A Pharmacodynamic Study With Ticagrelor in Hispanic Patients

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01523366
• Collaborator: (none)
• Enrollment: 53
• Locations: 5
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 10.6
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the pharmacodynamic effect of ticagrelor in Hispanic 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 Hispanic Patients with Stable Coronary Artery Disease

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 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 Hispanic Patients With Stable Coronary Artery Disease
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 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 P2Y12 Reactions Units (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose [At 2 hours after the loading dose]

   Participants with low (<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value

Secondary Outcome Measures

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

   Participants with low (<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value

2. Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 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 the end of dosing interval on Day 8]

   The end of dosing interval was approximately 12 hours after the last evening dose of ticagrelor and approximately 24 hours after the last morning dose of clopidogrel. Participants with low (<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value

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

   The standard deviation (SD) is a statistic using the log-transformed data and is not the geometric SD.

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

   The SD is a statistic using the log-transformed data and is not 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 Hispanic

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 requiring dialysis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States
2	Research Site	Hollywood	Florida	United States
3	Research Site	Jacksonville	Florida	United States
4	Research Site	Miami	Florida	United States
5	Research Site	Linden	New Jersey	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D5130L00012_Clinical_Study_Protocol_Redacted
• CSR_Synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01523366
• Other Study ID Numbers: D5130L00012
• First Posted: Feb 1, 2012
• Last Update Posted: Aug 18, 2014
• Last Verified: Aug 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 6 centers in the United States from April 2012 until May 2013.
Pre-assignment Detail	53 patients screened; 40 patients randomized; 38 patients completed the study (7, 8, or 9 days of both treatment sequences), and 39 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), 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	20
COMPLETED	19	20
NOT COMPLETED	1	0
Period Title: Treatment Period 1
STARTED	19	20
COMPLETED	19	20
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	19	20
COMPLETED	18	20
NOT COMPLETED	1	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 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), 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	20	40
Age, Customized (Number) [Number]
<18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 50%	12 60%	22 55%
>=65 years	10 50%	8 40%	18 45%
Sex: Female, Male (Count of Participants)
Female	6 30%	6 30%	12 30%
Male	14 70%	14 70%	28 70%
Race/Ethnicity, Customized (Number) [Number]
White	17 85%	18 90%	35 87.5%
Not Reported	3 15%	2 10%	5 12.5%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	20 100%	20 100%	40 100%
Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Number) [Number]
United States	20 100%	20 100%	40 100%
Region of Enrollment (Number) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Inhibition of the P2Y12 Receptor as Measured by P2Y12 Reactions Units (PRU) From VerifyNow™ (a Platelet Function Test Developed by Accumetrics) at 2 Hours After Loading Dose
Description	Participants with low (<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value
Time Frame	At 2 hours after the loading dose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) Analysis Set

Arm/Group Title	Ticagrelor Arm	Clopidogrel Arm
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	37	34
Least Squares Mean (95% Confidence Interval) [PRU]	34.2	201.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor Arm, Clopidogrel Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.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	-167.2
	Confidence Interval	(2-Sided) 95%; -197.0 to -137.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.6
	Estimation Comments	Ticagrelor minus clopidogrel

2. Secondary Outcome

Title	Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 0.5 and 8 Hours After Loading Dose
Description	Participants with low (<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value
Time Frame	At 0.5 and 8 hours after the loading dose

Outcome Measure Data

Analysis Population Description

PD Analysis Set

Arm/Group Title	Ticagrelor Arm	Clopidogrel Arm
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	38	34
0.5 hours	134.6	269.8
8 hours	34.0	202.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor Arm, Clopidogrel Arm
	Comments	Analysis at 0.5 hours after the loading dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.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	-135.2
	Confidence Interval	(2-Sided) 95%; -172.3 to -98.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.23
	Estimation Comments	Ticagrelor minus Clopidogrel

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor Arm, Clopidogrel Arm
	Comments	Analysis at 8 hours after the loading dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.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	-168.9
	Confidence Interval	(2-Sided) 95%; -204.0 to -133.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.28
	Estimation Comments	Ticagrelor minus Clopidogrel

3. Secondary Outcome

Title	Inhibition of the P2Y12 Receptor as Measured by PRU From VerifyNow™ at 2 and 8 Hours on Day 7 After Multiple Doses and at End of Dosing Interval on Day 8
Description	The end of dosing interval was approximately 12 hours after the last evening dose of ticagrelor and approximately 24 hours after the last morning dose of clopidogrel. Participants with low (<150) baseline PRU values (indicating an incomplete washout from anti-platelet therapy) were excluded during the period corresponding to the low baseline value
Time Frame	At 2 hours and 8 hours on Day 7 after multiple doses, and at the end of dosing interval on Day 8

