Pharmacokinetics, pharmacodynamics, and safety study of ticagrelor in hemodialysis patients and healthy subjects

Study identifier:D5130L00067

ClinicalTrials.gov identifier:NCT02022748

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

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

Medical condition

kidney failure, chronic

Phase

Phase 1

Healthy volunteers

Yes

Study drug

ticagrelor

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 80 Years

Date

Study Start Date: 29 Dec 2013

Primary Completion Date: 09 May 2016

Study Completion Date: 09 May 2016

Study design

Allocation: Randomized
Endpoint Classification: Pharmacokinetics/dynamics
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Jan 2018 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

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.

Location

Research Site

Minneapolis, MN, United States, 55404

Location

Research Site

Lakewood, CO, United States, 80228

Arms	Assigned Interventions
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 Name: 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 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 Name: Brilinta
Experimental: Treatment H Healthy subjects: ticagrelor oral 90 mg on 1 day of treatment	Drug: ticagrelor Group B is healthy subjects. Group B healthy subjects will receive oral 90 mg ticagrelor referred to as Treatment H. Other Name: Brilinta

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups

	Description
Sequence 1 (AB)	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.
Sequence 2 (BA)	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.
Treatment H	Healthy subjects: ticagrelor oral 90 mg on 1 day of treatment

Participant Flow: Overall Study

	Sequence 1 (AB)	Sequence 2 (BA)	Treatment H
STARTED	8	6	13
Subject who started treatment	8	6	13
Subjects who completed treatment	7	4	13
COMPLETED	7	4	13
NOT COMPLETED	1	2	0
Adverse Event	1	1	0
Withdrawal by Subject	0	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

All 14 randomized HD subjects after eligibility re-assessment (8 in Sequence 1 (AB) and 6 in Sequence 2 (BA)) and 13 eligibile HS are used for baseline analysis.

Reporting Groups

	Description
HD Subjects	Hemodialysis subjects
HS Subjects	Healthy subjects

Baseline Measures

	HD Subjects	HS Subjects	Total
Number of Participants [units: Participants]	14	13	27
Age Continuous [units: years] Mean ± Standard Deviation	50.6 ± 12.5	43.8 ± 10.4	47.3 ± 11.8
Gender, Male/Female [units: ]
Female	2	3	5
Male	12	10	22
Weight [units: kg] Mean ± Standard Deviation	85.1 ± 18.3	89.0 ± 16.2	87.0 ± 17.1
BMI [units: kg/m^2] Mean ± Standard Deviation	27.77 ± 4.18	28.27 ± 3.75	28.01 ± 3.91

Outcome Measures

1. Primary Outcome Measure: Pharmacokinetic Parameter Cmax of Ticagrelor [ Time Frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose ]

Measure Type	Primary
Measure Name	Pharmacokinetic Parameter Cmax of Ticagrelor
Measure Description
Time Frame	0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Measured Values

	Treatment A	Treatment B	Treatment H
Number of Participants Analyzed [units:participants]	12	13	13
Pharmacokinetic Parameter Cmax of Ticagrelor [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	560.32 (54.0%)	598.35 (47.9%)	370.76 (37.3%)

Statistical Analysis 1 for Pharmacokinetic Parameter Cmax of Ticagrelor

Groups^[1]	Treatment A, Treatment H
Other^[5]	151.13
90% Confidence Interval	( 112.03 to 203.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 2 for Pharmacokinetic Parameter Cmax of Ticagrelor

Groups^[1]	Treatment B, Treatment H
Other^[5]	161.38
90% Confidence Interval	( 122.52 to 212.58 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 3 for Pharmacokinetic Parameter Cmax of Ticagrelor

Groups^[1]	Treatment A, Treatment B
Other^[5]	90.10
90% Confidence Interval	( 78.07 to 103.98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	A linear mixed model with sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect, was used to analyze the natural log-transformed values of the PK parameters. Treatment B is the reference treatment.

2. Primary Outcome Measure: Pharmacokinetic Parameter Cmax of AR-C124910XX [ Time Frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose ]

Measure Type	Primary
Measure Name	Pharmacokinetic Parameter Cmax of AR-C124910XX
Measure Description
Time Frame	0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Measured Values

	Treatment A	Treatment B	Treatment H
Number of Participants Analyzed [units:participants]	12	13	13
Pharmacokinetic Parameter Cmax of AR-C124910XX [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	130.82 (38.3%)	152.25 (54.3%)	111.73 (60.0%)

Statistical Analysis 1 for Pharmacokinetic Parameter Cmax of AR-C124910XX

Groups^[1]	Treatment A, Treatment H
Other^[5]	117.09
90% Confidence Interval	( 84.51 to 162.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 2 for Pharmacokinetic Parameter Cmax of AR-C124910XX

Groups^[1]	Treatment B, Treatment H
Other^[5]	136.27
90% Confidence Interval	( 95.38 to 194.70 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 3 for Pharmacokinetic Parameter Cmax of AR-C124910XX

Groups^[1]	Treatment A, Treatment B
Other^[5]	82.29
90% Confidence Interval	( 68.43 to 98.96 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	A linear mixed model with sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect, was used to analyze the natural log-transformed values of the PK parameters. Treatment B is the reference treatment.

