Coronary Artery Disease, Human Immunodeficiency Virus
Conditions
Brief summary
The investigators are studying whether an anti-inflammatory intervention improves impaired coronary endothelial function (CEF) in HIV+ people with no clinical coronary artery disease (CAD).
Detailed description
Survival in people with HIV has significantly improved with the use of antiretroviral therapy (ART) but HIV+ people now experience an increasing burden of chronic diseases, including coronary atherosclerosis and coronary artery disease (CAD). HIV patients manifest an increased risk of CAD and its consequences possibly due to interplay of inflammation with traditional risk factors (smoking, high cholesterol, and poor diet), some of the latter accentuated by ART. What the investigators are studying in this program is the function of the coronary arteries and in particular the inner lining of the arteries called the endothelium in patients with HIV. The endothelium has several important functions; one of them is that under conditions of stress it releases a substance called nitric oxide which increases the size of the artery and increases blood flow. When it is not functioning normally the artery does not increase as much and blood flow does not increase during stress. The investigators study coronary artery function with magnetic resonance imaging, or MRI. MRI is a method of obtaining images of what is happening inside the body. MRI does not involve radiation, x-ray, or injection of contrast. The investigators can measure flow in the artery and the dimension of the artery at rest and with a handgrip stress and learn the extent to which the artery dilates and flow increases with the stress. The investigators believe that inflammation can interfere with normal function and that by decreasing inflammation abnormal endothelial function may be improved. Colchicine is an anti-inflammatory agent approved by the Food and Drug Administration (FDA) to treat arthritis and some other conditions. This drug is not approved for use to suppress inflammation in patients with coronary artery disease and improve coronary artery endothelial function. The FDA is allowing the use of colchicine or a placebo in this research study. This study will involve 24 weeks of colchicine or placebo and 3 Magnetic Resonance Imaging (MRI) scans of the heart and other study procedures.
Interventions
DRUGColchicine
Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.
DRUGPlacebo
A substance containing no medication
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients of either gender who are 21 years of age (no upper age limit), HIV positive and taking stable ART (no change in ART regimen in last 3 months), * HIV viral load \<100 copies/mL (plasma HIV RNA concentration), * Abnormal CEF at baseline (\<7ml/min change in CBF during IHE as compared to resting value).
Exclusion criteria
* Patients unable to understand the risks, benefits, and alternatives of participation and give meaningful consent, * Patients with contraindications to MRI such as implanted metallic objects (pre-existing cardiac pacemakers, cerebral clips) or indwelling metallic projectiles, * History of clinical CAD, including acute coronary syndrome, myocardial infarction or revascularization, * Resting ECG with evidence of Q wave myocardial infarction, * Pregnant women, * Recent history, within the past 3 months, of cocaine or heroin use, * Moderate or greater renal impairment (estimated glomerular filtration rate \<45ml/min), * Moderate-severe hepatic disease (elevation in hepatic transaminases \>3x upper limit of normal), * Leukopenia (\<3000/mm3) or thrombocytopenia (\<100,000/mm3), * CD4\<200 cell/mm3, * Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease, * Requirement for, or intolerance to, colchicine, * Women of childbearing potential (even if using oral contraceptive agents) or intention to breastfeed, * Chronic, continuous use of oral or IV steroid therapy or other immunosuppressive or biologic response modifiers or anti-inflammatory agents (chronic NSAIDs or acetylsalicylic acid (ASA) \>81mg daily), * History of chronic pericardial effusion, pleural effusion, ascites or peripheral neuropathy manifested by both signs and symptoms, * Taking protease inhibitors (PI), cobicistat, or CYP3A4 inhibitors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks | Difference between measurements at baseline compared to measurement at 8 weeks | Percent change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 8 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks | Difference between measurements at baseline compared to measurement at 8 weeks | Change in CSA as measured by the difference between CSA at rest and under IHE stress at 8 weeks |
| Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks | At 24 weeks | Change in CSA as measured by the difference between CSA at rest and under IHE stress at 24 weeks |
| High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks. | At 8 weeks. | High-sensitivity C-reactive protein (hsCRP) at 8 weeks |
| Coronary Endothelial Function at 24 Weeks; | At 24 weeks. | Change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 24 weeks. |
| Interleukin-6 (IL-6) at 8 Weeks | At 8 weeks | Interleukin-6 (IL-6) at 8 weeks |
| High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks | At 24 weeks | High-sensitivity C-reactive Protein (hsCRP) at 24 weeks |
| Brachial Flow Mediated Dilatation (FMD) at 24 Weeks. | At 24 weeks | Brachial Flow Mediated Dilatation (FMD) at 24 Weeks. |
| Brachial Flow Mediated Dilatation (FMD) at 8 Weeks. | At 8 weeks | Brachial flow mediated dilatation (FMD) at 8 weeks. |
Countries
United States
Participant flow
Pre-assignment details
Two participants randomized to colchicine withdrew before receiving study drug.
