STT-CLIPS: Switch to Ticagrelor in Critical Limb Ischemia Anti-platelet Study

• Sponsor: University of Southern California (Other)
• Overall Status: Completed
• CT.gov ID: NCT02091921
• Collaborator: (none)
• Enrollment: 53
• Location: 1
• Arm: 1
• Actual Duration (Months): 33.4
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

Critical Limb Ischemia (CLI) is defined as limb pain that occurs at rest, or impending limb loss that is caused by severe compromise of blood flow to the affected extremity. CLI is a major cause of death and disability (secondary to myocardial infarction, stroke and amputation). The mortality in patients with CLI approaches 13-25% and 50% at one and five years respectively. High on-treatment platelet reactivity (HPR) in patients treated with aspirin and clopidogrel is associated with increased risk of recurrent cardiovascular events after percutaneous coronary interventions and coronary syndromes. Preliminary studies suggest that the prevalence of HPR in patients with critical limb ischemia treated with aspirin and clopidogrel is as high a 78.5%. In patients with coronary artery disease ticagrelor overcomes non-responsiveness to clopidogrel. However, the antiplatelet effect of ticagrelor in patients with critical limb ischemia is unknown.

Condition or Disease	Intervention/Treatment	Phase
Critical Limb Ischemia	Drug: Ticagrelor	Phase 1/Phase 2

Detailed Description

Study Aim: This pilot study aims to investigate platelet function after switching from clopidogrel to ticagrelor in patients with critical limb ischemia.

Fifty patients with diagnosis of CLI (Rutherford class IV-VI) treated with clopidogrel 75 mg and aspirin 81 mg daily will be tested for inhibition of platelet aggregation using the VerifyNow P2Y12 and VASP assays before and 6±1 hours after their daily clopidogrel dose. All patients will then be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and Vasodilator-Stimulated Phosphoprotein (VASP) platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose. For exploratory analysis, patients will be divided in two groups based on the P2Y12 reaction units (PRU): Group 1. High on treatment platelet reactivity on clopidogrel (HPR), defined as P2Y12 reaction units (PRU) ≥208 and Group 2. Appropriate platelet inhibition on clopidogrel (API), defined as P2Y12 reaction units (PRU) <208. If subjects are withdrawn from the study prior to completion due to the high co-morbidity rate of this population, additional subjects will be enrolled to reach a total of 50 completed subjects for data analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Screening
• Official Title: Switch to Ticagrelor in Critical Limb Ischemia Anti-platelet Study
• Actual Study Start Date: Feb 16, 2014
• Actual Primary Completion Date: Nov 30, 2016
• Actual Study Completion Date: Nov 30, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental All subjects will receive Ticagrelor.	Drug: Ticagrelor; All patients will be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and VASP platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose.; Other Names: Brilinta

Outcome Measures

Primary Outcome Measures

1. To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI. [Two weeks]

   Patients platelet inhibition was analyzed based on the P2Y12 reaction units (PRU) as high on treatment platelet reactivity (HPR), defined as P2Y12 reaction units (PRU) ≥208 and appropriate platelet inhibition on (API), defined as P2Y12 reaction units (PRU) <208

Secondary Outcome Measures

1. Establish the Number of Participants in the High On-treatment Platelet Reactivity (HPR) on Clopidogrel Group Who Demonstrated Appropriate Platelet Inhibition (API) After Switching to Ticagrelor for Two Weeks. [Two weeks]

   This measure was obtained by the number of participants who demonstrated high on treatment platelet reactivity (PRU > / = 208) on Clopidogrel, and the number of participants who also resulted in the Appropriate Platelet Inhibition (PRU < 208) after switching to Ticagrelor for two weeks of uninterrupted therapy x 100% .

