
Pharmacokinetics Parameters of Metabolite (AR-C124910XX) on Day 7(3)	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---Accumulation ratio(ratio of Day 7 AUC(0-12h) to Day 1 AUC(0-12h))
Safety---Hematology Laboratory Variables Over Time---Hemoglobin	2 to 5 days after last dose	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Hemoglobin
Safety---Hematology Laboratory Variables Over Time---Leukocytes	2 to 5 days after last dose	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Leukocytes
Safety---Hematology Laboratory Variables Over Time---Platelets	2 to 5 days after last dose	The safety of ticagrelor in Chinese patients with stable coronary heart disease on chronic low dose ASA. Safety will be assessed by: • Haematology---Platelets
Safety---Clinical Chemistry Variables Over Time---Glucose	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Alanine Aminotransferase	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Aspartate Aminotransferase	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Alkaline Phosphatase	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Creatinine	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Total Bilirubin	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Sodium	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Potassium	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Chloride	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Phosphate	2 to 5 days after last dose	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
Safety---Clinical Chemistry Variables Over Time---Albumin	2 to 5 days after last dose	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
Pharmacokinetics Parameters of Metabolite : Parent on Day 1--AUC(0-inf)	Day 1	To determine AUC(0-inf) ratio for the metabolite to that of the parent compound on Day 1
Pharmacokinetics Parameters of Metabolite : Parent on Day 7---AUC(0-12h)	Day 7	To determine AUC(0-12h) ratio of metabolite to that of the parent compound on Day 7.