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

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

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.

Study Overview

• Status: Completed
• Conditions: Kidney Failure, Chronic
• Intervention / Treatment: Drug: ticagrelor; Drug: ticagrelor; Drug: ticagrelor

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Lakewood, Colorado, United States, 80228
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sequence 1; 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; 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.; Other Names: Brilinta; Drug: ticagrelor; 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.; Other Names: Brilinta; Drug: ticagrelor; Group B is healthy subjects. Group B healthy subjects will receive oral 90 mg ticagrelor referred to as Treatment H.; Other Names: Brilinta
EXPERIMENTAL: Sequence 2; 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; 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.; Other Names: Brilinta; Drug: ticagrelor; 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.; Other Names: Brilinta; Drug: ticagrelor; Group B is healthy subjects. Group B healthy subjects will receive oral 90 mg ticagrelor referred to as Treatment H.; Other Names: Brilinta
EXPERIMENTAL: Treatment H; Healthy subjects: ticagrelor oral 90 mg on 1 day of treatment	Drug: ticagrelor; 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.; Other Names: Brilinta; Drug: ticagrelor; 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.; Other Names: Brilinta; Drug: ticagrelor; Group B is healthy subjects. Group B healthy subjects will receive oral 90 mg ticagrelor referred to as Treatment H.; Other Names: Brilinta

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Jolene K Berg, MD, DaVita Clinical Research, Minneapolis, MN

Publications and helpful links

General Publications

• Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 29, 2013
• Primary Completion (ACTUAL): May 9, 2016
• Study Completion (ACTUAL): May 9, 2016

Study Registration Dates

• First Submitted: December 22, 2013
• First Submitted That Met QC Criteria: December 22, 2013
• First Posted (ESTIMATE): December 30, 2013

Study Record Updates

• Last Update Posted (ACTUAL): January 17, 2018
• Last Update Submitted That Met QC Criteria: January 12, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Renal Insufficiency; 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: D5130L00067