Peripheral Arterial Disease
Conditions
Keywords
Peripheral Arterial Disease, PAD, Claudication, Peripheral Vascular Disease
Brief summary
This research study will evaluate the effects of aspirin and dipyridamole alone and in combination on the blood flow in the vessels of the legs. We will examine how these medications are able to inhibit the clotting of platelets in the vessels of patients with PAD, and thereby affect the blood flow in the legs. Platelets are cells in the blood that have the ability to adhere to each other to form clots.
Detailed description
Dipyridamole has been reformulated to guarantee systemic bioavailability and steady state levels compatible with inhibition of platelet aggregation ex vivo (1). This newly formulated dipyridamole has been shown to roughly equal in efficacy to low dose aspirin in the secondary prevention of stroke and the drug combination seems roughly additive (2). The present study is designed to explore two potential mechanisms which have been linked to dipyridamole action on the vessel wall; modulation of vascular eicosanoid generation and prevention of oxidant stress (3). We shall address the hypothesis that dipyridamole affects these systems in patients with PAD. These individuals have disordered platelet-vascular interactions, as reflected by increased generation of thromboxane, an index of platelet activation and of prostacyclin, probably a homeostatic response to traumatic and chemical stimulation of the endothelium (4,5). Furthermore, we shall assess the functional consequences of dipyridamole action, alone and in combination with aspirin compared with aspirin alone on local measurements of flow and oxygenation, including exercise tolerance, Doppler Ultrasound and Near Infrared Spectroscopy (NIRS). Lipid peroxidation will be quantified based on mass spectrometric analysis of the major urinary isoprostane, 8,12-iso-iPF2a-VI (6,7).
Interventions
DRUGDipyridamole 200mg and Aspirin 25mg bid:
All subjects will receive their randomly assigned study medication to be taken each morning and evening approximately 8am and 8 pm for the 180 day duration of the study.
DRUGDipyridamole 200 mg bid
All subjects will receive their randomly assigned study medication to be taken each morning and evening approximately 8am and 8 pm for the 180 day duration of the study.
DRUGAspirin 25 mg bid
All subjects will receive their randomly assigned study medication to be taken each morning and evening approximately 8am and 8 pm for the 180 day duration of the study.
Sponsors
Boehringer Ingelheim
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Age between 18 - 79 * Women of child bearing potential using a medically acceptable method of birth control (oral/transdermal/vaginal hormonal contraception, depo-provera injection, IUD, condom with spermicide, progestin implant, tubal ligation, oophorectomy, TAH) or abstinence. * Capacity for giving written consent * Diagnosis of PAD by: * previous angiogram (\>0.5 stenosis of a peripheral artery) * ankle-brachial index (ABI) of systolic pressure \<0.80 * previous peripheral revascularization * Smokers who smoke \< 10 cigarettes / day
Exclusion criteria
* Female subjects who are pregnant or nursing a child. * Prior bleeding event related to drug therapy * History of gastrointestinal ulceration * History of known dipyridamole and/or aspirin allergy or intolerance * History of coagulation, bleeding or blood disorders. * Recent history of myocardial infarction or stroke in the previous 6 months * Resting blood pressure of \<110mmHg systolic or \<60mmHg diastolic or of \>165mmHg systolic or \>95mmHg diastolic * Patients with active infection as documented by abnormal laboratory tests at screen * Concomitant serious illness, such as cancer, as per the principal investigator's discretion * Current use of steroids for a chronic disease process * Presence of ischemic leg ulcers * History of contact allergies to the metal leads of the NIRS * History of drug or alcohol abuse within the last 6 months. * Subject who has received an experimental drug and/or used an experimental device within 30 days of screening. * Subject who has donated ≥ one pint of blood within 8 weeks prior to screen. * Use of aspirin for 2 weeks prior to the study * Use of any other NSAID or COX-inhibitor for one week prior to the start of the study * Use of any antioxidant vitamin for 2 weeks prior to the start of the study * Use of plavix, pletal or trental for one week prior to the start of the study * Use of acetaminophen for one week prior to each study visit * Use of alcohol, caffeine or high fat foods for 24 hours prior to each study visit * Has smoked any cigarettes for 24 hours prior to each study visit * Platelet aggregation blood test less than 60 percent at Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Present Study is Designed to Explore Two Potential Mechanisms Which Have Been Linked to Dipyridamole Action on the Vessel Wall; Modulation of Vascular Eicosanoid Generation and Prevention of Oxidant Stress. | Predose and dosing days 30, 90 and 180 | No analysis could be performed due to the insufficent number of participants enrolled. Data were not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess the Functional Consequences of Dipyridamole Action, Alone and in Combination With Aspirin Compared With Aspirin Alone on Local Measurements of Flow and Oxygenation. Blood Flow Reporting to Added Table. | Predose and dosing days 30, 90 and 180. | Done by doppler ultrasound. Data could not be analyzed due to insufficient number of participants enrolled. Data were not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria. |
| Assess the Functional Consequences of Dipyridamole Action, Alone and in Combination With Aspirin Compared With Aspirin Alone on Local Measurements of Flow and Oxygenation. Reporting Blood Oxygenation. | Predose and dosing days 30, 90 and 180. | Reporting blood oxygenation. Data could not be analyzed due to insufficient number of participants enrolled. Difficulty finding participants who fit into the inclusion/exclusion criteria. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dipyridamole 200mg and Aspirin 25mg Bid All subjects in this arm will take their assigned medication for 180 days and complete study visits on Day 1(Baseline), 30, 90 and 180. All subjects will bring a 24 hour urine collection and arrive in a fasting state on all visit days for a blood draw after which they will receive breakfast. After assessing vitals, Adverse Event status and medication compliance, they will be escorted to the vascular labs for Doppler Ultrasound and Near Infrared Spectroscopy. (NIRS) of the legs.
