Conditions: Coronary Artery Disease Human Immunodeficiency Virus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

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.

Arms:
arm 1: Colchicine 0.6 mg daily by mouth arm 2: Placebo for colchicine 1 tablet by mouth daily

Interventions: intervention 1: Colchicine intervention 2: Placebo
Intervention descriptions: intervention 1: Administered to determine the effect of anti-inflammatory agents on coronary and systemic endothelial function in patients with coronary artery disease. intervention 2: A substance containing no medication

Protocol document:
Prot_SAP_000.pdf: 
Official title:  Inflammatory pathogenesis of coronary atherosclerosis in 
HIV.  
NCT number:  NCT02624180 
  
 
Document date: June 25, 2018 
 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 1 of 22 
JHM IRB - eForm A – Protocol 
 
 
• 
Use the section headings to write the JHM IRB eForm A, inserting the appropriate 
material in each. If a section is not applicable, leave heading in and insert N/A. 
• 
When submitting JHM IRB eForm A (new or revised), enter the date submitted to the 
field at the top of JHM IRB eForm A. 
********************************************************************************************* 
1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research. 
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 artery disease (CAD). HIV patients manifest an increased risk of CAD and its 
consequences possibly due to interplay of inflammation with traditional risk factors, some of the 
latter accentuated by ART. In addition, epicardial adipose tissue (EAT), a metabolically-active 
paracrine source of local inflammatory mediators, accumulates in HIV+ people and may also 
contribute to local CAD development. Mechanistic studies of the role of inflammation in the 
pathogenesis of CAD in HIV+ people taking ART are desperately needed to define the importance 
of inflammation per se and to guide the testing of new practical treatment approaches.  
    Although current imaging methods can document anatomic CAD that has developed over years, 
there has not been a noninvasive means to identify and quantify the central, early mechanisms 
contributing to the pathogenesis of CAD such as coronary endothelial dysfunction. Two very recent 
advances now make it possible to overcome those hurdles and test the role of inflammation in HIV-
associated CAD. 
    First, colchicine is an anti-inflammatory agent used for over 20 years to treat gout and recurrent 
pericarditis. Low dose colchicine (LDC) reduces inflammatory biomarkers and was shown recently 
to reduce cardiovascular events by more than 65% (p<0.001) in stable CAD patients(1). In 
addition, we have recent evidence that colchicine does not suppress markers of immune function 
in HIV+ people. Thus LDC offers a practical, clinically relevant, untested means to probe the 
impact of inflammation on CAD pathogenesis in HIV+ people. 
    Second, inflammation undoubtedly enhances the development and progression of coronary 
atherosclerosis via several mechanisms, but endothelial dysfunction is believed to be one common 
result of these mechanisms. Coronary endothelial function (CEF) plays a pivotal role in the 
development, progression, and clinical manifestations of CAD and endothelial dysfunction is a 
marker for sub-clinical disease, an independent predictor of cardiovascular events, and a target for 
successful medical interventions(2-9). Endothelial-dependent function was historically only 
assessed invasively in the catheterization laboratory by changes in coronary arterial diameter and 
flow in response to endothelial-dependent vasomotor interventions. We recently developed and 
validated the first noninvasive methods to study CEF: these MRI-based methods allow safe, non-
invasive reproducible studies in the same individuals over time and in low risk populations (10, 11). 
Thus the impact of anti-inflammatory interventions on CAD pathogenesis in HIV+ people can now 
be assessed. 
    We propose here a randomized, double-blind, placebo-controlled, phase 2, proof-of-concept trial 
exploiting our new non-invasive CEF measures to determine whether LDC improves local CEF in 
HIV+ people with no history of clinical CAD. 
2. 
Objectives (include all primary and secondary objectives) 
To evaluate the role of inflammation on the pathogenesis of coronary atherosclerosis in HIV 
we will test the hypothesis that an anti-inflammatory intervention, low dose colchicine (LDC), 
improves impaired local coronary endothelial function in HIV+ people with no clinical CAD.   


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 2 of 22 
To test the hypotheses that 1) EAT in HIV+ people is associated with impaired local CEF, 
and 2) LDC improves CEF more in coronary segments with increased EAT, as a source of local 
inflammatory mediators, as compared to segments with less EAT. 
 
Primary Endpoint: Coronary endothelial function at 8 weeks; specifically, change in coronary 
blood flow (CBF) from rest to that during IHE stress (% rest and as ml/min) at 8 weeks. 
 
Secondary Endpoints:  
1. Change in coronary artery CBF from rest to IHE stress (as ml/min and as % rest) at 24 
weeks; 
2. Change in coronary artery CSA from rest to IHE stress (as mm2 and as % rest) at 8 and 24 
weeks; 
3. hsCRP and IL-6 at 8 and 24 weeks and change in hs-CRP& IL-6 between baseline and 8 
and 24 weeks;  
4. Brachial flow mediated dilatation (FMD) at 8 and 24 weeks: change in FMD between 
baseline and 8 and 24 weeks; 
 
To make full use of the data, changes in CEF from baseline to 8- and 24-weeks will be 
analyzed, along with changes in FMD and changes in inflammatory biomarkers (hsCRP, IL-6, 
VCAM-1, TNFa) from baseline to 8- and 24-weeks. Also, the relationship between change in 
inflammatory markers from baseline to 8 weeks (and 24 weeks) and change in CEF between 
baseline and 8 and 24 weeks will be quantified. CD4+ cell counts and HIV RNA (viral load) will be 
measured in subjects at baseline and 24 weeks. Additional variables for evaluation are coronary 
plaque burden (CWT, NWI, and percent luminal stenosis). 
 
Safety endpoints: metabolic panel and complete blood count, withdrawal due to side-effects 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
Since the advent of effective ART in the 1990’s, HIV+ people are living longer and developing 
chronic diseases including cardiovascular disease that is currently the cause of death in 8%-15% 
of HIV+ people(15-18). HIV+ people have accelerated atherosclerosis and an approximate 50%-
70% increase in the risk of myocardial infarction (MI) as compared to a comparable, age-matched 
population(19-21). Several factors are thought to contribute to this increased CAD risk including 
over-representation of traditional risk factors, chronic inflammation, and vascular activation in HIV+ 
people. However, the importance and interaction of these factors are very poorly understood and 
so in 2012 the NHLBI AIDS Working Group convened and published “Advancing HIV/AIDS 
Research in Heart, Lung, and Blood Disease” to outline critical gaps in HIV research.  
 
