Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02624180
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 81
• Location: 1
• Arms: 2
• Duration (Months): 58
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Human Immunodeficiency Virus	Drug: Colchicine; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV
• Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: Aug 1, 2020
• Actual Study Completion Date: Sep 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Colchicine Colchicine 0.6 mg daily by mouth	Drug: Colchicine; Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease.; Other Names: Colcrys
Placebo Comparator: Placebo Placebo for colchicine 1 tablet by mouth daily	Drug: Placebo; A substance containing no medication

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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

4. High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks. [At 8 weeks.]

   High-sensitivity C-reactive protein (hsCRP) at 8 weeks

5. Brachial Flow Mediated Dilatation (FMD) at 8 Weeks. [At 8 weeks]

   Brachial flow mediated dilatation (FMD) at 8 weeks.

6. Interleukin-6 (IL-6) at 8 Weeks [At 8 weeks]

   Interleukin-6 (IL-6) at 8 weeks

7. High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks [At 24 weeks]

   High-sensitivity C-reactive Protein (hsCRP) at 24 weeks

8. Brachial Flow Mediated Dilatation (FMD) at 24 Weeks. [At 24 weeks]

   Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Robert G Weiss, MD, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 25, 2018

More Information

Publications

• 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.
• Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007 Mar 13;115(10):1285-95. Review.
• 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.
• Hays AG, Kelle S, Hirsch GA, Soleimanifard S, Yu J, Agarwal HK, Gerstenblith G, Schär 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.
• Hays AG, Stuber M, Hirsch GA, Yu J, Schär 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.
• 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.
• 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. Review.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02624180
• Other Study ID Numbers: IRB00070892; 1R01HL125059
• First Posted: Dec 8, 2015
• Last Update Posted: Oct 21, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Coronary Artery Disease; Myocardial Ischemia; Atherosclerosis; Colchicine

Study Results

Participant Flow

Pre-assignment Detail	Two participants randomized to colchicine withdrew before receiving study drug.

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Period Title: Overall Study
STARTED	43	38
COMPLETED	37	34
NOT COMPLETED	6	4

Baseline Characteristics

Arm/Group Title	Colchicine	Placebo	Total
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication	Total of all reporting groups
Overall Participants	43	38	81
Age (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	54.66	52.0	54.25
Sex: Female, Male (Count of Participants)
Female	9 20.9%	8 21.1%	17 21%
Male	34 79.1%	30 78.9%	64 79%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.7%	1 2.6%	3 3.7%
Not Hispanic or Latino	41 95.3%	37 97.4%	78 96.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	33 76.7%	26 68.4%	59 72.8%
White	8 18.6%	11 28.9%	19 23.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 4.7%	1 2.6%	3 3.7%

Outcome Measures

1. Primary Outcome

Title	Coronary Endothelial Function Measured by Percent Change in Coronary Blood Flow With Exercise (%) at 8 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	37	34
Mean (Standard Deviation) [Percent change from rest measurement]	8.1 (4.4)	13.4 (4.0)

2. Secondary Outcome

Title	Coronary Endothelial Function at 24 Weeks;
Description	Change in coronary blood flow (CBF) from rest to that during isometric handgrip exercise (IHE) stress at 24 weeks.
Time Frame	At 24 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	34	32
Median (Inter-Quartile Range) [Percent change from rest measurement]	-1.27	16.60

3. Secondary Outcome

Title	Change in Coronary Artery Cross-sectional Area (CSA) at 8 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	37	34
Median (Inter-Quartile Range) [Percent change from baseline measurement]	-0.10	1.53

4. Secondary Outcome

Title	Change in Coronary Artery Cross-sectional Area (CSA) at 24 Weeks
Description	Change in CSA as measured by the difference between CSA at rest and under IHE stress at 24 weeks
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	34	33
Median (Inter-Quartile Range) [Percent change from rest measurement]	-0.96	5.04

