A Pharmacodynamic Study With Ticagrelor in African American Patients

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01523392
• Collaborator: (none)
• Enrollment: 50
• Locations: 8
• Arms: 2
• Duration (Months): 18
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the pharmacodynamic effect of ticagrelor in African American patients with stable coronary artery disease.

Condition or Disease	Intervention/Treatment	Phase
Stable Coronary Artery Disease	Drug: Ticagrelor; Drug: Clopidogrel	Phase 4

Detailed Description

A Randomized, Open-Label, Multiple Dose, Crossover, Multiple Center Study of the Antiplatelet Effects of Ticagrelor versus Clopidogrel in African American Patients with Stable Coronary Artery Disease

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Multiple Dose, Crossover, Multiple Center Study of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in African American Patients With Stable Coronary Artery Disease
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ticagrelor	Drug: Ticagrelor; Min - 90mg/Max - 180mg tablets (loading dose)
Active Comparator: Clopidogrel	Drug: Clopidogrel; 75mg (once daily)/Max - 600mg tablets (loading dose)

Outcome Measures

Primary Outcome Measures

1. Inhibition of the P2Y12 Receptor as Measured by Platelet Reaction Unit (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose [At 2 hours after the loading dose]

Secondary Outcome Measures

1. Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose [At 0.5 hour and 8 hours after the loading dose]

2. Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8 [At 2 hours and 8 hours on Day 7 after multiple doses and at end of dosing interval on Day 8]

3. Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses [Predose, 0.5 hour, 2 hours, 8 hours from loading dose; 0, 2 hours, 8 hours and 12 hours from last dose]

   The standard deviation (SD) is the geometric SD

4. AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses [Predose, 0.5 hour, 2 hours, 8 hours from loading dose and 0, 2 hours, 8 hours and 12 hours from last dose]

   The standard deviation (SD) is the geometric SD

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provision of signed and dated informed consent before initiation of any study-related procedures

• Male or female patients aged 18 years or older

• Documented stable CAD fulfilling and taking 75-100mg ASA daily treatment

• Females must be post menopausal or surgically sterile Self-identified as African American

Exclusion Criteria:

• Any indication for oral anticoagulant (e.g., atrial fibrillation, mitral stenosis or prosthetic heart valve) or dual antiplatelet treatment (e.g., clopidogrel, prasugrel, ASA dose other than 75 to 100 mg daily) during study period

• Patients who had ACS or stent placed within 12 months of screening Patients with a history of moderate or severe hepatic impairment

• Current smokers, including the use of tobacco containing products in the past 1 month of randomization Patients required dialysis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Newark	Delaware	United States
2	Research Site	Wilmington	Delaware	United States
3	Research Site	Washington	District of Columbia	United States
4	Research Site	Hollywood	Florida	United States
5	Research Site	Jacksonville	Florida	United States
6	Research Site	Atlanta	Georgia	United States
7	Research Site	Towson	Maryland	United States
8	Research Site	Beaumont	Texas	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Glenn Carlson, MD, AstraZeneca Pharmaceuticals Room C3B-718PO Box 15437 Wilmington, DE 19850-5437 USA

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D5130L00013_Study_Synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01523392
• Other Study ID Numbers: D5130L00013
• First Posted: Feb 1, 2012
• Last Update Posted: Oct 8, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by AstraZeneca: Stable Coronary Artery Disease, CAD
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Clopidogrel; Ticagrelor

Study Results

Participant Flow

Recruitment Details	Patients recruited from 8 participating centers in the United States from 28 March 2012 until 04 September 2013
Pre-assignment Detail	50 patients screened; 34 patients randomized; 30 patients completed the study (7, 8, or 9 days of both treatments), and 31 completed follow-up