Three main knowledge gaps regarding the pathogenesis of HIV heart disease were identified 
and this protocol proposes to address two of them: 1) mechanisms of the interplay of 
HIV/inflammation, anti-retroviral therapy, and traditional risk factors in the development of CAD, 
and 2) characterization of atherosclerosis in HIV+ people through cardiovascular imaging. We 
propose to conduct a mechanistic, phase 2 trial that elucidates the role of inflammation in the 
pathogenesis of CAD in HIV+ people.  
 
    
Coronary atherosclerosis is an inflammatory disease (22). Endothelial cell injury and 
activation occur at the earliest stages of atherosclerosis with expression of endothelial surface 
molecules (e.g. vascular cell adhesion molecule-1, (VCAM-1)), that attract leukocytes, mostly 
monocytes, which in turn invade the vessel wall, drawn by chemo-attractant molecules and then 
contribute to the development of fatty streaks (22, 23). HIV infection, as well as HIV tat and Nef 
proteins in the absence of infection, activate endothelial and circulating immune cells (24). 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 3 of 22 
Although ART reduces circulating inflammatory biomarkers, they are often not reduced to normal 
levels and circulating virus and the extent of immune and inflammatory activation correlate with the 
presence and extent of carotid and coronary atherosclerosis. Despite these associations the effect 
of inflammation per se on the processes which result in coronary atherosclerosis and whether an 
anti-inflammatory strategy alters these processes in HIV+ people is not known.  
 
Abnormal coronary endothelial function (CEF) is likely an important contributor to 
atherosclerosis and, therefore, a potential target for medical interventions (25-32). Inflammation 
and endothelial dysfunction are closely related at all stages of CAD. Exposure of the endothelium 
to proinflammatory cytokines impairs endothelium-dependent vascular relaxation and induces 
prothrombotic activity (33) while inflammatory markers like hsCRP correlate with abnormal brachial 
artery endothelial vasoreactivity(34). The effects of inflammation on endothelial function may be 
mediated through reactive oxygen species (ROS) that decrease the bioavailability of NO (35), and 
separately by events that lead to programmed cell death (36-38). ART improves brachial artery 
endothelial function in ART naïve HIV+ people(39). Although inflammatory biomarkers are 
associated with increased cardiac risk in HIV+ people, it is not known whether reducing 
inflammation will alter the fundamental biologic processes linked to CAD, such as abnormal CEF. 
Thus measures of CEF offer a fundamental pathophysiologic window into the processes 
responsible for CAD in HIV+ people and may provide a means to assess the relative importance, if 
any, of inflammatory markers and the impact of anti-inflammatory interventions on this important 
contributor to CAD. 
 
Endothelial-dependent function is assessed by the direction and magnitude of changes in 
arterial area and flow in response to endothelial-dependent vasomotor interventions (26). The 
invasive nature of coronary angiography with Doppler flow measures used in traditional measures 
of CEF limited clinical and research investigations, particularly those benefiting from repeated 
studies and/or studies in clinically stable subjects. We describe here, a novel validated approach 
using 3T magnetic resonance imaging (MRI) to assess NO-mediated endothelial-dependent 
coronary vasomotor function noninvasively. We combined 3T coronary MRI with isometric handgrip 
exercise (IHE), a previously proposed endothelial-dependent stressor (40-45), as a new approach 
to quantify CEF noninvasively. Our published findings demonstrate that 3T MRI combined with IHE 
can detect vasodilatation and increased blood flow in healthy subjects and paradoxical 
vasoconstriction and reduced coronary blood flow in patients with CAD, hallmarks of CEF. In 
addition, the heterogeneous response in CAD patients to the endothelial-dependent stressor, with 
more abnormal endothelial responses in coronary arteries with a more severe stenosis, calls into 
question the ability of peripheral endothelial function measures to accurately reflect the spectrum of 
CEF present within a given patient with CAD. The new capacity to noninvasively quantify CEF is a 
significant innovation that also provides new biologic insights. 
 
 
Role of Inflammation: Following the pathologic recognition of the role of inflammatory cells 
in acute coronary syndromes, corticosteroids were initially investigated as anti-inflammatory agents 
in CAD patients. Enthusiasm for corticosteroids was tempered by equivocal benefit (46) and 
concerns about wound healing, myocardial rupture, and adverse metabolic effects (47). 
Nonsteroidal anti-inflammatory drugs (NSAIDs) were later associated with higher MI and event 
rates in CAD patients (48). Thus, initial anti-inflammatory strategies were not successful. 
 
      
However there is renewed interest in anti-inflammatory strategies because patients with 
elevated inflammatory biomarkers (e.g., hsCRP) are at increased risk of primary and secondary 
cardiovascular   events (49-52) and because statins have anti-inflammatory properties (53-55) and 
lower cardiovascular mortality (56-59). Nevertheless cardiovascular event rates remain high in 
statin treated HIV+ people (54, 60) and statins alone do not fully suppress inflammation in many 
patients (54, 61). Thus it is not known whether an anti-inflammatory approach would be effective in 
improving CEF in HIV, which systemic inflammatory biomarkers best predict the local coronary 
response (if any), and whether the local CEF response is heterogeneous and related to the extent 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 4 of 22 
of underlying atherosclerosis (Aim 1) and/or surrounding epicardial adipose tissue (Aim 2) in a 
given HIV+ patient. To answer the question of whether inhibiting inflammation per se improves 
coronary endothelial dysfunction and impacts atherosclerosis in HIV+ people we need well-
tolerated anti-inflammatory agents that do not have profound effects on lipids and do not 
significantly suppress the immune system in HIV+ people receiving ART.  
 
     
Low dose colchicine (LDC) is an appealing choice to suppress inflammation in HIV+ people 
because it has been used for decades to treat inflammatory diseases and, in some populations, 
reduces inflammatory biomarkers, improves systemic endothelial function and is associated with 
fewer cardiac events.   
 