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Colchicine 0.6 mg daily by mouth
Colchicine: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. | 43 |
| Placebo Placebo for colchicine 1 tablet by mouth daily
Placebo: A substance containing no medication | 38 |
| Total | 81 |
Baseline characteristics
| Characteristic | Placebo | Total | Colchicine |
|---|---|---|---|
| Age, Continuous | 52.0 Years | 54.25 Years | 54.66 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 78 Participants | 41 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 | 26 Participants | 59 Participants | 33 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 | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 11 Participants | 19 Participants | 8 Participants |
| Sex: Female, Male Female | 8 Participants | 17 Participants | 9 Participants |
| Sex: Female, Male Male | 30 Participants | 64 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 38 |
| other Total, other adverse events | 39 / 41 | 37 / 38 |
| serious Total, serious adverse events | 0 / 41 | 2 / 38 |
Outcome results
Primary
Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks
Percent change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 8 weeks.
Time frame: Difference between measurements at baseline compared to measurement at 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine | Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks | 8.1 Percent change from rest measurement | Standard Deviation 4.4 |
| Placebo | Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks | 13.4 Percent change from rest measurement | Standard Deviation 4 |
Secondary
Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.
Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.
Time frame: At 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | Brachial Flow Mediated Dilatation (FMD) at 24 Weeks. | 3.82 % brachial artery dilation |
| Placebo | Brachial Flow Mediated Dilatation (FMD) at 24 Weeks. | 3.46 % brachial artery dilation |
Secondary
Brachial Flow Mediated Dilatation (FMD) at 8 Weeks.
Brachial flow mediated dilatation (FMD) at 8 weeks.
Time frame: At 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | Brachial Flow Mediated Dilatation (FMD) at 8 Weeks. | 4.26 % brachial artery dilation |
| Placebo | Brachial Flow Mediated Dilatation (FMD) at 8 Weeks. | 4.12 % brachial artery dilation |
Secondary
Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks
Change in CSA as measured by the difference between CSA at rest and under IHE stress at 24 weeks
Time frame: At 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks | -0.96 Percent change from rest measurement |
| Placebo | Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks | 5.04 Percent change from rest measurement |
Secondary
Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks
Change in CSA as measured by the difference between CSA at rest and under IHE stress at 8 weeks
Time frame: Difference between measurements at baseline compared to measurement at 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks | -0.10 Percent change from baseline measurement |
| Placebo | Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks | 1.53 Percent change from baseline measurement |
Secondary
Coronary Endothelial Function at 24 Weeks;
Change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 24 weeks.
Time frame: At 24 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | Coronary Endothelial Function at 24 Weeks; | -1.27 Percent change from rest measurement |
| Placebo | Coronary Endothelial Function at 24 Weeks; | 16.60 Percent change from rest measurement |
Secondary
High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks
High-sensitivity C-reactive Protein (hsCRP) at 24 weeks
Time frame: At 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks | 1.00 mg/l |
| Placebo | High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks | 1.30 mg/l |
Secondary
High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks.
High-sensitivity C-reactive protein (hsCRP) at 8 weeks
Time frame: At 8 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks. | 1.65 mg/l |
| Placebo | High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks. | 1.26 mg/l |
Secondary
Interleukin-6 (IL-6) at 8 Weeks
Interleukin-6 (IL-6) at 8 weeks
Time frame: At 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colchicine | Interleukin-6 (IL-6) at 8 Weeks | 0.53 pg/ml |
| Placebo | Interleukin-6 (IL-6) at 8 Weeks | 0.64 pg/ml |