TI-PAD EVR: Walking Effect of Long Term Ticagrelor in Subjects With PAD Who Have Undergone EVR

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02227368
• Collaborator: CPC Clinical Research (Other)
• Enrollment: 40
• Locations: 10
• Arms: 2
• Actual Duration (Months): 19.1
• Patients Per Site: 4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To compare the effect of ticagrelor versus aspirin on the change in peak walking time, evaluated on the graded treadmill test, from one to 26 weeks post-revascularization in patients with peripheral artery disease who have undergone endovascular revascularization for moderate to severe claudication or ischemic rest pain.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Artery Disease (PAD)	Drug: Ticagrelor; Drug: Comparator	Phase 2

Detailed Description

A Phase II Multicentre, Randomised, Double-Blind, Controlled, Parallel-Group Study to Evaluate the Walking Time Effect of Long-Term Ticagrelor in Comparison to Long-Term Aspirin Administration in Ambulatory Patients with Peripheral Artery Disease Undergoing Endovascular Revascularization - The Ticagrelor in Peripheral Artery Disease Endovascular Revascularization Study TI-PAD I EVR.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II Multicentre, Randomised, Double-Blind, Controlled, Parallel-Group Study to Evaluate the Walking Time Effect of Long-Term Ticagrelor in Comparison to Long-Term Aspirin Administration in Ambulatory Patients With Peripheral Artery Disease Undergoing Endovascular Revascularization - The Ticagrelor in Peripheral Artery Disease Endovascular Revascularization Study TI-PAD I EVR
• Actual Study Start Date: Oct 20, 2014
• Actual Primary Completion Date: May 23, 2016
• Actual Study Completion Date: May 23, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ticagrelor 26 Weeks of ticagrelor 90mg twice a day plus aspirin placebo once daily	Drug: Ticagrelor; Antiplatelet therapy approved for ACS. Antagonist of P2Y12 and inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation.; Other Names: Brilinta
Active Comparator: Aspirin 26 Weeks of aspirin 100mg once daily plus ticagrelor placebo twice a day	Drug: Comparator; Aspirin monotherapy anti-platelet treatment for PAD patients following EVR procedures; Other Names: Aspirin

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Log Transformed Peak Walking Time (PWT) at Week 26 or Early Termination (ET) [26 Weeks]

Secondary Outcome Measures

1. Change From Baseline in Log Transformed Claudication Onset Time (COT) at Week 26 or Early Termination (ET) [26 Weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Written informed consent prior to any study specific procedures.

2. Ambulatory male or female outpatients aged 50 years of age or older at the time of the Screening Visit.

3. EVR, below the inguinal ligament that includes the distal SFA and/or popliteal and/or tibial arteries, that is planned to occur within 5 weeks after the Screening Visit, as determined and clearly documented by the Principal Investigator or physician Sub-Investigator (MD/DO). Patients undergoing a proximal revascularization may be enrolled as long as their procedure also includes treating the distal SFA, popliteal or tibial arteries. The EVR must be confirmed as technically successful (a completed procedure where haemostasis has been achieved) before the patient is randomised.

4. Normal inflow into the lower extremity as determined by the Principal Investigator or physician Sub-Investigator (MD/DO). Adequacy of inflow can be assessed by hemodynamic measures, angiography or other imaging modalities obtained during Screening or recorded in the medical records up to 30 days prior to the Screening Visit or as defined by imaging at the time of the procedure. A patient with inadequate inflow at the time of Screening can still be enrolled if the inflow is addressed and resolved by the planned revascularization procedure.

5. Diagnosis of PAD confirmed by history and any one of the following observed in the index (intervention) leg at the Screening Visit:

6. Resting ABI ≤0.90, or

7. In patients with an ABI > 1.40 (non-compressible vessels) a resting GTI <0.70 can be used for inclusions.

8. Patient has been advised of the beneficial effects of smoking cessation and exercise therapy but is not in the process of changing their smoking status or exercise at the time of the Screening Visit.

Exclusion Criteria

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

2. Revascularisation planned only to treat proximal (inflow) disease in the iliac and/or common femoral arteries.

3. Previous randomisation in the present study.

4. Participation in another clinical study with an investigational product within the last 3 months or any new clinical trial during the course of this study.

5. Gangrene or ischemic ulcer of either lower extremity.

6. PAD of a non-atherosclerotic nature.

7. Clinical necessity to use dual antiplatelet therapy within 7 days prior to randomisation, or single anti-platelet therapy (ticlopidine, prasugrel, vorapaxar, ticagrelor or dipyridamole) other than clopidogrel or aspirin. Clopidogrel or aspirin can be taken up to and including the time that the loading dose is being given.