Colchicine and cardiac disease:  Colchicine is an anti-inflammatory agent used to treat gout, 
recurrent pericarditis, post-pericardiotomy syndrome, Bechet’s disease and sometimes life-long 
(<2mg/day) to treat Familial Mediterranean Fever (FMF) (62-65). Colchicine is believed to act 
through inhibition of microtubule assembly in immune cells, including neutrophils and monocytes, 
which leads to reduced cytokine production, modulation of chemokine and prostanoid production 
and inhibition and down-regulation of lymphocyte and endothelial cell adhesion molecule surface 
expression (66, 67). Colchicine is concentrated in leukocytes due to a prolonged half-life in those 
cells (~60 hrs) as compared to that in plasma (~20 min) (68-70).  
 
Because LDC manifests many potent anti-inflammatory effects, has been in clinical use for 
decades, and does not have adverse effects on lipids, it is an appealing choice for the treatment of 
inflammatory heart diseases. Chronic LDC was studied for the prevention of postoperative atrial 
fibrillation (70). Following cardiac surgery, 336 patients were randomized to placebo or colchicine 
(0.25-0.5mg twice daily) for 30 days. The incidence of atrial fibrillation was reduced in those 
receiving LDC (12.0% versus 22.0%, P<0.021; relative risk reduction, 45%; number needed to 
treat, 11) with shorter in-hospital and rehabilitation stays. No severe side effects were noted and 
the rates of withdrawal and side effects were similar in placebo and LDC groups. In another trial, 
patients with paroxysmal atrial fibrillation undergoing ablation were randomized to placebo or 
colchicine (0.5mg twice daily) for three months. LDC reduced recurrent atrial fibrillation by about 
60% (odds ratio 0.38, p=0.01; number needed to treat 5.6)(71). Notably, the inflammatory 
biomarkers, hsCRP and IL-6, were reduced by 35% and 19%, respectively (both p<0.01) after only 
3 days of LDC in these cardiac patients. In a recent randomized 240 patient trial of colchicine 
(0.5mg BID) for acute pericarditis, LDC reduced symptoms, hospitalizations and relapse rates, with 
discontinuation rates similar to those in patients taking placebo (72).  
 
       
Several observational studies in the last 3 years suggest a positive effect of LDC on 
cardiovascular outcomes. In a 2012 retrospective study, gout users taking colchicine had a lower 
incidence of MI (1.2% vs 2.6%, p<0.03) and exhibited trends toward reduced all-cause mortality 
and lower CRP level versus those who did not take colchicine, despite similar baseline risk factors 
(73). In stable CAD patients with hsCRP>2mg L-1, LDC (0.5mg twice daily) reduced hsCRP levels 
in four weeks by about 60%(74). More recently, the Low Dose Colchicine for Secondary Prevention 
of Coronary Artery Disease (LoDoCo) Trial results were reported(1). In this prospective, 
randomized, observer-blinded endpoint (PROBE) study, 532 patients with stable CAD received 
either placebo or colchicine (0.5mg/day) in addition to usual care. Patients were followed for a 
median of 3 years. LDC significantly reduced the primary composite endpoint of acute coronary 
syndrome, out-of-hospital cardiac arrest, and stroke by 67% (hazard ratio: 0.33; 95% confidence 
interval [CI] 0.18 to 0.59; p < 0.001; number needed to treat: 11). This occurred in a CAD 
population on aggressive background cardiovascular therapy. The LDC benefit was observed 
early, continued to accrue over time, and was largely driven by a reduction in coronary events (1). 
11% of colchicine patients withdrew during the first 30 days and another 11% over the ensuing 3 
years, mostly due to the well-known gastrointestinal side effects. An accompanying editorial 
commented that the 67% reduction in coronary events is about twice that seen with statins (47). 
Taken together, these studies demonstrate that LDC reduces inflammatory biomarkers rapidly in 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 5 of 22 
patients with CAD (possibly as early as 3 days), is safely tolerated in the vast majority of CAD 
patients for several years, and appears to reduce cardiac events (pending confirmation) by an 
unidentified mechanism. This protocol proposes to use LDC to mechanistically probe for the first 
time the role of inflammation in the pathogenesis of CAD in HIV+ people.  
 
Epicardial adipose tissue: a paracrine source of inflammatory cytokines contributing to 
CAD in HIV. 
Visceral adipose tissue (VAT) is metabolically active and its extent correlates more closely 
with increased cardiovascular risk than does subcutaneous adipose tissue in the general 
population (75-77). VAT releases several inflammatory cytokines associated with atherosclerosis, 
including TNF-α and IL-6, which in turn activate production of pro-atherosclerotic mediators such 
as ICAM, VCAM, PAI-I and endothelin-1 (78, 79). VAT is increased in the lipodystrophy syndrome 
associated with HIV (80, 81). Epicardial adipose tissue (EAT), shares a similar embryologic origin 
to VAT, releases inflammatory cytokines and is metabolically active and associated with increased 
cardiovascular risk (82-85). Importantly, EAT is increased in HIV+ people taking ART and 
associated with atherosclerosis (86-91). Studies relating EAT to cardiovascular risk factors and 
atherosclerosis in HIV populations are relatively recent and have relied on noninvasive imaging 
measures of EAT thickness, typically by echocardiography, DEXA, and/or EAT volumes by CT and 
MRI. Volumetric CT and MRI measures of EAT are more reproducible than thickness measures 
and in some recent studies, MRI is considered the gold-standard, in part due to its ability to 
chemically clearly distinguish lipid and water resonances (92-94).  
 
The hypothesis that EAT releases inflammatory cytokines that contribute through paracrine 
mechanisms to local coronary atherosclerosis is supported indirectly by observations that 
epicardial coronary artery segments coursing through cardiac muscle (“bridges” that do not contact 
EAT) do not develop atherosclerosis (95-97). Although a local, inflammatory-paracrine contribution 
of EAT to accelerated coronary atherosclerosis in HIV is appealing and directly in line with the aims 
of a recent NIH request for application (RFA HL14-023), there is no direct evidence linking EAT 
with the local pathogenesis of CAD via inflammatory or other mechanisms in HIV+ people.  
 
