Clinical trial NCT02624180: Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV
Official title: Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronary Artery Disease
Human Immunodeficiency Virus
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2015-12-08
Enrollment: 81
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks
timeFrame: Difference between measurements at baseline compared to measurement at 8 weeks
Secondary outcomes:
measure: Coronary Endothelial Function at 24 Weeks;
timeFrame: At 24 weeks.
measure: Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks
timeFrame: Difference between measurements at baseline compared to measurement at 8 weeks
measure: Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks
timeFrame: At 24 weeks
measure: High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks.
timeFrame: At 8 weeks.
measure: Brachial Flow Mediated Dilatation (FMD) at 8 Weeks.
timeFrame: At 8 weeks
measure: Interleukin-6 (IL-6) at 8 Weeks
timeFrame: At 8 weeks
measure: High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks
timeFrame: At 24 weeks
measure: Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.
timeFrame: At 24 weeks
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Robert G Weiss, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007 Mar 13;115(10):1285-95. doi: 10.1161/CIRCULATIONAHA.106.652859. No abstract available.
citation: Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003 Oct 1;42(7):1149-60. doi: 10.1016/s0735-1097(03)00994-x.
citation: Hays AG, Hirsch GA, Kelle S, Gerstenblith G, Weiss RG, Stuber M. Noninvasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease. J Am Coll Cardiol. 2010 Nov 9;56(20):1657-65. doi: 10.1016/j.jacc.2010.06.036.
citation: Hays AG, Stuber M, Hirsch GA, Yu J, Schar M, Weiss RG, Gerstenblith G, Kelle S. Non-invasive detection of coronary endothelial response to sequential handgrip exercise in coronary artery disease patients and healthy adults. PLoS One. 2013;8(3):e58047. doi: 10.1371/journal.pone.0058047. Epub 2013 Mar 11.
citation: Hays AG, Kelle S, Hirsch GA, Soleimanifard S, Yu J, Agarwal HK, Gerstenblith G, Schar M, Stuber M, Weiss RG. Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study. Circ Cardiovasc Imaging. 2012 May 1;5(3):341-8. doi: 10.1161/CIRCIMAGING.111.969691. Epub 2012 Apr 5.
citation: Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404-410. doi: 10.1016/j.jacc.2012.10.027. Epub 2012 Dec 19.
citation: Brown BG, Lee AB, Bolson EL, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation. 1984 Jul;70(1):18-24. doi: 10.1161/01.cir.70.1.18.
citation: Hays AG, Schar M, Barditch-Crovo P, Bagchi S, Bonanno G, Meyer J, Afework Y, Streeb V, Stradley S, Kelly S, Anders NM, Margolick JB, Lai S, Gerstenblith G, Weiss RG. A randomized, placebo-controlled, double-blinded clinical trial of colchicine to improve vascular health in people living with HIV. AIDS. 2021 Jun 1;35(7):1041-1050. doi: 10.1097/QAD.0000000000002845.