3. Primary Outcome Measure: 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 ]

Measure Type	Primary
Measure Name	Pharmacokinetic Parameter AUC0-∞ (Area under the plasma concentration-time curve from time zero to infinity) of Ticagrelor
Measure Description
Time Frame	0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Measured Values

	Treatment A	Treatment B	Treatment H
Number of Participants Analyzed [units:participants]	12	13	13
Pharmacokinetic Parameter AUC0-∞ (Area under the plasma concentration-time curve from time zero to infinity) of Ticagrelor [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)	3015.1 (54.2%)	3256.1 (52.5%)	2188.8 (22.6%)

Statistical Analysis 1 for Pharmacokinetic Parameter AUC0-∞ (Area under the plasma concentration-time curve from time zero to infinity) of Ticagrelor

Groups^[1]	Treatment A, Treatment H
Other^[5]	137.75
90% Confidence Interval	( 105.70 to 179.52 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 2 for Pharmacokinetic Parameter AUC0-∞ (Area under the plasma concentration-time curve from time zero to infinity) of Ticagrelor

Groups^[1]	Treatment B, Treatment H
Other^[5]	148.76
90% Confidence Interval	( 115.07 to 192.32 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 3 for Pharmacokinetic Parameter AUC0-∞ (Area under the plasma concentration-time curve from time zero to infinity) of Ticagrelor

Groups^[1]	Treatment A, Treatment B
Other^[5]	90.35
90% Confidence Interval	( 77.55 to 105.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	A linear mixed model with sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect, was used to analyze the natural log-transformed values of the PK parameters. Treatment B is the reference treatment.

4. Primary Outcome Measure: Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX [ Time Frame: 0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose ]

Measure Type	Primary
Measure Name	Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX
Measure Description
Time Frame	0, 1, 2, 4, 6, 12, 24, 36, 48 hours post-dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Measured Values

	Treatment A	Treatment B	Treatment H
Number of Participants Analyzed [units:participants]	12	13	13
Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)	1127.8 (39.3%)	1144.2 (36.2%)	1000.4 (33.2%)

Statistical Analysis 1 for Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX

Groups^[1]	Treatment A, Treatment H
Other^[5]	112.73
90% Confidence Interval	( 88.61 to 143.42 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 2 for Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX

Groups^[1]	Treatment B, Treatment H
Other^[5]	114.37
90% Confidence Interval	( 91.19 to 143.45 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment H is the reference treatment.

Statistical Analysis 3 for Pharmacokinetic Parameter AUC0-∞ of AR-C124910XX

Groups^[1]	Treatment A, Treatment B
Other^[5]	93.13
90% Confidence Interval	( 80.31 to 108.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	A linear mixed model with sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect, was used to analyze the natural log-transformed values of the PK parameters. Treatment B is the reference treatment.

5. Secondary Outcome Measure: Pharmacokinetic Parameter t1/2 of Ticagrelor [ Time Frame: 3 days ]

Measure Type	Secondary
Measure Name	Pharmacokinetic Parameter t1/2 of Ticagrelor
Measure Description
Time Frame	3 days
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Measured Values

	Treatment A	Treatment B	Treatment H
Number of Participants Analyzed [units:participants]	12	13	13
Pharmacokinetic Parameter t1/2 of Ticagrelor [units: hour] Mean (Standard Deviation)	8.303 (1.250)	8.691 (2.298)	8.412 (1.248)

Statistical Analysis 1 for Pharmacokinetic Parameter t1/2 of Ticagrelor

Groups^[1]	Treatment A, Treatment H
Mean Difference (Net)^[5]	-0.11
90% Confidence Interval	( -0.97 to 0.75 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment A - Treatment H.

Statistical Analysis 2 for Pharmacokinetic Parameter t1/2 of Ticagrelor

Groups^[1]	Treatment B, Treatment H
Mean Difference (Net)^[5]	0.28
90% Confidence Interval	( -0.96 to 1.52 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment B - Treatment H.

Statistical Analysis 3 for Pharmacokinetic Parameter t1/2 of Ticagrelor

Groups^[1]	Treatment A, Treatment B
Other^[5]	-0.36
90% Confidence Interval	( -1.73 to 1.02 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	A linear mixed model with sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect, was used to analyze the natural log-transformed values of the PK parameters. Treatment A - Treatment B.

