Pharmacokinetics, Pharmacodynamics, and Safety Study of Ticagrelor in Hemodialysis Patients and Healthy Subjects

Study Overview
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Brief Summary
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A phase I, open-label study comparing the pharmacokinetics, pharmacodynamics, safety and tolerability of ticagrelor in hemodialysis patients to healthy subjects with normal renal function.

Detailed Description
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This will be a single dose, randomised, open label, parallel group study conducted in the US to examine the Pharmacokinetics (PK), Pharmacodynamics (PD), safety, and tolerability of ticagrelor in end stage renal disease (ESRD) subjects on hemodialysis (HD) compared with healthy subjects with normal renal function. Up to a total of 30 male and female adult subjects aged 18 to 80 years (inclusive) with a weight of at least 50 kg and a body mass index between 18 and 40 kg/m2 (inclusive), will be dosed to assure that there will be 20 evaluable subjects (10 subjects on HD and in 10 healthy subjects with normal renal function (CrCL ≥90 mL/min). The normal renal function groups should have a similar distribution with respect to age, weight and gender. Subjects will be required to have an inpatient stay from the day prior to dosing until the 48-hour post-dose time-point to ensure that all PK samples are collected at the appropriate timepoints. The study will be conducted in two groups: Group A consisting of ESRD subjects on HD, Group B consisting of healthy subjects. A crossover design will be implemented for Group A subjects as follows: Group A subjects will be randomized into two sequences, Sequence 1 and Sequence 2. In Sequence 1, subjects will receive treatment A in Period 1 and treatment B in Period 2. There will be washout period of at least 7 days between Period 1 and Period 2 in Sequence 1. Similarly in Sequence 2, subjects will receive treatment B in Period 1 and treatment A in Period 2. There will be a washout period of at least 7 days between Period 1 and Period 2 in Sequence 2 as well. Treatment A and treatment B are defined as follows: Treatment A: subjects will be dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session; • Treatment B: subjects will be dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.(NB: Treatment B dosing should occur within 5 minutes of dialysis start). Group B subjects (healthy subjects) with normal renal function (CrCL of ≥ 90 mL/min) will receive just an oral 90 mg ticagrelor referred to as treatment H. All doses will be administered in an open-label design.

Official Title
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A Single Dose, Randomized, Open-Label, Parallel Group Study Comparing the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Ticagrelor in Hemodialysis Patients to Subjects With Normal Renal Function

Conditions
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Kidney Failure, Chronic

Intervention / Treatment
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* Drug: ticagrelor
* Drug: ticagrelor
* Drug: ticagrelor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female aged 18 to 80 years (inclusive). Normal renal function (CrCl of ≥90 mL/min) or End Stage Renal Disease (ESRD) requiring hemodialysis. Exclusion Criteria: Any indication for oral anticoagulant or anti platelet treatment during study period. Must be off treatment for at least 3 weeks (low dose 81mg aspirin is allowed for hemodialysis subjects only). Acute Coronary Syndrome (ACS) within past 12 months. Contraindications to ticagrelor (ie: active pathological bleeding, severe hepatic impairment, history of hemorrhagic stroke, allergic to ticagrelor). Platelet count <100000/μL, hemoglobin <9g/dL Blood donation within 90 days of dosing Risk for bradycardia Investigational drug within 30 days or 6 half-lives, whichever is longer, before dosing Concomitant therapy with CYP3A inhibitors/substrates with narrow therapeutic index,or strong CYP3A inducers 14 days before dosing until completion of the follow-up visit. History of alcohol, drug, or substance abuse within the past year Clinically significant laboratory abnormalities as judged by the investigator. Increased bleeding risk including GI bleeding in past 30 days; history of intracranial, retroperitoneal, or spinal bleeding, recent major trauma within 30 days of dosing, Sustained uncontrolled hypertension, history of hemorrhagic disorders. Pregnant or lactating females, or females of child-bearing potential (ie, those who are not chemically or surgically sterilised or who are not post-menopause) who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator throughout the duration of the study OR females who have a positive pregnancy test at Visit 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1<br>hemodialysis patients: subjects will receive treatment A (ticagrelor oral 90 mg 1 day following the dialysis session but 2 days before the next dialysis session) in period 1 and treatment B (ticagrelor oral 90 mg just prior to dialysis session) in period 2. | Drug: ticagrelor<br>* Group A is hemodialysis subjects. Crossover design will be implemented for Group A subjects. Group A will be randomized into 2 sequences, Sequence 1 and Sequence 2. In Sequence 1, subjects will receive treatment A in Period 1 and treatment B in Period 2. Washout period of at least 7 days between Period 1 and Period 2 in Sequence 1. Treatment A and Treatment B are defined as follows: Treatment A subjects will be dosed with oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session. Treatment B will be dosed with oral 90 mg ticagrelor tablet just prior to dialysis session.<br>* Other names: Brilinta;|
| Experimental: Sequence 2<br>hemodialysis patients: subjects will receive treatment B (ticagrelor oral 90 mg just prior to dialysis session) in period 1 and treatment A (ticagrelor oral 90 mg 1 day following the dialysis session but 2 days before the next dialysis session) in period 2. | Drug: ticagrelor<br>* Group A is hemodialysis subjects. Crossover design will be implemented for Group A subjects. Group A will be randomized into 2 sequences, Sequence 1 and Sequence 2. In Sequence 2, subjects will receive treatment B in Period 1 and treatment A in Period 2. Washout period of at least 7 days between Period 1 and Period 2 in Sequence 2. Treatment A and Treatment B are defined as follows: Treatment A subjects will be dosed with oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session. Treatment B will be dosed with oral 90 mg ticagrelor tablet just prior to dialysis session.<br>* Other names: Brilinta;|
| Experimental: Treatment H<br>Healthy subjects: ticagrelor oral 90 mg on 1 day of treatment | Drug: ticagrelor<br>* Group B is healthy subjects. Group B healthy subjects will receive oral 90 mg ticagrelor referred to as Treatment H.<br>* Other names: Brilinta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameter Cmax of Ticagrelor |  | 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose | 
| Pharmacokinetic Parameter Cmax of AR-C124910XX |  | 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose | 
| Pharmacokinetic Parameter AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time Zero to Infinity) of Ticagrelor |  | 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose | 
| Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX |  | 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameter t1/2 of Ticagrelor |  | 3 days | 
| Pharmacokinetic Parameter t1/2 of AR-C124910XX |  | 3 days |