Ticagrelor China Pharmacokinetic/Pharmacodynamic Study

An 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

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

Study Overview

• Status: Completed
• Conditions: Stable Coronary Heart Disease (CHD)
• Intervention / Treatment: Drug: Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor)

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Research Site

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ticagrelor 45mg; 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.	Drug: Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor); 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).; Other Names: "Brilinta"(Ticagrelor)
Experimental: Ticagrelor 60mg; 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.	Drug: Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor); 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).; Other Names: "Brilinta"(Ticagrelor)
Experimental: Ticagrelor 90mg; 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.	Drug: Inhibition of Platelet Aggregation by "Brilinta"(Ticagrelor); 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).; Other Names: "Brilinta"(Ticagrelor)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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).	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	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])	Baseline, Day 1 to Day 7 and 2 to 5 days after last dose
Percent Change From Baseline in PRU 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.	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.	Day 1
TIPA(Max)---Day 7	The time to peak IPA (TIPAmax) was estimated for ADP-induced final extent IPA.	Day 7
AUEC(Final Extent) on Day 1	The area-under-the-effect curve (AUEC) was estimated for ADP-induced final extent IPA.	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.	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	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).	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	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	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	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	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	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	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	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	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	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	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	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	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)	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))	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)	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)	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)	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)	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)	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))	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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.	Day 7

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Haiyan Li, PhD, The 3rd Hospital of Peking University

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: February 12, 2014
• First Submitted That Met QC Criteria: February 14, 2014
• First Posted (Estimate): February 17, 2014

Study Record Updates

• Last Update Posted (Estimate): May 11, 2016
• Last Update Submitted That Met QC Criteria: April 5, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; 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
• Other Study ID Numbers: D5130C00086