We propose to evaluate this for the first time by combining EAT and CEF imaging 
techniques with the LDC intervention to probe the role of inflammation in HIV+ people. Because 
endothelial dysfunction is a critical step in the pathogenesis of atherosclerosis and because we can 
detect spatially heterogeneous CEF with MRI, we will use MRI to study CEF and relate CEF to 
local atherosclerosis and local EAT, in the same examination.  We will study for the first time, in 
observational fashion, the baseline relationships among EAT, CEF and early atherosclerosis in 
HIV+ people as well as probe, in interventional fashion, the effects of an anti-inflammatory agent 
on those relationships in HIV+ people.  
 
We searched the Johns Hopkins HIV Clinic database and observed that mean circulating 
neutrophil and CD4 counts were measured in 48 HIV+ people before, during and after clinical 
treatment with colchicine. There was no significant suppression of neutrophil or CD4 counts by 
colchicine. Most patients received >0.6mg daily, the same or more than proposed here. Mean 
duration of colchicine use was 104 days (quartiles: 54:181 days; range 10-316 days). Thus 75% of 
HIV+ people treated clinically with colchicine in our database are treated at least ~8 weeks, the 
primary endpoint of our proposed trial, and this duration of colchicine administration is not 
associated with a decrease in mean cell counts. 
 
    
Although the FDA would not provide us safety information on colchicine in HIV apart from 
that publicly available, due to proprietary concerns, the one supplier of colchicine in the US did. Dr. 
Morehead of Takeda Pharmaceuticals wrote in an email that their Medical Director of 
Pharmacovigilance (PV) reviewed the last 12 months in the PV database with a search that 
involved HIV-positive patients who may have taken colchicine and wrote to me that “No reports of 
safety concerns were found.” They also conducted literature searches and did not find information 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 6 of 22 
suggesting safety concerns (adverse events or drug interactions) in HIV+ people other than those 
in prescribing information. Our proposed trial will provide critical LDC safety data in HIV+ people. 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
 
The following are research procedures: 
 
Randomized, double-blind, placebo-controlled phase 2 trial of the effect of LDC on coronary 
and systemic endothelial function and inflammatory biomarkers in 102 HIV+ people with no clinical 
CAD. More specifically, HIV+ people on stable clinically-guided ART will undergo baseline MRI 
quantification of CEF and EAT. Those with abnormal CEF (an increase in coronary CBF during IHE 
of ≤7ml/min from the resting value) will then have assessment of brachial FMD by ultrasound, 
measurement of inflammatory markers and lipids, and then be randomized to 24 weeks of either 
(1) colchicine (0.6mg daily) or (2) matching placebo. The Johns Hopkins Research Pharmacy will 
conduct the randomization procedure, prepare study medications in similar appearing formulations, 
and maintain group assignment documentation, keeping investigators blinded. Stratified 
randomization will be performed for smoking (yes/no). In addition the Research Pharmacy will 
review the two groups after 50% of the subjects have been randomized for gender and prevalence 
of diabetes, hypertension and statin use and adjust subsequent group assignment if they are not 
balanced for potential confounding factors. CEF, FMD, and biomarker endpoints will be re-
assessed at 8 and 24 (unless subjects experience a clinical event that increases inflammation, in 
which case evaluation will occur after the inflammatory clinical event resolves). Subjects will be 
evaluated every 6 weeks for safety. 
 
Initial evaluation: A careful history and physical examination will be performed. Blood samples will 
be acquired for complete blood cell count, CD4+ count and HIV RNA level, routine chemistry panel 
including hepatic transaminases and creatinine, LDL and HDL cholesterol and triglycerides, as well 
as serum hsCRP, IL-6, IL-1β, TNFα, IFN-γ, ICAM-1, VCAM-1, sE-selectin, sP-selectin, 
thombomodulin, vWF, PAI-1, endothelin-1, adiponectin and other biomarkers. Patients will also be 
tested for hepatitis B and C. 
 
Systemic Endothelial Function: Brachial Flow Mediated Dilatation (FMD) and Velocity: These 
studies will be conducted at the ICTR on participants in the fasting state (>10 hours) asked to 
refrain from drinking alcohol or beverages containing caffeine in the prior 24 h using a standardized 
protocol (98, 99). Supine subjects will have the brachial artery visualized with a high-resolution 
ultrasound probe proximal to the antecubital fossa. After baseline images and flow measurements, 
a pressure cuff on the upper arm will be inflated to 200–250 mmHg for 5 min. Blood flow will be 
measured during the 15 s following cuff release and vessel diameter between 60 and 90 s after 
cuff deflation. Flow-mediated dilation (FMD) and velocity time interval (VTI) will be calculated (98, 
99). Images will be coded and analyzed in blinded fashion. 
 
MRI methods for Coronary Vasoreactivity: an index of CEF: Patients will undergo a detailed 
baseline MRI study of CEF in the fasting state using MRI methodology at rest and during 
continuous IHE as previously described (10). The MRI will be used to measure cross-sectional 
area (CSA), coronary flow velocity (CFV), and coronary blood flow (CBF) changes in response to 
IHE stress (continuous isometric handgrip for 4 min at 30% of each subject’s maximum, 
determined prior to entering the MRI), as previously reported(11),(10). Coronary black blood 
imaging will also be performed in the same coronary slices for vessel wall measurements: CWT, 
vessel wall area and normalized wall index (NWI), an index of arterial remodeling calculated as: 
vessel wall area divided by the total vessel area (11). In addition, fat-excited and Dixon EAT 
acquisitions will be obtained in the same coronary segments as measures of CEF and CWT, so 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 7 of 22 
that the volume of EAT can be assessed in the same coronary segment. In the event of technical 
or other difficulties in obtaining adequate images, the MRI may be repeated with the participant’s 
permission. 
 
Fasting:  Subjects will be asked to fast after midnight and delay eating breakfast and taking 
morning cardiovascular medicines until after the study procedure, which will be completed by noon.  
In insulin-dependent diabetics, we will ask the subjects to delay their morning insulin dose until 
after the study procedure and will complete their studies by 10am.  In addition, we will have a 
snack available and access to a finger-stick glucometer for any insulin-dependent diabetics who 
become symptomatic. 
 