Arm/Group Title	Ticagrelor (Period 1) Then Clopidogrel (Period 2) Sequence	Clopidogrel (Period 1) Then Ticagrelor (Period 2) Sequence
Arm/Group Description	Ticagrelor 180 milligrams (mg) loading dose followed by 90 mg twice daily (bd) for 7, 8 or 9 days (Period 1), and then clopidogrel 600 mg loading dose followed by 75 mg once daily (od) for 7, 8 or 9 days (Period 2)	Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days (Period 1), and then ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days (Period 2)
Period Title: Treatment Period 1
STARTED	20	14
COMPLETED	17	14
NOT COMPLETED	3	0
Period Title: Treatment Period 1
STARTED	18	14
COMPLETED	17	14
NOT COMPLETED	1	0
Period Title: Treatment Period 1
STARTED	17	14
COMPLETED	17	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ticagrelor (Period 1) Then Clopidogrel (Period 2) Sequence	Clopidogrel (Period 1) Then Ticagrelor (Period 2) Sequence	Total
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days (Period 1), and then clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days (Period 2)	Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days (Period 1), and then ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days (Period 2)	Total of all reporting groups
Overall Participants	20	14	34
Age, Customized (Number) [Number]
<18 years	0 0%	0 0%	0 0%
>=18 to <65 years	12 60%	10 71.4%	22 64.7%
>= 65 years	8 40%	4 28.6%	12 35.3%
Sex: Female, Male (Count of Participants)
Female	8 40%	3 21.4%	11 32.4%
Male	12 60%	11 78.6%	23 67.6%
Race/Ethnicity, Customized (Number) [Number]
Black or African American	20 100%	14 100%	34 100%
Race/Ethnicity, Customized (Number) [Number]
Not Hispanic or Latino	20 100%	14 100%	34 100%
Region of Enrollment (Number) [Number]
United States	20 100%	14 100%	34 100%

Outcome Measures

1. Primary Outcome

Title	Inhibition of the P2Y12 Receptor as Measured by Platelet Reaction Unit (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose
Time Frame	At 2 hours after the loading dose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) Analysis Set (N=32) - included all participants for whom PD data was available with no major protocol deviations thought to significantly affect the PD of ticagrelor or clopidogrel

Arm/Group Title	Ticagrelor	Clopidogrel
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days	Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days
Measure Participants	29	28
Least Squares Mean (95% Confidence Interval) [PRU]	27.6	211.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Model contained treatment group, period, and sequence as fixed effects and a random effect for patient within sequence
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-183.6
	Confidence Interval	(2-Sided) 95%; -213.9 to -153.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.68
	Estimation Comments	Ticagrelor minus clopidogrel

2. Secondary Outcome

Title	Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 Hour and 8 Hours After Loading Dose
Time Frame	At 0.5 hour and 8 hours after the loading dose

Outcome Measure Data

Analysis Population Description

PD Analysis Set

Arm/Group Title	Ticagrelor	Clopidogrel
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days	Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days
Measure Participants	29	28
0.5 hours	166.3	270.1
8 hours (N=28 ticagrelor, N=27 clopidogrel)	27.2	192.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments	Analysis at 0.5 hours after loading dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Model contained treatment group, period, and sequence as fixed effects, and a random effect for participant within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-103.8
	Confidence Interval	(2-Sided) 95%; -142.5 to -65.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.79
	Estimation Comments	Ticagrelor minus clopidogrel

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments	Analysis at 8 hours after loading dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Model contained treatment group, period, and sequence as fixed effects, and a random effect for participant within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-165.3
	Confidence Interval	(2-Sided) 95%; -197.4 to -133.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.45
	Estimation Comments	Ticagrelor minus clopidogrel

3. Secondary Outcome

Title	Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 Hours and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8
Time Frame	At 2 hours and 8 hours on Day 7 after multiple doses and at end of dosing interval on Day 8

Outcome Measure Data

Analysis Population Description

PD Analysis Set

Arm/Group Title	Ticagrelor	Clopidogrel
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days	Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days
Measure Participants	28	27
2 hours on Day 7 (N=27 for clopidogrel)	22.9	157.8
8 hours on Day 7	28.5	146.5
End of dosing interval on Day 8	39.3	172.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments	Analysis at 2 hours on Day 7 after multiple doses
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Model contained treatment group, period, and sequence as fixed effects, and a random effect for participant within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-135.0
	Confidence Interval	(2-Sided) 95%; -160.4 to -109.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.35
	Estimation Comments	Ticagrelor minus clopidogrel

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments	Analysis at 8 hours on Day 7 after multiple doses
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Model contained treatment group, period, and sequence as fixed effects, and a random effect for participant within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-118.1
	Confidence Interval	(2-Sided) 95%; -143.9 to -92.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.55
	Estimation Comments	Ticagrelor minus clopidogrel

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Clopidogrel
	Comments	Analysis at end of dosing interval on Day 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Model contained treatment group, period, and sequence as fixed effects, and a random effect for participant within sequence
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-133.4
	Confidence Interval	(2-Sided) 95%; -159.7 to -107.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.77
	Estimation Comments	Ticagrelor minus clopidogrel

