Study to Assess the Bioavailability of Ticagrelor OD Tablet vs. IR Tablet

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

Detailed Description
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Study to evaluate the bioavailability of ticagrelor OD tablets administered with water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets.

Official Title
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An Open-label, Randomised, Four-period, Four-treatment, Crossover, Single-centre, Single-dose Study to Assess the Bioavailability of Ticagrelor Orodispersible Tablets, Compared to Ticagrelor Immediate-release Tablets in Healthy Subjects

Conditions
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Bioavailability, Healthy Subjects

Intervention / Treatment
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* Drug: Ticagrelor OD tablet (90 mg single dose) administered with 200 ml of water
* Drug: Ticagrelor OD tablet (90 mg single dose) administered without water
* Drug: Ticagrelor OD tablet (90 mg single dose) suspended in water administered via nasogastric tube
* Drug: Brilique®, Ticagrelor IR tablet (90 mg) administered with 200mL of water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture. - 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 amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the postmenopausal range or Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. - Have a body mass index (BMI) between 18.5 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. -Able to understand, read and speak the German language. 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 influence the results or the potential subject's ability to participate in the study. Any abnormalities in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), urea, creatinine, thyroid-stimulating hormone (TSH), International Normalised Ratio (INR), activated partial thromboplastin time (aPTT), white blood cell (WBC) count, haemoglobin (Hb) or platelet count. Any other abnormal haematology, clinical chemistry, coagulation or urinalysis results, as judged with an unacceptable deviation that is considered to be clinically significant by the investigator. Any clinically significant abnormal findings in vital signs, as judged by the investigator. at screening and at baseline (Day -1 of Treatment period 1), defined as: Systolic blood pressure < 90mmHg or ≥ 140 mmHg Diastolic blood pressure < 50mmHg or ≥ 90 mmHg Pulse < 50 or > 85 beats per minute (bpm) Current smokers or those who have smoked or used nicotine products within the previous 3 months. History of haemophilia, 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 haemorrhage, hematemesis, melena, haemoptysis, severe epistaxis, severe thrombocytopenia, intracranial haemorrhage; 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 randomisation. Platelet count less than 150 x 109/L. Criteria applicable to insertion of a nasogastric tube: History of severe midface trauma and/or recent nasal surgery. History of coagulation abnormality, oesophageal varices or stricture, recent banding or cautery of oesophageal varices, and/or alkaline ingestion, at the discretion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Treatments A-D-B-C sequence<br>Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 200 ml of water<br>* 90 mg single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* 90 mg single dose<br>* Other names: Treatment B;Drug: Ticagrelor OD tablet (90 mg single dose) suspended in water administered via nasogastric tube<br>* 90 mg single dose<br>* Other names: Treatment C;Drug: Brilique®, Ticagrelor IR tablet (90 mg) administered with 200mL of water<br>* 90 mg single dose<br>* Other names: Treatment D;|
| Experimental: Treatments B-A-C-D sequence<br>Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 200 ml of water<br>* 90 mg single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* 90 mg single dose<br>* Other names: Treatment B;Drug: Ticagrelor OD tablet (90 mg single dose) suspended in water administered via nasogastric tube<br>* 90 mg single dose<br>* Other names: Treatment C;Drug: Brilique®, Ticagrelor IR tablet (90 mg) administered with 200mL of water<br>* 90 mg single dose<br>* Other names: Treatment D;|
| Experimental: Treatments C-B-D-A sequence<br>Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 200 ml of water<br>* 90 mg single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* 90 mg single dose<br>* Other names: Treatment B;Drug: Ticagrelor OD tablet (90 mg single dose) suspended in water administered via nasogastric tube<br>* 90 mg single dose<br>* Other names: Treatment C;Drug: Brilique®, Ticagrelor IR tablet (90 mg) administered with 200mL of water<br>* 90 mg single dose<br>* Other names: Treatment D;|
| Experimental: Treatments D-C-A-B sequence<br>Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4 | Drug: Ticagrelor OD tablet (90 mg single dose) administered with 200 ml of water<br>* 90 mg single dose<br>* Other names: Treatment A;Drug: Ticagrelor OD tablet (90 mg single dose) administered without water<br>* 90 mg single dose<br>* Other names: Treatment B;Drug: Ticagrelor OD tablet (90 mg single dose) suspended in water administered via nasogastric tube<br>* 90 mg single dose<br>* Other names: Treatment C;Drug: Brilique®, Ticagrelor IR tablet (90 mg) administered with 200mL of water<br>* 90 mg single dose<br>* Other names: Treatment D;|

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. | Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 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. | Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 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 [0-∞]). | Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 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. | Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 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. | Blood samples for the determination of plasma concentrations of both ticagrelor and AR-C124910XX were collected at pre-dose (0 hours) and post-dose at 0.5, 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 Cmax to Parent Cmax, Adjusted for Differences in Molecular Weights (MRCmax) of Metabolite AR-C124910XX. | Assesssment 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 water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets. | 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 Metabolite AR-C124910XX. | Assesssment 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 water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets. | 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-∞] to Parent AUC [0-∞], Adjusted for Differences in Molecular Weights (MRAUC [0-∞]) of Metabolite AR-C124910XX. | Assesssment of MRAUC [0-∞] (Ratio of metabolite AUC [0-∞] to parent AUC [0-∞], adjusted for differences in molecular weights) of ticagrelor and its active metabolite AR-C124910XX following single doses of the OD tablet when administered with water, without water and suspended in water to be administered through nasogastric tubes, compared to ticagrelor IR tablets. | 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. | 
| Percentage 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. | SAEs were recorded from the signing of informed consent and AEs were recorded from randomisation until the final follow-up visit. | 
| 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 (2, 4 hours post-dose) and Day 2 (24 hours post-dose). | 
| Mean Change From Baseline for Vital Signs in Supine Pulse Rate. | Vital signs were collected after the participant has rested in the supine position for at least 5 minutes. | Day 1 (2, 4 hours post-dose) and Day 2 (24 hours post-dose). | 
| 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. | 
| 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, at admission on Day -1 to each treatment period and at follow-up. | 

 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, relative bioavailability, Phase I, healthy subjects