MRI analysis: MR images will be analyzed in blinded fashion without operator knowledge of time 
or treatment group for CEF (eg changes in CBF, CBV, and CSA) as previously validated and 
described (10). In addition, black blood coronary images will be analyzed for coronary wall 
thickness (CWT), an early marker of coronary atherosclerosis, and NWI, as described (11). Fat 
images (from fat selective excitation and/or mDixon method) will be analyzed for EAT for maximum 
thickness, CSA, and segment volume in each coronary segment evaluated for CEF. Baseline, 8-
week and 24-week images will be analyzed at the same time for each subject (again blinded to 
time and treatment group with equal numbers of placebo and LDC) to reduce variability and assure 
identical segments are analyzed at each time. If the participant withdraws from the study before 
week 24, we will request participant permission to perform an MRI and FMD at termination of 
study.  
 
Blood Draw and Biomarker Analysis: Blood samples will be obtained from a peripheral vein 
using standard venipuncture techniques. Biomarkers will be analyzed in replicate by the ICTR CRU 
Core Laboratory directed by Dr. Neal Fedarko from blood specimens collected into collection tubes 
without anticoagulant and centrifuged 30 min after collection (time allowed for clotting) using a 
centrifuge with an integrated refrigeration system (at 4°C/1000 g for 15 min) and kept at -80°C.  
Each aliquot will be thawed and analyzed once, and no aliquots will be refrozen(71). Analysis will 
be 
performed 
with 
ELISA 
or 
multiplexed 
ELISA 
for 
the 
following 
biomarkers 
of 
inflammation/activation/clotting (coefficient of variation listed in parentheses): hsCRP (6%), IL-6 
(5%), IL-1β (8%), TNFα (8%), IFN-γ, ICAM-1 (6%), VCAM-1 (4%), sE-selectin (6%), sP-selectin 
(4%), thombomodulin, vWF (3%), PAI-1 (3%), endothelin-1, adiponectin (5%), and serum 
monocyte activation markers (sCD163) (100), PCSK9 and other inflammatory markers. All of these 
can be acquired from <900ul of serum. To minimize variability of assays of longitudinal markers, 
the baseline, 8- and 24-week specimens of each individual will be analyzed on the same plate, with 
equal numbers of subjects who received placebo and LDC. 
 
Safety surveillance: Patients will undergo surveillance safety monitoring every 6 weeks that will 
include complete blood counts, and liver and renal function tests. Dr. Lisa Christopher-Stine, Co-
Director of the Johns Hopkins Myositis Center will serve as the Chair of the DSMB and will review 
laboratory results from a safety standpoint. She will not be involved in primary or secondary data 
analysis or interpretation. Patients will also return 4 weeks after the last dose of study drug for a 
safety evaluation. 
 
Follow up End-point Evaluation: After 8 and 24 weeks of study-drug administration, subjects will 
undergo repeat evaluation, lipid and inflammatory biomarker analysis, CD4+ count and HIV RNA 
levels, as well as brachial FMD and coronary MRI with the same protocols used at baseline. In 
particular, coronary MRI will be repeated with an identical protocol and special attention taken to 
interrogate the same coronary segments as those studied at baseline, using anatomic landmarks 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 8 of 22 
of coronary ostia and branch vessels- as we have done in the past (10). Study drug compliance will 
be assessed by questionnaire and pill count at 6, 12, 18 and 24 weeks.  
 
b. Study duration and number of study visits required of research participants. 
Each participant will be followed for a 7-8 month period with the possibility of 8 – 9 study 
visits. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Participants will be randomly assigned to one of two study groups (placebo or LDC) after 
providing informed consent and meeting all inclusion criteria. To keep the investigators blinded, the 
Johns Hopkins research pharmacy will conduct the randomization procedure, prepare medications 
(colchicine and placebo) in similar appearing formulations, and maintain group assignment 
documentation. The Johns Hopkins research pharmacy has many decades of experience in this 
process including randomization for study group assignment, blinding of medications, and 
maintenance of appropriate records for group assignment. It is important to blind the investigators 
and the subjects so that there is no bias in reporting or recording of potential side effects. 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped.   
 
All participants will receive routine care and will not have current therapy stopped because 
of participating in the study. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
The placebo group is included as a separate control group and will be used as a 
comparator group. Anti-inflammatory strategies like colchicine are not a standard part of 
contemporary therapy for patients with coronary artery disease thus there is no ethical problem 
with withholding them in a placebo group. Because it is not known whether these anti-inflammatory 
agents improve coronary endothelial function and/or limit atherosclerosis in CAD patients it is 
critical to have a placebo group to determine the efficacy of the anti-inflammatory drugs and to 
evaluate their safety. 
 
f. 
Definition of treatment failure or participant removal criteria. 
 
  
Participants who experience significant symptoms will be evaluated and those or others 
who develop new laboratory abnormalities will be reviewed and labs possibly repeated.  If any of 
the following criteria are met (CBC<2000, platelets<50,000, Hct<27%, GFR <30ml/min or a >50% 
reduction in GFR compared to baseline values, and LFTs >3x upper limit of normal), the test would 
be repeated. If confirmed on repeat, there would be a temporary stop of study drugs. If the 
abnormality resolves, study drugs would be resumed at the same or lower dose. If the abnormality 
does not resolve or the temporary stop occurs on three consecutive measures, then the case will 
be reviewed for discontinuation from the study. Based on the clinical status, severity of the 
problem, and reversal of symptoms/laboratory findings, a decision will be made as to whether the 
study drug can be restarted under close observation (weekly surveillance) or the participant 
withdrawn from the study. Participants who wish to end participation in the trial at any time may do 
so upon request without penalty. 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
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Participants withdrawn from receiving additional study drug due to an adverse experience 
will be followed by the Investigator until the outcome is determined.  Every effort will be made to 
follow the subject for the full study period as per the schedule of study visits. 
 
5. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  
A. Patients of either gender who are ³21 years of age (no upper age limit), HIV positive and taking 
stable ART (no change in ART regimen in last 3 months),  
B.  HIV viral load <100 copies/mL (plasma HIV RNA concentration),  
C. Abnormal CEF at baseline (<7ml/min change in CBF during IHE as compared to resting value).  
 
Exclusion criteria:  
A. Patients unable to understand the risks, benefits, and alternatives of participation and give 
meaningful consent,  
B. Patients with contraindications to MRI such as implanted metallic objects (pre-existing cardiac 
pacemakers, cerebral clips) or indwelling metallic projectiles,  
C. History of clinical CAD, including acute coronary syndrome, myocardial infarction or 
revascularization,  
D. Resting ECG with evidence of Q wave myocardial infarction,  
E. Pregnant women,  
F. Recent history, within the past 3 months, of cocaine or heroin use,  
G. Moderate or greater renal impairment (estimated glomerular filtration rate <45ml/min),  
H. Moderate-severe hepatic disease (elevation in hepatic transaminases >3x upper limit of 
normal),  
I. Leukopenia (<3000/mm3) or thrombocytopenia (<100,000/mm3),  
J. CD4<200 cell/mm3,  
K. Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's 
disease,  
L. Requirement for, or intolerance to, colchicine,  
M. Women of childbearing potential (even if using oral contraceptive agents) or intention to 
breastfeed,  
N. Chronic, continuous use of oral or IV steroid therapy or other immunosuppressive or biologic 
response modifiers or anti-inflammatory agents (chronic NSAIDs or ASA>81mg daily),  
O. History of chronic pericardial effusion, pleural effusion, ascites or peripheral neuropathy 
manifested by both signs and symptoms,  
P. Taking protease inhibitors (PI), cobicistat, or CYP3A4 inhibitors. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
The chosen low dose of colchicine is based on those used in clinical practice and recent 
studies showing that it reduces inflammation and improves endothelial function in patients with 
rheumatoid arthritis and other conditions. Colchicine is an anti-inflammatory agent used for over 20 
years to treat gout, recurrent pericarditis, and post-pericardiotomy syndrome. Colchicine 
(1-2mg/day) is used chronically, sometimes life-long, to treat Familial Mediterranean Fever (FMF), 
where it is well tolerated (62-64). It is also used to treat Bechet’s disease (65).  The dose we have 
chosen, 0.6mg daily, is a dose that is available in the United States and most similar to the dose 
that reduced recurrent cardiac events in CAD patients in the Low Dose Colchicine for Secondary 
Prevention of Coronary Artery Disease (LoDoCo, 0.5mg daily) trial (1) where the drug was 
reasonably well tolerated. The 0.5 mg dose is not available in the United States. In addition, we 
provide evidence in the Preliminary Studies section that colchicine does not suppress immune 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 10 of 22 
function in that it is does not lower CD4 or neutrophil counts in HIV+ people in the Johns Hopkins 
HIV clinic. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-
FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
Low dose colchicine is an FDA approved medication that is, however, not approved for this 
indication. We received an exemption from the FDA that an IND is not needed.  Safety information 
on the use of these drugs is detailed above.  
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  NA 
 
 
7. 
Study Statistics 
 
a. Primary outcome variable. 
Coronary endothelial function at 8 weeks; specifically, change in coronary blood flow 
(CBF) from rest to that during IHE stress (% rest and as ml/min) at 8 weeks 
b. Secondary outcome variables. 
(i) Change in coronary artery CBF from rest to IHE stress (as ml/min and as % 
rest) at 24 weeks 
(ii) Change in coronary artery CSA from rest to IHE stress (as mm2 and as % 
rest) at 8 and 24 weeks 
(iii) hsCRP and IL-6 at 8 and 24 weeks and change in hs-CRP& IL-6 between 
baseline and 8 and 24 weeks  
(iv) Brachial FMD at 8 and 24 weeks: change in FMD between baseline and 8 
and 24 weeks 
 
To make full use of the data, changes in CEF from baseline to 8- and 24-weeks will be analyzed, 
along with changes in FMD and changes in inflammatory biomarkers (hsCRP, IL-6, VCAM-1, 
TNFa) from baseline to 8- and 24-weeks. Also, the relationship between change in inflammatory 
markers from baseline to 8 weeks (and 24 weeks) and change in CEF between baseline and 8 and 
24 weeks will be quantified. Additional variables for evaluation are coronary plaque burden (CWT, 
NWI, and percent luminal stenosis). 
 