Outcome Measure Data

Analysis Population Description

PD Analysis Set

Arm/Group Title	Ticagrelor Arm	Clopidogrel Arm
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	37	34
2 hours on day 7	28.5	179.0
8 hours on Day 7 -ticagrelor N=36 clopidogrel N=33	38.7	178.9
End of Dosing Interval on Day 8 - N's per 8 hours	51.5	182.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor Arm, Clopidogrel Arm
	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	<.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	-150.5
	Confidence Interval	(2-Sided) 95%; -176.9 to -124.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.97
	Estimation Comments	Ticagrelor minus Clopidogrel

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor Arm, Clopidogrel Arm
	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	<.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	-140.2
	Confidence Interval	(2-Sided) 95%; -168.4 to -111.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.84
	Estimation Comments	Ticagrelor minus clopidogrel.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor Arm, Clopidogrel Arm
	Comments	Analysis at end of dosing interval on Day 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.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	-130.6
	Confidence Interval	(2-Sided) 95%; -158.0 to -103.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.41
	Estimation Comments	Ticagrelor minus clopidogrel.

4. Secondary Outcome

Title	Ticagrelor Plasma Concentrations After the Loading and Maintenance Doses
Description	The standard deviation (SD) is a statistic using the log-transformed data and is not the geometric SD.
Time Frame	Predose, 0.5, 2, 8 hours from loading dose; 0, 2, 8 and 12 hours from last dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Analysis Set, defined as all participants 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	18	19
Baseline (0 hours - pre-dose)	1.2 (7.5)	1.1 (1.8)
0,.5 hours after the loading dose	206.7 (413.1)	118.6 (352.0)
2 hours after the loading dose - Period 2 N=18	665.4 (566.2)	758.5 (716.6)
8 hours after the loading dose	376.9 (378.8)	479.6 (210.7)
0 hours after multiple doses	248.8 (238.9)	220.1 (295.8)
2 hours after multiple doses	609.3 (271.3)	466.5 (534.5)
8 hours after multiple doses	340.4 (283.8)	305.2 (301.6)
End of dosing interval on Day 8 - Period 1 N=17	283.3 (438.1)	200.7 (268.4)

5. Secondary Outcome

Title	AR-C124910XX (an Active Metabolite of Ticagrelor) Plasma Concentrations After the Loading and Maintenance Doses
Description	The SD is a statistic using the log-transformed data and is not the geometric SD.
Time Frame	Predose, 0.5, 2, 8 hours from loading dose; 0, 2, 8 and 12 hours from last dose

Outcome Measure Data

Analysis Population Description

PK Analysis Set

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	18	19
Baseline (0 hours - pre-dose)	1.1 (2.3)	1.0 (0.0)
0,.5 hours after the loading dose	13.6 (66.3)	9.3 (26.9)
2 hours after the loading dose - Period 2 N=18	153.2 (128.6)	170.8 (156.5)
8 hours after the loading dose	113.8 (54.6)	97.7 (61.9)
0 hours after multiple doses	113.3 (102.1)	62.7 (76.7)
2 hours after multiple doses	183.4 (120.8)	97.4 (147.9)
8 hours after multiple doses	132.8 (61.9)	83.5 (71.4)
End of dosing interval on Day 8 - Period 1 N=17	124.8 (56.6)	57.7 (83.5)

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 Arm		Clopidogrel Arm
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 Arm		Clopidogrel Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ticagrelor Arm		Clopidogrel Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/39 (0%)
Other (Not Including Serious) Adverse Events
	Ticagrelor Arm		Clopidogrel Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/40 (12.5%)		6/39 (15.4%)
Gastrointestinal disorders
Diarrhea	1/40 (2.5%)		0/39 (0%)
Abdominal pain upper	0/40 (0%)		1/39 (2.6%)
General disorders
Malaise	1/40 (2.5%)		0/39 (0%)
Infections and infestations
Nasopharyngitis	0/40 (0%)		1/39 (2.6%)
Injury, poisoning and procedural complications
Fall	0/40 (0%)		2/39 (5.1%)
Rib fracture	0/40 (0%)		1/39 (2.6%)
Investigations
Heart rate irregular	1/40 (2.5%)		0/39 (0%)
Heart rate increased	1/40 (2.5%)		0/39 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/40 (2.5%)		0/39 (0%)
Nervous system disorders
Headache	1/40 (2.5%)		2/39 (5.1%)
Dizziness	1/40 (2.5%)		0/39 (0%)
Dysgeusia	1/40 (2.5%)		0/39 (0%)
Burning Sensation	1/40 (2.5%)		0/39 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/40 (5%)		0/39 (0%)
Oropharyngeal discomfort	1/40 (2.5%)		0/39 (0%)

Limitations/Caveats

Total N for the secondary outcome analysis after multiple doses and for PK measures was not the same for 2 hours, 8 hours and end of dosing. Only the first time point total N can be reported via the form. Row titles indicate N's where they differ.

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 AZ-authorized publication or up to 18 months from study completion at all sites.