Endothelial Dysfunction
Conditions
Keywords
coronary endothelial dysfunction, coronary vasospasm
Brief summary
AIM III is a prospective, randomized, double-blinded, placebo controlled trial. The study is directly connected to IRB 08-008161 as a specific aim of the National Institute of Health (NIH) grant. Participants may either consent to and qualify for AIM I and AIM II (IRB 08-008161) or have a cardiac catheterization with acetylcholine testing in the Cardiac Catheterization Laboratory at Mayo Clinic in Rochester, Minnesota to be considered for this study.
Detailed description
The main goal of AIM III is to assess and quantify the effect of long-term administration of darapladib 160 mg once a day, a selective, reversible, orally active inhibitor of plasma and vascular Lp-PLA2, on coronary endothelial function, progression of coronary atherosclerosis as determined by intravascular ultrasound (IVUS), and atherosclerosis in patients with early atherosclerosis. Patients with evidence of coronary endothelial dysfunction, as determined by intracoronary administration of acetylcholine during angiography and IVUS, will be followed for 6 months during once daily dosing of darapladib. Coronary endothelial function is determined by the changes in coronary artery diameter and coronary blood flow response to the intracoronary administration of acetylcholine and adenosine. The patients will be followed in clinic 6 months. They will have follow-up angiography, assessment of endothelial function, and IVUS during the six month visit.
Interventions
DRUGdarapladib
darapladib, tablet, 160 mg, by mouth, one time daily, 6 month duration
DRUGplacebo
placebo, by mouth, once daily for six months
Sponsors
GlaxoSmithKline
National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Aging (NIA)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Patients undergoing coronary angiography including endothelial function testing with the medication acetylcholine in the cardiac catheterization laboratory at Mayo Clinic. Patients may be enrolled in AIM I and AIM II IRB 08-008161 :Lp-PLA2, Progenitor Cells and Atherosclerosis in Humans. 2. Male or female aged at least 18 years, inclusive, at screening. Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator in accordance with local practice in relation to adequate contraception. 3. Age greater than 18 up to age 85
Exclusion criteria
1. Current severe heart failure New York Heart Association class III or IV with ejection fraction less than 40% 2. Unstable angina 3. Myocardial infarction or angioplasty within 6 months prior to entry into the study 4. Planned coronary revascularization (PCI or CABG) 5. Planned major surgical procedure 6. Patients with segments with endothelial dysfunction of less than 10 mm in length or complete occlusion will be excluded. 7. Angiographic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Coronary Artery Diameter | baseline, six months | The change of coronary artery diameter was measured in response to a maximal dose of acetylcholine administered intracoronary during an invasive coronary endothelial function assessment. Percentage change in coronary artery diameter provides a measure of endothelium dependent epicardial function. |
| Percentage Change in Coronary Blood Flow (CBF) | baseline, six months | The change in coronary blood flow was measured in response to maximal dose of acetylcholine administered intracoronary during an invasive coronary endothelial function assessment. Percentage change in coronary blood flow provides a measure of endothelium dependent microvascular function. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at the Mayo Clinic in Rochester, Minnesota between February 2010 and February 2015.
Pre-assignment details
70 subjects signed informed consent, but 5 subjects withdrew (subject decision) prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Darapladib Subjects randomized to this arm will receive a darapladib tablet, 160 mg, by mouth, once per day for 6 months. | 25 |
| Placebo Subjects randomized to this arm will receive a placebo tablet matching the study drug, once per day for 6 months. | 29 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Darapladib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.2 years STANDARD_DEVIATION 11.7 | 54.0 years STANDARD_DEVIATION 10.5 | 54.5 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 25 participants | 29 participants | 54 participants |
| Sex: Female, Male Female | 17 Participants | 26 Participants | 43 Participants |
| Sex: Female, Male Male | 8 Participants | 3 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 34 |
| other Total, other adverse events | 6 / 31 | 16 / 34 |
| serious Total, serious adverse events | 2 / 31 | 3 / 34 |
Outcome results
Primary
Percentage Change in Coronary Artery Diameter
The change of coronary artery diameter was measured in response to a maximal dose of acetylcholine administered intracoronary during an invasive coronary endothelial function assessment. Percentage change in coronary artery diameter provides a measure of endothelium dependent epicardial function.
Time frame: baseline, six months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Darapladib | Percentage Change in Coronary Artery Diameter | 3 % change coronary artery diameter |
| Placebo | Percentage Change in Coronary Artery Diameter | 3 % change coronary artery diameter |
Primary
Percentage Change in Coronary Blood Flow (CBF)
The change in coronary blood flow was measured in response to maximal dose of acetylcholine administered intracoronary during an invasive coronary endothelial function assessment. Percentage change in coronary blood flow provides a measure of endothelium dependent microvascular function.
Time frame: baseline, six months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Darapladib | Percentage Change in Coronary Blood Flow (CBF) | -5 % change coronary blood flow |
| Placebo | Percentage Change in Coronary Blood Flow (CBF) | 39 % change coronary blood flow |