Clinical trial NCT01709981
Conditions: Coronary Artery Disease
Sponsor: NYU Langone Health
Start date: 2013-05-30; Completion date: 2021-12-13
Enrollment: 280 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Peri-procedural inflammation is associated with increased rates of post-procedural myocardial infarction (MI), which occur in up to 35% of PCI patients and are themselves associated with increased risk of later MI and death. Statins suppress both inflammatory markers and MI rates during and after PCI, but ≥ 40% of PCI patients go statin-untreated, due in part to side effects such as myalgia. Moreover, because their mechanism of action relies on post-translational effects, statins must be given ≥ 12 to 24 hours prior to PCI, a time frame that is not always feasible. The investigators propose a novel alternative approach to reduce inflammation during PCI employing colchicine, an anti-inflammatory medication used frequently in gout and pericarditis. Colchicine may be particularly applicable to the PCI setting due to its rapid onset of action and excellent side-effect profile at low doses, as well as its known mechanisms of action. However, data on colchicine use in patients with coronary disease is extremely limited, and no studies to date have evaluated the use of colchicine in patients undergoing PCI. The investigators aim to characterize a potential mechanism of benefit in patients undergoing PCI by evaluating the effects of colchicine on soluble and leukocyte surface markers after PCI. The investigators also aim to determine the effects of colchicine on peri-procedural myonecrosis and MI. Accordingly, the investigators propose a prospective randomized study to characterize the effect of colchicine on inflammation and peri-procedural myocnecrosis. Patients referred for possible PCI will be randomized in a double-blinded fashion to placebo or colchicine (1.2mg 1 to 2 hours before PCI, followed by 0.6mg 1 hour later). The primary endpoint will be post-procedural interleukin-6 level. Secondary endpoints will include other relevant soluble and leukocyte-associated inflammatory markers. Sample size needed is 200 patients undergoing PCI. To adjust for a floor effect, 280 patients undergoing PCI will be needed. 400 patients will likely be needed to be enrolled to reach 280 PCIs (the remaining will have undergone a diagnostic only procedure). Of note, this is a substudy of the COLCHICINE-PCI trial (NCT 02594111)

Detailed description:

Arms: arm 1: 1.2mg colchicine 1 to 2 hours prior PCI, followed by 0.6mg one hour later arm 2: Placebo 1-2 hours prior PCI, followed by placebo 1 hour later
Interventions: intervention 1: Colchicine intervention 2: Placebo
Intervention descriptions: intervention 1: Colchicine 1.2mg 1 to 2 hours prior PCI, followed by 0.6mg 1 hour later intervention 2: Placebo 1 to 2 hours prior PCI, followed by Placebo 1 hour later

Protocol documents:
SAP_002.pdf: 
 
 
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Anti-inflammatory therapy during percutaneous 
coronary intervention 
Statistical Analysis Plan (SAP) 
 
 
Authors: Judy Zhong, Ph.D., Binita Shah, MD, MS 
 
Version History 
Version 2.0: August 7, 2019 
 
New York University School of Medicine 
Department of Internal Medicine, Division of Cardiology 


 
 
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This document provides the Statistical Analysis Plan for the Anti-inflammatory 
therapy during percutaneous coronary intervention study. 
 
1 INTRODUCTION 
This statistical analysis plan (SAP) incorporates all of the elements of study design, and 
analysis of primary and secondary endpoints for this randomized clinical trial (RCT). The 
SAP is a stand-alone section that describes the statistical design and analysis 
considerations.  
2 STUDY OVERVIEW 
2.0. Purpose of the study 
We hypothesize that colchicine may effectively reduce inflammation and peri-procedural 
MI in patients not acutely loaded with high-dose statin prior to percutaneous coronary 
intervention (PCI).  We further hypothesize that colchicine’s effects would be additive in 
patients undergoing PCI on a background of acute high-dose statin pre-treatment. We aim 
to determine the effects of colchicine 1.2 mg administered 1 to 2 hours prior to coronary 
angiography, followed by a 0.6 mg dose 1 hour later, on post-procedural markers of 
inflammation and cardiac biomarkers and events.     
2.1. Study Design 
Prospective, randomized, double-blinded, placebo-controlled trial of patients undergoing 
coronary angiography in the Manhattan Veterans Affairs Hospital (primary site is 
Manhattan Veterans Affairs Hospital), Bellevue Hospital Center, and New York 
University (NYU) Langone Medical Center cardiac catheterization laboratories.  Patients 
will be stratified into one of two groups:  
1) Patients who received a load with high-dose statin therapy (an increase in the 
patient’s maintenance regimen or started newly on a statin) 24 hours to 7 days prior to 
the procedure and continued on a daily regimen 
2) Patients who did not receive a load with high-dose statin therapy 24 hours to 7 days 
prior to the procedure  
*The decision to load with high-dose statin therapy prior to PCI is made clinically by 
the treating physician. 
Patients will then be randomized to one of two groups: 
1) Colchicine 1.2mg 1 to 2 hours before coronary angiography, followed by colchicine 
0.6mg 1 hour later 
2) Placebo at the same time points above 
 
