Kidney Failure, Chronic
Conditions
Brief summary
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
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.
Interventions
DRUGticagrelor
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.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| 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
| Measure | Time frame |
|---|---|
| Pharmacokinetic Parameter t1/2 of Ticagrelor | 3 days |
| Pharmacokinetic Parameter t1/2 of AR-C124910XX | 3 days |
Countries
United States
Participant flow
Recruitment details
56 subjects signed ICF, 34 Hemodialysis (HD) subjects and 22 Healthy subjects (HS) at 2 study centers in the US. 27 subjects received treatment (14 HD and 13 HS). First patient signed ICF on 29 December 2013. Due to protocol amendment, the first patient was randomized 22 months later on 20 October 2015, last patient last visit was 09 May 2016.
Pre-assignment details
21 out of 34 HD subjects were randomized (13 failed to fulfill eligibility criteria) and 14 were eligible after eligibility re-assessment (5 no longer met the eligibility criteria and 2 experienced Adverse Events (AE) prior to treatment). 13 out of 22 HS were eligible to be treated (9 failed to meet the eligibility criteria).
Participants by arm
| Arm | Count |
|---|---|
| HD Subjects Hemodialysis subjects | 14 |
| HS Subjects Healthy subjects | 13 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | HD Subjects | HS Subjects | Total |
|---|---|---|---|
| Age, Continuous | 50.6 years STANDARD_DEVIATION 12.5 | 43.8 years STANDARD_DEVIATION 10.4 | 47.3 years STANDARD_DEVIATION 11.8 |
| BMI | 27.77 kg/m^2 STANDARD_DEVIATION 4.18 | 28.27 kg/m^2 STANDARD_DEVIATION 3.75 | 28.01 kg/m^2 STANDARD_DEVIATION 3.91 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 22 Participants |
| Weight | 85.1 kg STANDARD_DEVIATION 18.3 | 89.0 kg STANDARD_DEVIATION 16.2 | 87.0 kg STANDARD_DEVIATION 17.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 3 / 13 | 2 / 13 |
| serious Total, serious adverse events | 0 / 12 | 1 / 13 | 0 / 13 |
Outcome results
Primary
Pharmacokinetic Parameter AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time Zero to Infinity) of Ticagrelor
Time frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Population: The PK analysis set included all subjects who received at least 1 dose of study medication and for whom PK data are available with no major protocol deviations thought to significantly affect the pharmacokinetics of ticagrelor or its active metabolite AR-C124910XX.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Pharmacokinetic Parameter AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time Zero to Infinity) of Ticagrelor | 3015.1 ng*h/mL | Geometric Coefficient of Variation 54.2 |
| Treatment B | Pharmacokinetic Parameter AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time Zero to Infinity) of Ticagrelor | 3256.1 ng*h/mL | Geometric Coefficient of Variation 52.5 |
| Treatment H | Pharmacokinetic Parameter AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time Zero to Infinity) of Ticagrelor | 2188.8 ng*h/mL | Geometric Coefficient of Variation 22.6 |
90% CI: [105.7, 179.52]
90% CI: [115.07, 192.32]
90% CI: [77.55, 105.27]
Primary
Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX
Time frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Population: The PK analysis set included all subjects who received at least 1 dose of study medication and for whom PK data are available with no major protocol deviations thought to significantly affect the pharmacokinetics of ticagrelor or its active metabolite AR-C124910XX.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX | 1127.8 ng*h/mL | Geometric Coefficient of Variation 39.3 |
| Treatment B | Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX | 1144.2 ng*h/mL | Geometric Coefficient of Variation 36.2 |
| Treatment H | Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX | 1000.4 ng*h/mL | Geometric Coefficient of Variation 33.2 |
90% CI: [88.61, 143.42]
90% CI: [91.19, 143.45]
90% CI: [80.31, 108]
Primary
Pharmacokinetic Parameter Cmax of AR-C124910XX
Time frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Population: The PK analysis set included all subjects who received at least 1 dose of study medication and for whom PK data are available with no major protocol deviations thought to significantly affect the pharmacokinetics of ticagrelor or its active metabolite AR-C124910XX.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Pharmacokinetic Parameter Cmax of AR-C124910XX | 130.82 ng/mL | Geometric Coefficient of Variation 38.3 |
| Treatment B | Pharmacokinetic Parameter Cmax of AR-C124910XX | 152.25 ng/mL | Geometric Coefficient of Variation 54.3 |
| Treatment H | Pharmacokinetic Parameter Cmax of AR-C124910XX | 111.73 ng/mL | Geometric Coefficient of Variation 60 |
90% CI: [84.51, 162.22]
90% CI: [95.38, 194.7]
90% CI: [68.43, 98.96]
Primary
Pharmacokinetic Parameter Cmax of Ticagrelor
Time frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Population: The Pharmacokinetic (PK) analysis set included all subjects who received at least 1 dose of study medication and for whom PK data are available with no major protocol deviations thought to significantly affect the pharmacokinetics of ticagrelor or its active metabolite AR-C124910XX.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Pharmacokinetic Parameter Cmax of Ticagrelor | 560.32 ng/mL | Geometric Coefficient of Variation 54 |
| Treatment B | Pharmacokinetic Parameter Cmax of Ticagrelor | 598.35 ng/mL | Geometric Coefficient of Variation 47.9 |
| Treatment H | Pharmacokinetic Parameter Cmax of Ticagrelor | 370.76 ng/mL | Geometric Coefficient of Variation 37.3 |
90% CI: [112.03, 203.86]
90% CI: [122.52, 212.58]
90% CI: [78.07, 103.98]
Secondary
Pharmacokinetic Parameter t1/2 of AR-C124910XX
Time frame: 3 days
Population: The PK analysis set included all subjects who received at least 1 dose of study medication and for whom PK data are available with no major protocol deviations thought to significantly affect the pharmacokinetics of ticagrelor or its active metabolite AR-C124910XX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Pharmacokinetic Parameter t1/2 of AR-C124910XX | 7.574 hour | Standard Deviation 2.079 |
| Treatment B | Pharmacokinetic Parameter t1/2 of AR-C124910XX | 7.596 hour | Standard Deviation 1.757 |
| Treatment H | Pharmacokinetic Parameter t1/2 of AR-C124910XX | 8.644 hour | Standard Deviation 2.414 |
90% CI: [-2.62, 0.48]
90% CI: [-2.46, 0.37]
90% CI: [-1.27, 0.27]
Secondary
Pharmacokinetic Parameter t1/2 of Ticagrelor
Time frame: 3 days
Population: The PK analysis set included all subjects who received at least 1 dose of study medication and for whom PK data are available with no major protocol deviations thought to significantly affect the pharmacokinetics of ticagrelor or its active metabolite AR-C124910XX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Pharmacokinetic Parameter t1/2 of Ticagrelor | 8.303 hour | Standard Deviation 1.25 |
| Treatment B | Pharmacokinetic Parameter t1/2 of Ticagrelor | 8.691 hour | Standard Deviation 2.298 |
| Treatment H | Pharmacokinetic Parameter t1/2 of Ticagrelor | 8.412 hour | Standard Deviation 1.248 |
90% CI: [-0.97, 0.75]
90% CI: [-0.96, 1.52]
90% CI: [-1.73, 1.02]