Study to Assess the Bioequivalence Between Ticagrelor Orodispersible Tablets and Ticagrelor Immediate-release Tablets in Japanese Subjects

Study Overview
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Brief Summary
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This study will be an open-label, randomised, three-period, three-treatment, crossover study in healthy Japanese male and female of non-childbearing potential subjects, performed at a single study centre. The objective of the study is to assess the bioequivalence of ticagrelor orodispersible (OD) tablets when administered with water and without water and ticagrelor immediate-release (IR) tablets.

Detailed Description
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Study to evaluate the bioequivalence of ticagrelor orodispersible (OD) tablets administered with water and without water and ticagrelor immediate-release (IR) tablets.

Official Title
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An Open-label, Randomized, Three-period, Three-treatment, Crossover, Single-centre, Single-dose Study to Assess the Bioequivalence Between Ticagrelor Orodispersible Tablets and Ticagrelor Immediate-release Tablets in Healthy Japanese Subjects.

Conditions
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Bioequivalence, Healthy Japanese Subjects, Pharmacokinetics

Intervention / Treatment
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* Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water
* Drug: Ticagrelor OD tablet (90 mg single dose) administered without water
* Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female subjects aged 20 to 45 years with suitable veins for cannulation or repeated venepuncture. Be Japanese. Japanese is defined as having both parents and four grandparents who are Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan. Females must have a negative pregnancy test at screening and on each admission to the clinical unit, must not be lactating, and must be of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria: Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the postmenopausal range. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. Have a body mass index (BMI) between 18.0 and 27.0 kg/m2 inclusive and weigh at least 45 kg and no more than 85 kg inclusive. Be able and willing to communicate with the investigator and comply with all study procedures, including reproductive restrictions. Exclusion Criteria: - History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the potential subject at risk because of participation in the study, or influences the results or the potential subject's ability to participate in the study. Current smokers or those who have smoked or used nicotine products within the previous 3 months. History of hemophilia, von Willebrand's disease, lupus anticoagulant, or other diseases/syndromes that can either alter or increase the propensity for bleeding. A personal history of vascular abnormalities including aneurysms; a personal history of severe hemorrhage, hematemesis, melena, hemoptysis, severe epistaxis, severe thrombocytopenia, intracranial hemorrhage; or rectal bleeding within 1 year prior to screening; or history suggestive of peptic ulcer disease; or at the discretion of the investigator. History of a clinically significant non-traumatic bleed or clinically significant bleeding risk, as judged by the investigator. Use of aspirin, ibuprofen, non-steroidal anti-inflammatory drugs (NSAIDs), or any other drug known to increase the propensity for bleeding for 2 weeks before randomization. Platelet count less than 150 x 10^9/L.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence ABC<br>Treatment A in Period 1, Treatment B in Period 2 and Treatment C in Period 3 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment B;Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water<br>* Ticagrelor 90 mg IR tablet, single dose<br>* Other names: Treatment C;|
| Experimental: Sequence BCA<br>Treatment B in Period 1, Treatment C in Period 2 and Treatment A in Period 3 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment B;Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water<br>* Ticagrelor 90 mg IR tablet, single dose<br>* Other names: Treatment C;|
| Experimental: Sequence CAB<br>Treatment C in Period 1, Treatment A in Period 2 and Treatment B in Period 3 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment B;Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water<br>* Ticagrelor 90 mg IR tablet, single dose<br>* Other names: Treatment C;|
| Experimental: Sequence ACB<br>Treatment A in Period 1, Treatment C in Period 2 and Treatment B in Period 3 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment B;Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water<br>* Ticagrelor 90 mg IR tablet, single dose<br>* Other names: Treatment C;|
| Experimental: Sequence BAC<br>Treatment B in Period 1, Treatment A in Period 2 and Treatment C in Period 3 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment B;Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water<br>* Ticagrelor 90 mg IR tablet, single dose<br>* Other names: Treatment C;|