4. Secondary Outcome

Title	Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses
Description	The standard deviation (SD) is the geometric SD
Time Frame	Predose, 0.5 hour, 2 hours, 8 hours from loading dose; 0, 2 hours, 8 hours and 12 hours from last dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Analysis Set - included all patients for whom at least one valid PK reading was available

Arm/Group Title	Ticagrelor (Treatment Period 1)	Ticagrelor (Treatment Period 2)
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days
Measure Participants	20	11
Baseline (0 pre-dose hours)	1.0 (1.0)	1.2 (1.8)
0.5 hours after the loading dose	206.6 (5.2)	33.7 (8.2)
2 hours after the loading dose	1167.3 (1.8)	756.9 (1.9)
8 hours after the loading dose - Period 1 N=19	395.9 (1.5)	141.9 (12.1)
0 hours after multiple doses - Period 1 N=18	168.4 (7.3)	187.4 (2.1)
2 hours after multiple doses - Period 1 N=18	324.6 (8.9)	608.8 (1.9)
8 hours after multiple doses - Period 1 N=18	179.2 (7.4)	311.3 (1.7)
End of dosing interval on Day 8 - Period 1 N=18	284.9 (2.2)	295.7 (1.9)

5. Secondary Outcome

Title	AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses
Description	The standard deviation (SD) is the geometric SD
Time Frame	Predose, 0.5 hour, 2 hours, 8 hours from loading dose and 0, 2 hours, 8 hours and 12 hours from last dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Analysis Set - included all patients for whom at least one valid PK reading was available

Arm/Group Title	Ticagrelor (Treatment Period 1)	Ticagrelor (Treatment Period 2)
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days
Measure Participants	20	11
Baseline (0 pre-dose hours)	1.0 (1.0)	1.0 (1.0)
0.5 hours after the loading dose	9.8 (4.9)	2.3 (3.2)
2 hours after the loading dose	222.6 (2.7)	150.9 (2.5)
8 hours after the loading dose - Period 1 N=19	119.0 (1.7)	54.8 (7.5)
0 hours after multiple doses - Period 1 N=18	93.2 (5.8)	74.5 (2.0)
2 hours after multiple doses - Period 1 N=18	136.7 (6.3)	172.3 (1.7)
8 hours after multiple doses - Period 1 N=18	89.8 (5.6)	112.6 (1.3)
End of dosing interval on Day 8 - Period 1 N=18	140.8 (1.9)	110.3 (1.4)

Adverse Events

Time Frame	Adverse events were collected from the time of signature of the informed consent throughout the treatment period including the follow up visit (approximately 11 weeks for each participant).
Adverse Event Reporting Description	Adverse events were solicited at each scheduled visit and could be reported by the participant at any time during the study. When summarizing Treatment Period 1 and Treatment Period 2 totals, each participant was counted only once for an individual adverse event, regardless of whether it occurred on ticagrelor, clopidogrel or both.
Arm/Group Title	Ticagrelor		Clopidogrel
Arm/Group Description	Ticagrelor 180 mg loading dose followed by 90 mg bd for 7, 8 or 9 days		Clopidogrel 600 mg loading dose followed by 75 mg od for 7, 8 or 9 days
All Cause Mortality
	Ticagrelor		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ticagrelor		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)		0/31 (0%)
Cardiac disorders
Acute Myocardial Infarction	1/34 (2.9%)	1	0/31 (0%)	0
Other (Not Including Serious) Adverse Events
	Ticagrelor		Clopidogrel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/34 (14.7%)		2/31 (6.5%)
Gastrointestinal disorders
Haemorroidal haemorrhage	1/34 (2.9%)		0/31 (0%)
General disorders
Application site bruise	0/34 (0%)		1/31 (3.2%)
Vessel puncture site bruise	0/34 (0%)		1/31 (3.2%)
Injury, poisoning and procedural complications
Contusion	1/34 (2.9%)		0/31 (0%)
Investigations
Blood glucose decreased	1/34 (2.9%)		0/31 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/34 (0%)		1/31 (3.2%)
Reproductive system and breast disorders
Vaginal haemmorhage	0/34 (0%)		1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/34 (2.9%)		0/31 (0%)
Dyspnoea	2/34 (5.9%)		0/31 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

An Investigator agrees to provide a copy of the publication to AstraZeneca (AZ) for review at least 60 days in advance of the submission for publication. The Investigators in the Multi-Center (MC) study agree to postpone MC publications until the earlier of the first AstraZeneca-authorized publication or up to eighteen months from study completion at all sites.