2. Establish the Number of Participants With Appropriate Platelet Inhibition on Clopidogrel Who Demonstrated Appropriate Platelet Inhibition After Switching to Ticagrelor for Two Weeks. [Two weeks]

   The measure was obtained from the number of participants in the Appropriate Platelet Inhibition (PRU < 208) on Clopidogrel and who remained with Appropriate Platelet Inhibition after switching to Ticagrelor for two weeks of uninterrupted therapy x 100

3. Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy. [Two weeks]

   Correlation between the P2Y12 Reaction Units (PRU) and the Vasodilator-Stimulated Phosphoprotein Assay-Platelet Reactivity Index (VASP-PRI) used to test the inhibition of platelet aggregation after two weeks of uninterrupted therapy with Clopidogrel versus Ticagrelor in CLI participants

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Patients with diagnosis of CLI (Rutherford class IV, V and VI) on continuous dual antiplatelet therapy with aspirin 81 mg and clopidogrel 75 mg daily for at least 14+2 days .

Exclusion Criteria:

• Chronic use of nonsteroidal anti-inflammatory drugs, thrombocytopenia (platelet count <100 × 103/μl), hemoglobin <10 g/dL, use of an oral anticoagulant (warfarin) or low molecular weight heparin within 14 days, GPIIb/IIIa inhibitors, or fibrinolytic drugs within 30 days. Pregnancy, <18 or >80 years of age, current smoking (>1 pack per day), concomitant therapy with strong cytochrome P450 3A inhibitors or inducers within 14 days, concomitant antithrombotic therapy other than aspirin within 14 days, hypercoaguable states. History of medication non-compliance, drug or alcohol abuse within 2 years. Acute coronary syndrome or coronary drug-eluting stenting within 1 year. Peripheral vascular revascularization procedures (surgical or endovascular) and/or amputation within one month. Contraindications for ticagrelor including: hypersensitivity to ticagrelor or any of the excipients, Active pathological bleeding, History of intracranial hemorrhage and Severe hepatic impairment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90033

Sponsors and Collaborators

• University of Southern California

Investigators

• Principal Investigator: Leonardo Clavijo, MD, PhD, University of Southern California

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Leonardo Clavijo, Principal Investigator, Director, University of Southern California
• ClinicalTrials.gov Identifier: NCT02091921
• Other Study ID Numbers: D5130L00068//ISSBRIL0198; HS-13-00562
• First Posted: Mar 19, 2014
• Last Update Posted: Jun 19, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Leonardo Clavijo, Principal Investigator, Director, University of Southern California: Critical Limb Ischemia, ticagrelor, Brilinta
• Additional relevant MeSH terms: Ischemia; Ticagrelor

Study Results

Participant Flow

Recruitment Details	Patients with diagnosis of CLI (Rutherford class IV, V and VI) on continuous dual antiplatelet therapy with clopidogrel 75 mg and aspirin 81 mg daily for at least 14+2 days
Pre-assignment Detail	A total of 53 patients consented and enrolled the study. 3 patients were excluded from the study and did not complete the study; one developed a skin reaction after the first IP dose; the other two due to events unrelated to the study (Pneumonia and Rheumatoid arthritis pericarditis). 50 Patients completed the study.

Arm/Group Title	Experimental
Arm/Group Description	All subjects will receive Ticagrelor. Ticagrelor: All patients will be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and VASP platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose.
Period Title: Overall Study
STARTED	53
COMPLETED	50
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Experimental
Arm/Group Description	All subjects will receive Ticagrelor. Ticagrelor: All patients will be switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks and the VerifyNow and VASP platelet reactivity assays repeated, samples will be collected before and 6±1 hours after the last ticagrelor dose.
Overall Participants	50
Overall blood samples	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (10.6)
Sex: Female, Male (Count of Participants)
Female	23 46%
Male	27 54%
Region of Enrollment (Count of Participants)
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	To Determine Platelet Inhibition Before and After Switching for Two Weeks From Clopidogrel to Ticagrelor in Patients With CLI.
Description	Patients platelet inhibition was analyzed based on the P2Y12 reaction units (PRU) as high on treatment platelet reactivity (HPR), defined as P2Y12 reaction units (PRU) ≥208 and appropriate platelet inhibition on (API), defined as P2Y12 reaction units (PRU) <208
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ticagrelor
Arm/Group Description	All patients were switched from clopidogrel to ticagrelor 90 mg twice daily for two weeks
Measure Participants	50
Clopidogrel Baseline	173
Clopidogrel 6+-1 hour after the baseline dose	140
Ticagrelor Baseline	71
Ticagrelor 6+-1 hour after baseline	63