6. Secondary Outcome Measure: Pharmacokinetic Parameter t1/2 of AR-C124910XX [ Time Frame: 3 days ]

Measure Type	Secondary
Measure Name	Pharmacokinetic Parameter t1/2 of AR-C124910XX
Measure Description
Time Frame	3 days
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Measured Values

	Treatment A	Treatment B	Treatment H
Number of Participants Analyzed [units:participants]	12	13	13
Pharmacokinetic Parameter t1/2 of AR-C124910XX [units: hour] Mean (Standard Deviation)	7.574 (2.079)	7.596 (1.757)	8.644 (2.414)

Statistical Analysis 1 for Pharmacokinetic Parameter t1/2 of AR-C124910XX

Groups^[1]	Treatment A, Treatment H
Mean Difference (Net)^[5]	-1.07
90% Confidence Interval	( -2.62 to 0.48 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment A - Treatment H.

Statistical Analysis 2 for Pharmacokinetic Parameter t1/2 of AR-C124910XX

Groups^[1]	Treatment B, Treatment H
Mean Difference (Net)^[5]	-1.05
90% Confidence Interval	( -2.46 to 0.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Treatment B - Treatment H.

Statistical Analysis 3 for Pharmacokinetic Parameter t1/2 of AR-C124910XX

Groups^[1]	Treatment A, Treatment B
Other^[5]	-0.50
90% Confidence Interval	( -1.27 to 0.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	A linear mixed model with sequence, period, and treatment as fixed effects, and subject-within-sequence as a random effect, was used to analyze the natural log-transformed values of the PK parameters. Treatment A - Treatment B.

Serious Adverse Events

Time Frame	Starting from the date of first dose of study medication to follow-up (5-10 days post discharge unit). For HD Subjects, events that occurred during the washout or follow-up periods are attributed to the previous treatment taken.
Additional Description	No text entered.

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Serious Adverse Events

Treatment A

Treatment B

Treatment H

Total, serious adverse events

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

Injury, poisoning and procedural complications

Thoracic vertebral fracture¹,^†

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Other Adverse Events

Time Frame	Starting from the date of first dose of study medication to follow-up (5-10 days post discharge unit). For HD Subjects, events that occurred during the washout or follow-up periods are attributed to the previous treatment taken.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Treatment A	HD subjects were dosed with an oral 90 mg ticagrelor tablet 1 day following the dialysis session but 2 days before the next dialysis session;
Treatment B	HD subjects were dosed with an oral 90 mg ticagrelor tablet just prior to dialysis session.
Treatment H	Healthy subjects (HS) with normal renal function (CrCL of ≥90 mL/min) received one oral 90 mg ticagrelor tablet

Other Adverse Events

Treatment A

Treatment B

Treatment H

Total, other (not including serious) adverse events

# participants affected / at risk

2/12 (16.67%)

3/13 (23.08%)

2/13 (15.38%)

Metabolism and nutrition disorders

Fluid overload¹,^†

# participants affected / at risk

1/12 (8.33%)

0/13 (0.00%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/12 (8.33%)

0/13 (0.00%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

0/12 (0.00%)

0/13 (0.00%)

1/13 (7.69%)

Nervous system disorders

Migraine¹,^†

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

Nervous system disorders

Restless legs syndrome¹,^†

# participants affected / at risk

0/12 (0.00%)

0/13 (0.00%)

1/13 (7.69%)

Respiratory, thoracic and mediastinal disorders

Bronchospasm¹,^†

# participants affected / at risk

1/12 (8.33%)

0/13 (0.00%)

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/12 (8.33%)

1/13 (7.69%)

0/13 (0.00%)

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

Musculoskeletal and connective tissue disorders

Osteoporosis¹,^†

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

General disorders

Tenderness¹,^†

# participants affected / at risk

0/12 (0.00%)

1/13 (7.69%)

0/13 (0.00%)

Injury, poisoning and procedural complications

Skin abrasion¹,^†

# participants affected / at risk

0/12 (0.00%)

0/13 (0.00%)

1/13 (7.69%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The PIs shall be entitled to publish or make presentations related to the Study within 2 years of completion of the Study with Sponsor's prior written consent. PIs shall provide the Sponsor with copies of any materials at least thirty (30) days in advance of publication, submission or presentation. All such publications or presentations shall be consistent with applicable standards, guidelines and laws, not be false or misleading, and not be made for any commercial purpose.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	Naeem Khan, MD
Organization:	AstraZeneca Pharmaceuticals LP
Phone	+1 302-885-8976
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

DaVita Clinical Research (DCF)

1-855-327-7883

Investigators

Principal Investigator

Jolene K Berg

DaVita Clinical Research, Minneapolis, MN

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Trial Results Summaries