Peripheral Artery Disease (PAD)
Conditions
Keywords
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
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.
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.
Interventions
DRUGTicagrelor
Antiplatelet therapy approved for ACS. Antagonist of P2Y12 and inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation.
DRUGComparator
Aspirin monotherapy anti-platelet treatment for PAD patients following EVR procedures
Sponsors
CPC Clinical Research
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 130 Years
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: 1. Resting ABI ≤0.90, or 2. In patients with an ABI \> 1.40 (non-compressible vessels) a resting GTI \<0.70 can be used for inclusions. 6. 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. 1. Pentoxifylline or cilostazol for relief of claudication symptoms 2. Chronic oral or parenteral anticoagulant therapy (greater than 7 days) 3. Strong inhibitors of CYP3A enzymes (Section 5.6.9.1) 4. Strong inducers of CYP3A enzymes (Section 5.6.9.2) 5. Simvastatin or lovastatin at daily doses over 40 mg 9. 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. 10. 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. 11. 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). 12. Myocardial infarction or stroke in the previous 3 months. 13. 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. 14. Dementia likely to jeopardise understanding of information pertinent to study conduct or compliance to study procedures. 15. Concern for the inability of the patient to comply with study procedures and/or followup (e.g., alcohol or drug abuse). 16. 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. 17. A known bleeding diathesis, haemostatic or coagulation disorder, or systemic bleeding, whether resolved or ongoing. 18. Known severe liver disease (e.g., ascites and or clinical signs of coagulopathy). 19. Renal failure requiring dialysis. 20. 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). 21. History of thrombocytopenia or neutropenia. 22. Hypersensitivity to ticagrelor, aspirin or lactose. 23. Initiation of antidiabetic, antihypertensive, lipid-lowering and beta-blocking drugs within 1 month prior to the Screening Visit. 24. 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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Log Transformed Peak Walking Time (PWT) at Week 26 or Early Termination (ET) | 26 Weeks |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Log Transformed Claudication Onset Time (COT) at Week 26 or Early Termination (ET) | 26 Weeks |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor Ticagrelor 90mg twice a day plus aspirin placebo once daily | 16 |
| Aspirin Aspirin 100mg once daily plus ticagrelor placebo twice a day | 24 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | No EVR/not PAD/PI decision/RLE bypass | 0 | 4 |
Baseline characteristics
| Characteristic | Ticagrelor | Aspirin | Total |
|---|---|---|---|
| Age, Continuous | 69.1 years STANDARD_DEVIATION 9.15 | 67.0 years STANDARD_DEVIATION 8.31 | 67.9 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 21 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 20 Participants | 31 Participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 7 Participants | 15 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 16 | 1 / 24 |
| serious Total, serious adverse events | 4 / 16 | 2 / 24 |
Outcome results
Primary
Change From Baseline in Log Transformed Peak Walking Time (PWT) at Week 26 or Early Termination (ET)
Time frame: 26 Weeks
Population: ITT population is the analysis population. Six subjects without evaluable baseline were excluded from the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Change From Baseline in Log Transformed Peak Walking Time (PWT) at Week 26 or Early Termination (ET) | 0.0 log(Second) |
| Aspirin | Change From Baseline in Log Transformed Peak Walking Time (PWT) at Week 26 or Early Termination (ET) | 0.1 log(Second) |
p-value: 0.344195% CI: [-0.4, 0.1]t-test, 2 sided
Secondary
Change From Baseline in Log Transformed Claudication Onset Time (COT) at Week 26 or Early Termination (ET)
Time frame: 26 Weeks
Population: ITT population is the analysis population. Twelve subjects without evaluable baseline were excluded from the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Change From Baseline in Log Transformed Claudication Onset Time (COT) at Week 26 or Early Termination (ET) | 0.6 log(Second) |
| Aspirin | Change From Baseline in Log Transformed Claudication Onset Time (COT) at Week 26 or Early Termination (ET) | 0.5 log(Second) |
p-value: 0.618695% CI: [-0.4, 0.6]t-test, 2 sided