2.2. Subject Population and Selection 
2.2.1. Patient Population 
Patients referred for coronary angiography at Manhattan Veterans Affairs Hospital 
(primary site is Manhattan Veterans Affairs Hospital), Bellevue Hospital Center, and 
NYU Langone Medical Center,  


 
 
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2.2.2. Gender of Subjects 
Subjects will include both men and women.  Every effort will be made to include 
equitable numbers of each gender. 
2.2.3. Age of Subjects 
Subjects more than 18 years of age will be eligible to participate in the study.  The 
research in question applies to the entire adult population and therefore all adults may 
participate. 
2.2.4. Racial and Ethnic Origin 
Subjects of any racial or ethnic background may participate in the study.  There will be 
no enrollment restrictions based on race or ethnic origin. 
2.2.5. Inclusion Criteria 
Patients must be more than 18 years of age and referred for coronary angiography with a 
possibility of PCI. 
2.2.6. Exclusion Criteria 
Patients will be excluded if they meet one of the following criteria: 1) Plan for 
diagnostic-only coronary angiography, 2) On colchicine chronically, 3) History of 
intolerance to colchicine, 4) Glomerular filtration rate <30mL/minute or on dialysis, 5) 
Active malignancy or infection, 6) History of myelodysplasia, 7) High-dose statin load 
<24 hours prior to procedure, 8) Use of oral steroids or non-steroidal anti-inflammatory 
agents other than aspirin within 72 hours or 3 times the agent’s half-life (whichever is 
longer), 9) Use of strong CYP3A4/P-glycoprotein inhibitors (specifically ritonavir, 
ketoconazole, clarithromycin, cyclosporine, diltiazem and verapamil), 10) Unable to 
consent, 11) Participating in a competing study, 12) Pregnant women, or 13) any 
condition (e.g., psychiatric illness) or situation that, in the investigator's opinion, may put 
the subject at significant risk, may confound the study results, or may interfere 
significantly with the subject's ability to adhere with study procedures.   
2.3. Methods and Procedures 
Subjects who meet inclusion/exclusion criteria will be randomized in a double-blinded 
fashion to a pre-procedural loading dose of colchicine or placebo. Patients will undergo 
assessment of cardiac biomarkers at baseline, 6-8 hours post-PCI, and 22-24 hours post-
PCI and clinical assessment at 30 days (maximum follow-up out to 5 years). Patients in 
the inflammatory marker substudy will undergo assessment of inflammatory biomarkers 
at baseline, 30 minutes to 1 hour post-PCI, 6-8 hours post-PCI, and 22-24 hours post-PCI. 
3. RANDOMIZATION OF PARTICIPANTS  
Recruitment will be conducted in accordance of the policies of the Manhattan VA 
Hospital, Bellevue Hospital, and NYU IRB and Federal guidelines. The attending 
interventional cardiology physician of all potential subjects will be contacted to 
determine if the subject is willing to be approached about the study. Informed consent 
will be sought and documented from all subjects at the earliest time possible, or at least 2 
hours before coronary angiography. The rationale, procedures and potential risks of the 
procedures in the study will be explained to each participant by the Principal Investigator 


 
 