8. Clinical necessity to use the following restricted concomitant medications within 4 weeks prior to randomisation. Patients taking any of these medications at the Screening Visit may be considered for randomisation after a 4 week washout period from the medication.

9. Pentoxifylline or cilostazol for relief of claudication symptoms

10. Chronic oral or parenteral anticoagulant therapy (greater than 7 days)

11. Strong inhibitors of CYP3A enzymes (Section 5.6.9.1)

12. Strong inducers of CYP3A enzymes (Section 5.6.9.2)

13. Simvastatin or lovastatin at daily doses over 40 mg

14. Any disease process (e.g. angina, cardiac abnormality, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), respiratory disease, obesity, stroke, severe neuropathy of the foot, symptomatic musculoskeletal disease of the lower extremity), other than PAD, that would interfere with exercise performance during the ETT or prevent the patient from reaching their claudication-limited PWT as the primary endpoint of the study.

15. Coronary, aortic surgery, angioplasty, lumbar sympathectomy or lower extremity surgery that impacts the ability to walk on a treadmill within the past 3 months prior to EVR. Revascularization of the non-index lower extremity within the past 4 weeks prior to EVR.

16. Any major lower limb amputation due to PAD anticipated within the next 3 months or prior major amputation due to PAD (minor toe amputations allowed if it does not interfere with ambulation).

17. Myocardial infarction or stroke in the previous 3 months.

18. Any concomitant disease process with a life expectancy of less than 1 year or which is sufficiently severe as to compromise the validity of test performance.

19. Dementia likely to jeopardise understanding of information pertinent to study conduct or compliance to study procedures.

20. Concern for the inability of the patient to comply with study procedures and/or followup (e.g., alcohol or drug abuse).

21. Resting systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥95 mmHg at the Screening Visit, in spite of antihypertensive treatments allowed by the protocol.

22. A known bleeding diathesis, haemostatic or coagulation disorder, or systemic bleeding, whether resolved or ongoing.

23. Known severe liver disease (e.g., ascites and or clinical signs of coagulopathy).

24. Renal failure requiring dialysis.

25. History of previous intracranial bleed at any time, gastrointestinal bleed within the past 6 months, or major surgery within 30 days (if the surgical wound is judged to be associated with an increased risk of bleeding).

26. History of thrombocytopenia or neutropenia.

27. Hypersensitivity to ticagrelor, aspirin or lactose.

28. Initiation of antidiabetic, antihypertensive, lipid-lowering and beta-blocking drugs within 1 month prior to the Screening Visit.

29. Pregnancy, lactation, fertility without protection against pregnancy (for women of childbearing potential; a urine or serum pregnancy test will be performed at the Screening Visit).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Daytona Beach	Florida	United States	32114
2	Research Site	Jacksonville	Florida	United States	32216
3	Research Site	Ocala	Florida	United States	34471
4	Research Site	Sarasota	Florida	United States	34239
5	Research Site	Munster	Indiana	United States	46321
6	Research Site	New York	New York	United States	10001
7	Research Site	Yonkers	New York	United States	10701
8	Research Site	Cleveland	Ohio	United States	44195
9	Research Site	McKinney	Texas	United States	75069
10	Research Site	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• AstraZeneca
• CPC Clinical Research

Investigators

• Principal Investigator: William Hiatt, MD, Colorado Prevention Center Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02227368
• Other Study ID Numbers: D5135L00003
• First Posted: Aug 28, 2014
• Last Update Posted: Jul 19, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by AstraZeneca: Myocardial Infarction; Peripheral Arterial disease; Mycardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Altherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Ticagrelor; Ticlopidine; Platelet Aggregation inhibitors; Hematologic Agents; Therapeutic Uses; Pharmacologic Actions; Purinegic P2Y Receptor Antagonists; Purinegic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Actions; Physiological Effects of Drugs; Fibrinolytic Agents; Crardiovascular Agents
• Additional relevant MeSH terms: Peripheral Arterial Disease; Aspirin; Ticagrelor

Study Results

Participant Flow

Recruitment Details	A total of 71 subjects were screened at 16 centers throughout the United States of America (USA). First subject enrolled: 20Oct2014. Last subject last visit: 23May2016. Date of early study termination: 21Oct2015
Pre-assignment Detail	A total of 40 subjects were randomised. Thirty-one subjects were not randomised due to not meeting inclusion/exclusion criteria (20 subjects), withdrawing consent prior to randomisation (2 subjects), and other reasons (9 subjects) including not being able to return for randomisation within 48 hours of the qualifying revascularization.