Safety endpoints: metabolic panel and complete blood count, withdrawal due to side-effects 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
The principal outcome in this double blind randomized trial of low dose colchicine versus 
placebo in HIV+ people without clinical CAD and abnormal CEF is the change in coronary blood 
flow (CBF) from rest to IHE at 8 weeks in the LDC and placebo groups.  We chose to study the 
change in CBF because it 1.) reflects both macrovascular and microvascular changes related to 
the endothelial-dependent IHE stressor, 2.) offers a large dynamic range in responses between 
healthy subjects and HIV+ people, 3.) is reproducible over this period, and 4.) because endothelial 
function is an independent predictor of atherosclerotic progression and clinical events (25-27, 98, 
99). The 8 week time was chosen to minimize confounding events occurring over longer times and 
because improvements in endothelial function have been observed in HIV+ people in as little as 4 
weeks following the initiation of ART (39) and as little as 8 weeks of treatment with statins (101) or 
salsalate (102). We will also collect CEF measures at 24 weeks to evaluate safety and avoid 
missing a longer-term CEF effect, if present. Drugs that improve cardiovascular outcomes improve 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
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endothelial function in fewer than 24 weeks, so there is little need to re-study beyond 24 weeks 
based on the literature (8, 103, 104). An increase in the IHE-CBF response in HIV subjects to 50% 
of that of healthy subjects does not assume complete normalization of CEF in HIV/CAD subjects 
with LDC but, instead, an increase that would be biologically significant and consistent with the 
changes in endothelial function observed with medications shown to reduce cardiovascular 
outcomes. For example, a landmark study demonstrated that statins improve CEF in CAD patients 
to approximately half of normal/maximal responses (8). Methotrexate, an anti-inflammatory agent, 
improved abnormal endothelial function to that of healthy subjects in patients with rheumatoid 
arthritis (105, 106). In studies without healthy subjects, comparisons are typically made with 
baseline or placebo measures and such studies consistently show that statins and ACE inhibitors 
improve abnormal endothelial function by ~50% or more in CAD patients (107-110). A similar 50% 
increase in endothelial function was also observed in HIV+ people treated for 8 weeks with statins 
(101). Thus based on the existing literature of the impact of established cardiovascular medications 
(statins, ACE-I) on endothelial function and based on our observations of coronary endothelial 
function (CBF increases during IHE in healthy subjects +43%±30% (mean±SD)) and does not 
increase in HIV/CAD patients, change of  -2%±17% (mean±SD), we propose that there will be no 
increase in the 8-week CBF response to IHE in placebo-administered HIV+ people and that there 
will be +20% increase (i.e. approximately 50% of the 43% increase we observe in healthy 
individuals) in the LDC-administered HIV+ people.   We assume that at 8 weeks:  
(1) Mean CBF will be unchanged from rest to IHE in HIV+ people on placebo (ie -2% change 
during IHE) 
(2) Mean CBF will increase by 20% from rest to IHE in HIV+ people on LDC (ie +20% increase 
during IHE) 
(3) Standard deviation (variability) of 24% for both groups 
 The variability is conservatively based on the mean standard deviation in CBF response 
observed in this population and in healthy subjects. With a sample size of 35 in each group, we will 
have power of 92% (alpha=0.05, two-sided test) to detect such a difference in CBF-IHE response 
between the placebo and LDC groups (111). We will conservatively assume a 20% dropout rate 
over 8 weeks due to unwillingness to repeat MRI and to withdrawal and/or side effects from LDC 
(with 10% 30-day discontinuation rate in the LoDoCo Trial in CAD patients most without HIV (1)). 
Thus we plan to randomize 43 in each group for a total of 86 HIV+ people with subclinical CAD. 
Based on our preliminary studies, we expect that 15% of subjects undergoing the initial screening 
MRI will not meet the CEF inclusion criterion of an IHE-induced change in CBF <7ml/min of 
baseline. Therefore we plan to screen 102 HIV+ people with CAD with MRI-IHE in order to identify 
86 who meet entry criteria for randomization so as to ultimately have 35 in each of the 2 groups 
complete the 8 week follow-up for the primary endpoint. For secondary endpoints occurring at the 
24-week time, we anticipate that as many an additional 10% may dropout or decline follow-up MRI. 
However if as many as 20% dropout or decline to return for the 24 week MRI, that would leave ~25 
in each group and there would be an 85% power to detect the same difference in the reduced 
sample size at 24 weeks (for secondary endpoints).  
 
d. Early stopping rules. 
 
Participants who experience significant symptoms will be evaluated and those or others who 
develop new laboratory abnormalities will be reviewed and labs possibly repeated.  If any of the 
following criteria are met (CBC<2000, platelets<50,000, Hct<27%, GFR <30ml/min or a >50% 
reduction in GFR compared to baseline values, and LFTs >3x upper limit of normal), the test would 
be repeated. If confirmed on repeat, there would be a temporary stop of study drugs. If the 
abnormality resolves, study drugs would be resumed at the same or lower dose. If the abnormality 
does not resolve or the temporary stop occurs on three consecutive measures, then the case will 
be reviewed for discontinuation from the study. Based on the clinical status, severity of the 
problem, and reversal of symptoms/laboratory findings, a decision will be made as to whether the 
study drug can be restarted under close observation (weekly surveillance) or the patient withdrawn 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
Application Number: IRB00070892 
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Version 3 Dated:   06/2007 
 
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from the study. Participants who wish to end participation in the trial at any time may do so upon 
request without penalty. 
 
8. 
Risks 
 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency.  
 
 
The MRI procedures do not expose patients to ionizing radiation and are not considered a 
significant risk (112).  No long-term side effects have been noted at these magnetic field strengths. 
The potential risks of the MRI study are few and primarily relate to injury from metallic objects 
attracted to the MR scanner or the isometric handgrip exercise (see below).   A blood pressure cuff 
is inflated and maintained for a few minutes during brachial endothelial function testing and this is 
associated with transient discomfort but no known major risks or long-term problems. The 
likelihood of MRI-related risks is minimized by thoroughly screening participants for metal prior to 
entering the scanner, and limiting access to the scanner area. A minority of individuals develop a 
claustrophobic sensation inside the magnet, which ceases when the subject exits the scanner.  
Patients with a prior history of being a machinist, welder, metal worker, or a similar activity that 
poses the potential risk of metal exposure to the eyes, will be asked to undergo screening orbit x-
rays to rule out the presence of metal fragments.  The amount of radiation exposure from the 
required series of skull x-rays is approximately 0.03 rems.    
Isometric handgrip exercise performed in the MRI scanner results in modest increases 
blood pressure and heart rate and can result in paradoxical vasoconstriction in atherosclerotic 
coronary vessels, and is relatively safe (41). The cited side effect in patients with coronary disease 
of handgrip exercise is non-sustained ventricular ectopy, which occurred in one percent of patients 
and which spontaneously resolved after termination of the exercise (113). Voice contact between 
subject and MR system operator will be available at all times, during both coronary endothelial 
function studies (isometric handgrip exercise), as well as direct observation via a video camera in 
the scan room.  In addition, a Cardiologist will be available during the MRI examinations.  Isometric 
hand-grip exercise is terminated prematurely if participants develop symptoms that would typically 
stop their activities or if abnormal heart rate or blood pressure findings develop. We have 
performed isometric hand-grip exercise testing in conjunction with cardiac spectroscopy studies 
since 1988 (114) and have not had any significant complications.   
Low dose colchicine is fairly well tolerated but has a relatively narrow therapeutic window.  
There were no serious adverse events reported in the LoDoCo trial (using a similar colchicine dose 
0.5 mg QD to the dose proposed here 0.6mg QD) over three years although 11% of individuals 
within 30 days and another 11% over the next 3 years withdrew from the study. The most common 
reasons for withdrawal were unrelated intercurrent illnesses (3.9%), patient choice (1.8%), 
intestinal upset (2.5%), myalgia (0.9%), myositis (<0.5%), rash (<0.5%), alopecia (<0.5%), itch 
(<0.5%) and peripheral neuritis (<0.5%) (1). In a study of cardiac patients with atrial fibrillation, no 
serious adverse events were noted but diarrhea was reported in 8.6% (vs 1.3% on placebo) and 
nausea in 4.9% (vs 3.8% in placebo) and one case of elevated LFTs which reversed after stopping 
drug (115).   
Flow mediated dilatation of the brachial artery: A blood pressure cuff is inflated and 
maintained for a few minutes with the testing of brachial endothelial function and this is associated 
with transient discomfort but no known major risks or long term problems. 
Having blood drawn may produce discomfort or minor bleeding and the possibility of 
bruising at the site of the needle puncture.  There is also a slight risk of infection at the site of the 
needle puncture. Some people may experience nausea, light-headedness, and fainting in 
association with a blood draw. 
 
