Ticagrelor China Pharmacokinetic/Pharmacodynamic Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Stable Coronary Heart Disease (CHD)

Intervention / Treatment
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* Drug: Inhibition of Platelet Aggregation by Brilinta(Ticagrelor)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor 45mg<br>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)<br>* 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).<br>* Other names: Brilinta(Ticagrelor);|
| Experimental: Ticagrelor 60mg<br>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)<br>* 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).<br>* Other names: Brilinta(Ticagrelor);|
| Experimental: Ticagrelor 90mg<br>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)<br>* 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).<br>* Other names: Brilinta(Ticagrelor);|

What is the study measuring?
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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 |