2. Secondary Outcome

Title	Establish the Number of Participants in the High On-treatment Platelet Reactivity (HPR) on Clopidogrel Group Who Demonstrated Appropriate Platelet Inhibition (API) After Switching to Ticagrelor for Two Weeks.
Description	This measure was obtained by the number of participants who demonstrated high on treatment platelet reactivity (PRU > / = 208) on Clopidogrel, and the number of participants who also resulted in the Appropriate Platelet Inhibition (PRU < 208) after switching to Ticagrelor for two weeks of uninterrupted therapy x 100% .
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

Participants who demonstrated on the High Platelet Reactivity (HPR) on clopidogrel and had Appropriate Platelet Inhibition (API) on ticagrelor

Arm/Group Title	HPR on Clopidogrel and API on Ticagrelor
Arm/Group Description	Participants who demonstrated HPR on clopidogrel
Measure Participants	18
Count of Participants [Participants]	17 34%

3. Secondary Outcome

Title	Establish the Number of Participants With Appropriate Platelet Inhibition on Clopidogrel Who Demonstrated Appropriate Platelet Inhibition After Switching to Ticagrelor for Two Weeks.
Description	The measure was obtained from the number of participants in the Appropriate Platelet Inhibition (PRU < 208) on Clopidogrel and who remained with Appropriate Platelet Inhibition after switching to Ticagrelor for two weeks of uninterrupted therapy x 100
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

Participants who demonstrated API on Clopidogrel and remained with API after switching to Ticagrelor

Arm/Group Title	API on Clopidogrel and API on Ticagrelor
Arm/Group Description	Participants with Appropriate Platelet Inhibition (API) on Clopidogrel.
Measure Participants	32
Count of Participants [Participants]	32 64%

4. Secondary Outcome

Title	Evaluate the Correlation Between PRU and VASP-PRI in CLI Patients During Clopidogrel Versus Ticagrelor Antiplatelet Therapy.
Description	Correlation between the P2Y12 Reaction Units (PRU) and the Vasodilator-Stimulated Phosphoprotein Assay-Platelet Reactivity Index (VASP-PRI) used to test the inhibition of platelet aggregation after two weeks of uninterrupted therapy with Clopidogrel versus Ticagrelor in CLI participants
Time Frame	Two weeks

Outcome Measure Data

Analysis Population Description

All participants were on Clopidogrel 75mg daily for at least two weeks and then switched to Ticagrelor 90mg twice daily for two weeks of uninterrupted therapy

Arm/Group Title	Correlation of PRU and VASP-PRI
Arm/Group Description	Participants who were switched from clopidogrel to ticagrelor
Measure Participants	50
Measure Correlation Coefficient	200
Clopidogrel	0.73
Ticagrelor	0.47
Overall Group	0.6

Adverse Events

Time Frame	Two weeks
Adverse Event Reporting Description	The adverse event and/or serious adverse event, used to collect adverse event information, adheres to the clinicaltrials.gov definition
Arm/Group Title	Experimental
Arm/Group Description	All participants will switch from clopidogrel to ticagrelor for two weeks
All Cause Mortality
	Experimental
	Affected / at Risk (%)	# Events
Total	0/53 (0%)
Serious Adverse Events
	Experimental
	Affected / at Risk (%)	# Events
Total	1/53 (1.9%)
Immune system disorders
Rheumatoid arthritis pericarditis	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Hospitalization for Pneumonia	1/53 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Experimental
	Affected / at Risk (%)	# Events
Total	1/53 (1.9%)
Skin and subcutaneous tissue disorders
Skin reaction	1/53 (1.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.