b. Steps taken to minimize the risks. 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
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MRI will be performed with exposure to static and time-dependent magnetic fields within 
FDA guidelines (112). Special precautions will be taken to exclude patients with implanted metallic 
objects, including pacemakers, cerebral clips, or prior occupational exposure to small metallic 
projectiles (eg, lathe operators). Those subjects with a history suggesting possible risk will undergo 
orbital x-rays and those at risk will be excluded.  All participants will be carefully screened by the 
investigators for the exclusions stated above.  A Cardiologist will be present for each MRI study.  
Heart rate will be monitored continuously during MR studies via ECG, and blood pressure 
monitored with a remotely activated sphygmomanometer during isometric handgrip stress.  
Participants will be in direct verbal contact with the MR system operator at all times.  Participants 
who experience a worsening condition or who wish to end the exam at any time may do so upon 
request without penalty. The scanner area is equipped with standard medical emergency 
equipment (including a crash cart) for a hospital-based clinical MR center with appropriately trained 
personnel in attendance.  
 
To protect against and minimize the potential risks of low dose colchicine, patients with pre-
existing liver or renal disease, blood dyscrasia, protease inhibitor use and other conditions that 
might increase risk will be excluded from participation (please see Exclusion Criteria above). In 
addition, patients will undergo a careful history and physical and screening laboratory examination 
at baseline to identify the presence of any of conditions which might increase their risk from the 
medications but not have been known to the patients or documented in their medical records. In 
addition, patients will be evaluated closely at 6-week intervals while on study drug for side-effects 
and surveillance metabolic and hematologic screening studies. The patients will also return 4 
weeks after completing the study (28 weeks after randomization and initial dosing) for a follow-up 
safety surveillance. That evaluation will not affect the study drug dosing of that participant but if 
safety concerns are identified, it could be used to minimize risk in future participants. Patients who 
experience significant symptoms will be evaluated and those and any others who develop 
laboratory abnormalities will have the study drug withheld. Based on the clinical status, severity of 
the problem, and reversal of symptoms/laboratory findings, a decision will be made as to whether 
the study drug can be restarted under close observation (weekly surveillance) or the patient 
withdrawn from the study. Subjects who wish to end participation in the trial at any time may do so 
upon request without penalty. 
 
 Trained personnel will perform the blood collection procedure and will make every effort to 
minimize any risks or discomfort. 
 
c. Plan for reporting unanticipated problems or study deviations. 
All unanticipated problems or study deviations will be reported to the Data Safety and 
Monitoring Committee and according to The Johns Hopkins Medicine Institutional Review Boards 
published guidelines. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
  
Once the data are acquired, they will be assigned a code for each subject with identification 
secured and accessible only to the PI, senior investigators, and the research coordinator. Patient 
clinical information such as copies of clinical studies and imaging reports shall be filed in a locked 
filing cabinet with access under control of Dr. Weiss and Research Coordinator.. Patient 
information summarized and/or converted into electronic form (tables, images, etc) shall be 
identified by the assigned code. It is a Johns Hopkins Institutional policy that all identifiers in 
images and data acquired under IRB-approved research protocols must be removed if they leave 
the institution, for example in presentations.   
 
e. Financial risks to the participants. 


Date: June 25, 2018 
Principal Investigator: Robert G. Weiss, MD 
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Version 3 Dated:   06/2007 
 
Page 14 of 22 
All study related costs will be paid from research sources, as stated in the consent form. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
Results from this study may benefit patients with HIV and coronary heart disease in the 
future by providing information on the role of anti-inflammatory medications and inflammatory 
biomarkers in coronary atherosclerosis of HIV+ people. This would support the use of anti-
inflammatory medications to complement existing cardiovascular prevention strategies. However, 
we do not currently know whether subjects will have an immediate benefit. It could be that this 
agent (colchicine) reduces inflammation and improves coronary endothelial function and this 
would, at least in the short term, benefit the patients receiving those drugs. If the patients’ 
physicians felt the subjects benefited, they could make the decision, apart from this study, to 
continue the colchicine if they are inclined to do so. Although there are small risks associated with 
low dose colchicine, the risks would be relatively short term since this is only a 24-week study (with 
at least 6 week surveillance). In addition, low dose colchicine is associated with reduced heart 
disease risk in patients with arthritis and in HIV- people with clinical CAD.  
 
Contraindications to MRI studies as listed above will be strictly observed and should not 
constitute added risks for patients enrolled in this study. The low risk is reasonable in relation to the 
potential knowledge gained that may guide future therapeutic studies.   
 
10. 
Payment and Remuneration 
a. Detail compensation for participants including possible total compensation, proposed 
bonus, and any proposed reductions or penalties for not completing the protocol. 
Participants will receive parking at each visit and will be offered a $10 meal voucher. 
Compensation of $75 will be given for each completed MRI (3 total) and $50 for each completed 
safety monitoring visit (4 total) for a possible total compensation of $425. 
 
11. 
Costs 
a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
There is no cost to the participants related to the study procedures or drugs.  
 
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Principal Investigator: Robert G. Weiss, MD 
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JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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Principal Investigator: Robert G. Weiss, MD 
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JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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