| Experimental: Sequence CBA<br>Treatment C in Period 1, Treatment B in Period 2 and Treatment A in Period 3 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 150 mL of water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* Ticagrelor 90 mg OD tablet, single dose<br>* Other names: Treatment B;Drug: Ticagrelor IR tablet (90 mg) administered with 150 mL of water<br>* Ticagrelor 90 mg IR tablet, single dose<br>* Other names: Treatment C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Ticagrelor and Its Active Metabolite AR-C124910XX. | Comparison of Cmax (maximum observed plasma concentration) of ticagrelor and its active metabolite AR-C124910XX following single doses of the orodispersible (OD) tablet - when administered with and without water - and ticagrelor immediate-release (IR) tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Analyte Concentration AUC (0-t) of Ticagrelor and Its Active Metabolite AR-C124910XX. | Comparison of AUC(0-t) (Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Area Under Plasma Concentration-time Curve From Zero to Infinity (AUC) of Ticagrelor and Its Active Metabolite AR-C124910XX. | Comparison of AUC (Area under plasma concentration-time curve from zero to infinity) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Observed Concentration (Tmax) of Ticagrelor and Its Active Metabolite AR-C124910XX. | Comparison of tmax (Time to reach maximum observed concentration) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz) of Ticagrelor and Its Active Metabolite AR-C124910XX. | Comparison of t½λz (half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Terminal Elimination Rate Constant (λz) of Ticagrelor and Its Active Metabolite, AR-C124910XX. | Comparison of terminal elimination rate constant (λz) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Mean Residence Time (MRT) of Ticagrelor and Its Active Metabolite AR-C124910XX | Comparison of MRT (mean residence time) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| MRCmax (Ratio of Metabolite Cmax to Parent Cmax, Adjusted for Differences in Molecular Weights) of Active Metabolite AR-C124910XX | Assessment of MRCmax (ratio of metabolite Cmax to parent Cmax, adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Ratio of Metabolite AUC(0-t) to Parent AUC(0-t), Adjusted for Differences in Molecular Weights (MRAUC [0-t]) of Active Metabolite AR-C124910XX | Assessment of MRAUC(0-t) (Ratio of metabolite AUC(0-t) to parent AUC(0-t), adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Ratio of Metabolite AUC to Parent AUC, Adjusted for Differences in Molecular Weights (MRAUC) of Active Metabolite AR-C124910XX | Assessment of MRAUC (Ratio of metabolite AUC to parent AUC, adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Number of Participants With Adverse Events (AEs) | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. The term AE is used generally to include any AE whether serious or non-serious. A serious AE (SAE) is an AE that fulfills one or more of the following criteria: results in death, is immediately life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; is a congenital abnormality or birth defect; is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above. | From the date of randomization (Day 1 of the first treatment period) until the final follow-up visit (5 to 10 days after last administration of IMP). | 
| Elimination Rate Constant (Kel) of Ticagrelor and Its Active Metabolite AR-C124910XX | Comparison of kel (elimination rate constant) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet - when administered with and without water - and ticagrelor IR tablet. Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX will be collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). | 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours in each treatment period. | 
| Mean Change From Baseline for Vital Signs of Supine Blood Pressure (SBP) and Diastolic BP (DBP) | The following variables were collected after the participants had rested in the supine position for at least 5 minutes: SBP and DBP. | Day 1 (pre dose, 2 hours, and 4 hours post dose) and Day 2 (24 hours post dose). | 
| Mean Change From Baseline for Vital Signs in Supine Pulse Rate. | Vital signs i.e. Pulse (beats per minute [bpm]) were collected after the participant has rested in the supine position for at least 5 minutes. | At Screening and at Follow-up (these two examinations are 7 to 8 weeks apart) and during treatment periods at pre-dose and post-dose at 2, 4 and 24 hours. | 
| Participants With Significant Findings in 12-Lead Electrocardiography (ECG). | A 12-lead ECG was obtained after the participant rested in supine position for at least 10 minutes. The study physician was to judge the overall interpretation as normal or abnormal. If abnormal, it was decided as to whether or not the abnormality was clinically significant and the reason for the abnormality was recorded. | At Screening and at Follow-up (these two examinations are 7 to 8 weeks apart). | 
| Participants With Clinically Significant Findings in Hematology, Clinical Chemistry and Urinalysis. | Participants were assessed through each laboratory variables for any significant abnormalities. Hematology assessments included white blood cell count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and others. Clinical chemistry assessment included testing levels of sodium, potassium, urea, creatinine, albumin, calcium, glucose (fasting) and others. Urinalysis assessment included glucose, protein, blood and microscopy (if positive for blood or protein). | At Screening and at Follow-up (these two examinations are 7 to 8 weeks apart). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ticagrelor orodispersible tablet, ticagrelor immediate-release tablet, bioequivalence, Phase I, healthy Japanese subjects