Dipyridamole 200mg and Aspirin 25mg bid:: All subjects will receive their randomly assigned study medication to be taken each morning and evening approximately 8am and 8 pm for the 180 day duration of the study. | 8 |
| Dipyridamole 200 mg Bid All subjects in this arm will take their assigned medication for 180 days and complete study visits on Day 1(Baseline), 30, 90 and 180. All subjects will bring a 24 hour urine collection and arrive in a fasting state on all visit days for a blood draw after which they will receive breakfast. After assessing vitals, Adverse Event status and medication compliance, they will be escorted to the vascular labs for Doppler Ultrasound and Near Infrared Spectroscopy. (NIRS) of the legs.
Dipyridamole 200 mg bid: All subjects will receive their randomly assigned study medication to be taken each morning and evening approximately 8am and 8 pm for the 180 day duration of the study. | 9 |
| Aspirin 25 mg Bid All subjects in this arm will take their assigned medication for 180 days and complete study visits on Day 1(Baseline), 30, 90 and 180. All subjects will bring a 24 hour urine collection and arrive in a fasting state on all visit days for a blood draw after which they will receive breakfast. After assessing vitals, Adverse Event status and medication compliance, they will be escorted to the vascular labs for Doppler Ultrasound and Near Infrared Spectroscopy (NIRS) of the legs.
Aspirin 25 mg bid: All subjects will receive their randomly assigned study medication to be taken each morning and evening approximately 8am and 8 pm for the 180 day duration of the study. | 8 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Dipyridamole 200mg and Aspirin 25mg Bid | Dipyridamole 200 mg Bid | Aspirin 25 mg Bid | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 8 Participants | 7 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 8 participants | 9 participants | 8 participants | 25 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 5 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 8 | 4 / 9 | 5 / 8 |
| serious Total, serious adverse events | 2 / 8 | 1 / 9 | 1 / 8 |
Outcome results
Primary
The Present Study is Designed to Explore Two Potential Mechanisms Which Have Been Linked to Dipyridamole Action on the Vessel Wall; Modulation of Vascular Eicosanoid Generation and Prevention of Oxidant Stress.
No analysis could be performed due to the insufficent number of participants enrolled. Data were not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria.
Time frame: Predose and dosing days 30, 90 and 180
Population: Data could not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria. Data could not be analyzed due to insufficient number of participants enrolled.
Secondary
Assess the Functional Consequences of Dipyridamole Action, Alone and in Combination With Aspirin Compared With Aspirin Alone on Local Measurements of Flow and Oxygenation. Blood Flow Reporting to Added Table.
Done by doppler ultrasound. Data could not be analyzed due to insufficient number of participants enrolled. Data were not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria.
Time frame: Predose and dosing days 30, 90 and 180.
Population: Data could not be analyzed due to insufficient number of participants enrolled. Data were not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria.
Secondary
Assess the Functional Consequences of Dipyridamole Action, Alone and in Combination With Aspirin Compared With Aspirin Alone on Local Measurements of Flow and Oxygenation. Reporting Blood Oxygenation.
Reporting blood oxygenation. Data could not be analyzed due to insufficient number of participants enrolled. Difficulty finding participants who fit into the inclusion/exclusion criteria.
Time frame: Predose and dosing days 30, 90 and 180.
Population: Data could not be analyzed due to insufficient number of participants enrolled. Data were not collected due to study termination related to the difficulty finding participants that matched the inclusion/exclusion criteria.