5. Secondary Outcome

Title	High-sensitivity C-reactive Protein (hsCRP) at 8 Weeks.
Description	High-sensitivity C-reactive protein (hsCRP) at 8 weeks
Time Frame	At 8 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	37	34
Median (Inter-Quartile Range) [mg/l]	1.65	1.26

6. Secondary Outcome

Title	Brachial Flow Mediated Dilatation (FMD) at 8 Weeks.
Description	Brachial flow mediated dilatation (FMD) at 8 weeks.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	37	34
Median (Inter-Quartile Range) [% brachial artery dilation]	4.26	4.12

7. Secondary Outcome

Title	Interleukin-6 (IL-6) at 8 Weeks
Description	Interleukin-6 (IL-6) at 8 weeks
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	37	34
Median (Inter-Quartile Range) [pg/ml]	0.53	0.64

8. Secondary Outcome

Title	High-sensitivity C-reactive Protein (hsCRP) at 24 Weeks
Description	High-sensitivity C-reactive Protein (hsCRP) at 24 weeks
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	35	32
Median (Inter-Quartile Range) [mg/l]	1.00	1.30

9. Secondary Outcome

Title	Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.
Description	Brachial Flow Mediated Dilatation (FMD) at 24 Weeks.
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colchicine	Placebo
Arm/Group Description	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.	Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
Measure Participants	30	30
Median (Inter-Quartile Range) [% brachial artery dilation]	3.82	3.46

Adverse Events

Time Frame	Adverse event data were collected over study enrollment (up to 24 weeks after randomization to study drug)
Adverse Event Reporting Description	Two participants randomized to colchicine withdrew before receiving study drug so number of participants at risk listed here as 41.
Arm/Group Title	Colchicine		Placebo
Arm/Group Description	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.		Placebo for colchicine 1 tablet by mouth daily Placebo: A substance containing no medication
All Cause Mortality
	Colchicine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/38 (0%)
Serious Adverse Events
	Colchicine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		2/38 (5.3%)
Renal and urinary disorders
Hospitalization	0/41 (0%)	0	1/38 (2.6%)	1
Surgical and medical procedures
Hospitalization	0/41 (0%)	0	1/38 (2.6%)	1
Other (Not Including Serious) Adverse Events
	Colchicine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/41 (95.1%)		37/38 (97.4%)
Blood and lymphatic system disorders
Decreased White Blood Cell	7/41 (17.1%)	7	4/38 (10.5%)	4
Decreased Hematocrit	10/41 (24.4%)	10	8/38 (21.1%)	8
Eye disorders
Vision	1/41 (2.4%)	1	0/38 (0%)	0
Gastrointestinal disorders
Gastrointestinal disorder	12/41 (29.3%)	12	9/38 (23.7%)	9
General disorders
Extremity swelling	0/41 (0%)	0	1/38 (2.6%)	1
Dental pain/infection	0/41 (0%)	0	3/38 (7.9%)	3
Hepatobiliary disorders
Increased Aspartate Amino Trans	7/41 (17.1%)	7	6/38 (15.8%)	6
Increased Alanine Amino Trans	7/41 (17.1%)	7	5/38 (13.2%)	5
Infections and infestations
Infection	9/41 (22%)	9	19/38 (50%)	19
Injury, poisoning and procedural complications
Physical Injury	1/41 (2.4%)	1	3/38 (7.9%)	3
Musculoskeletal and connective tissue disorders
Joint/Muscle Soreness/Stiffness	8/41 (19.5%)	8	9/38 (23.7%)	9
Fatigue	1/41 (2.4%)	1	1/38 (2.6%)	1
Renal and urinary disorders
Decreased Estimated GFR	10/41 (24.4%)	10	7/38 (18.4%)	7
Skin and subcutaneous tissue disorders
Skin Irritation	2/41 (4.9%)	2	5/38 (13.2%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.