Arm/Group Title	Ticagrelor	Aspirin
Arm/Group Description	Ticagrelor 90mg twice a day plus aspirin placebo once daily	Aspirin 100mg once daily plus ticagrelor placebo twice a day
Period Title: Overall Study
STARTED	16	24
Sujects Who Received Treatment	16	24
Sujects Who Completed Treatment	10	17
COMPLETED	14	20
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	Ticagrelor	Aspirin	Total
Arm/Group Description	Ticagrelor 90mg twice a day plus aspirin placebo once daily	Aspirin 100mg once daily plus ticagrelor placebo twice a day	Total of all reporting groups
Overall Participants	16	24	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.1 (9.15)	67.0 (8.31)	67.9 (8.60)
Sex: Female, Male (Count of Participants)
Female	9 56.3%	9 37.5%	18 45%
Male	7 43.8%	15 62.5%	22 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 18.8%	3 12.5%	6 15%
Not Hispanic or Latino	13 81.3%	21 87.5%	34 85%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 25%	2 8.3%	6 15%
White	11 68.8%	20 83.3%	31 77.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 6.3%	2 8.3%	3 7.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Log Transformed Peak Walking Time (PWT) at Week 26 or Early Termination (ET)
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

ITT population is the analysis population. Six subjects without evaluable baseline were excluded from the analysis.

Arm/Group Title	Ticagrelor	Aspirin
Arm/Group Description	Ticagrelor 90mg twice a day plus aspirin placebo once daily	Aspirin 100mg once daily plus ticagrelor placebo twice a day
Measure Participants	14	20
Mean (95% Confidence Interval) [log(Second)]	0.0	0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Aspirin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3441
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is Ticagrelor - Aspirin. LOCF was used for missing data imputation.

2. Secondary Outcome

Title	Change From Baseline in Log Transformed Claudication Onset Time (COT) at Week 26 or Early Termination (ET)
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

ITT population is the analysis population. Twelve subjects without evaluable baseline were excluded from the analysis.

Arm/Group Title	Ticagrelor	Aspirin
Arm/Group Description	Ticagrelor 90mg twice a day plus aspirin placebo once daily	Aspirin 100mg once daily plus ticagrelor placebo twice a day
Measure Participants	12	16
Mean (95% Confidence Interval) [log(Second)]	0.6	0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ticagrelor, Aspirin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6186
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference is Ticagrelor - Aspirin. LOCF was used for missing data imputation.

Adverse Events

Time Frame	26 weeks treatment period + 30 days followup
Adverse Event Reporting Description	Only SAEs and AEs of interest were collected for this study. Treatment Emergent SAEs and Treatment Emergent AEs of interest are reported here.
Arm/Group Title	Ticagrelor		Aspirin
Arm/Group Description	Ticagrelor 90mg twice a day plus aspirin placebo once daily		Aspirin 100mg once daily plus ticagrelor placebo twice a day
All Cause Mortality
	Ticagrelor		Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ticagrelor		Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/16 (25%)		2/24 (8.3%)
Cardiac disorders
Coronary artery disease	1/16 (6.3%)		0/24 (0%)
Infections and infestations
Cellulitis	0/16 (0%)		1/24 (4.2%)
Osteomyelitis	0/16 (0%)		1/24 (4.2%)
Nervous system disorders
Syncope	1/16 (6.3%)		0/24 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/16 (0%)		1/24 (4.2%)
Vascular disorders
Haemorrhage	1/16 (6.3%)		0/24 (0%)
Hypotension	1/16 (6.3%)		0/24 (0%)
Peripheral artery stenosis	0/16 (0%)		1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Ticagrelor		Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)		1/24 (4.2%)
Injury, poisoning and procedural complications
Procedural haemorrhage	1/16 (6.3%)		0/24 (0%)
Vascular disorders
Arterial occlusive disease	0/16 (0%)		1/24 (4.2%)

Limitations/Caveats

This study was terminated early for low enrolment. Less than 25% of anticipated number of subjects were enroled and there was an imbanlance between groups. Therefore, the results should be interpreted with caution.

More Information

Certain Agreements

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

The 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 from the time submitted to the sponsor for review. The sponsor can require Confidential Information to be removed and the sponsor can extend the embargo for an additional 90 days.