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or his appointed designee.  Each subject will be told that participation in the studies 
described in this proposal is strictly voluntary, that refusal to participate will not alter the 
patient's relationship with their physician, that the studies constitute research and that the 
information obtained will not be specifically helpful to the individual patient's care. After 
the subject has read the consent form, comprehension of the key elements of the study 
procedures and risks will be tested with verbal questions of the consent form content. If 
the subject is willing to participate, the subject will sign the IRB-approved informed 
consent form.  
A randomization code will be generated by an independent statistician using random 
block sizes and held by the research pharmacist. Study drug and a unique subject 
identifier linked to group assignment will be allocated by the research pharmacist. 
However, the research pharmacist will not release group assignment to the investigative 
team until after all subjects have completed the protocol and the database has been 
locked.  
Patients will then be randomized to one of two groups: 
1) Colchicine 1.2mg 1 to 2 hours before coronary angiography, followed by 
colchicine 0.6mg 1 hour later. 
2) Placebo at the same time points above 
 
4. DATA COLLECTION  
4.1 Baseline Variables: 
 Demographics, Height, Weight, Body mass index, Abdominal circumference (race-
ethnicity self-reported, other variables measured) 
 Medical history:  Previous MI, previous PCI, previous coronary artery bypass surgery, 
hypertension, hypercholesterolemia, diabetes mellitus, peripheral vascular disease, 
previous stroke or transient ischemic attack, carotid artery disease (>50% stenosis), 
hepatitis C, and tobacco use (collected from medical records and confirmed by patient)  
       
 Medications:  statin (type and dose), aspirin, thienopyridine, cilostazol, dipyridamole, 
beta blocker, calcium channel blocker, nitrate, ranolazine, hydralazine, ACE inhibitor, 
angiotensin receptor blocker, statin, fibrate, niacin, ezetimibe, diuretic, aldosterone 
receptor blocker, digoxin, antiarrhythmic agent, unfractionated heparin, low molecular 
weight heparin within 12 hours of procedure, insulin, protease inhibitor (collected from 
medical records and confirmed by patient) 
 Laboratory data: BUN, creatinine, glomerular filtration rate, glucose, white blood cell 
count, hemoglobin, total cholesterol, high density lipoprotein, low density lipoprotein, 
triglyceride, hemoglobin A1c, ejection fraction (normal, mild to moderately reduced, or 
severely reduced left ventricular systolic function) (collected from medical records) 
4.2. Procedural data: 
 Time of baseline blood draw and drug administration (recorded in real time) 
 Indication for coronary angiography (determined by research team according to data 
provided in medical records) 


 
 
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 Time of procedural access and type of arterial access (femoral or radial) (collected from 
catheterization report) 
 Type of contrast agent used (Hexabrix, Visipaque, Isovue) (collected from 
catheterization report) 
 Number of native and graft vessels with greater than 70% stenosis (collected from 
catheterization report) 
 Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) score is a scoring 
system that provides information on atherosclerosis burden in patients undergoing 
revascularization (grouped as <17 (low), 17-32 (intermediate), or >33 (high) scores).  
 
 If PCI performed (collected from operator questionnaire administered in real time and 
catheterization report): 
o Segment treated (left main, left anterior descending, left circumflex, right coronary 
artery, saphenous vein graft, arterial graft) and single vessel or multivessel 
intervention 
o Single vessel or multivessel intervention 
o Percent diameter stenosis pre- and post-PCI on semi-quantitative coronary 
angiography 
o Type of lesion treated (de novo or restenotic, chronic total occlusion, bifurcation 
lesion, calcification, visible thrombus, lesion length >33 mm), lesion site (ostial, 
proximal, mid-vessel, distal), and number of lesions treated 
o Type of intervention with devices used (balloon only, balloon plus stent, cutting 
balloon, thrombectomy device, rotational atherectomy device, chronic total 
occlusion crossing device, filter basket, laser) 
o Time of first coronary balloon inflation  
o Number of pre-dilations or use of direct-stenting  
o Type of stent, number of stents, stent diameter and total stent length 
o Stent deployment pressure 
o Use of post-dilations and maximum pressure on post-dilation 
o Use of Intracoronary medications used (e.g. nitroglycerin, nitroprusside, 
glycoprotein IIb/IIIa inhibitors) 
o Pre- and post-TIMI flow grade 
o Procedural success (defined as residual stenosis <20% at the end of procedure) 
 Time of end of procedure 
 Complications  
o Abrupt vessel closure at any time during procedure (main vessel or side branch) 
o Perforation 


 
 
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o Distal embolization 
o Plaque shift with side branch compromise (>70% residual stenosis in at conclusion 
of procedure) 
o <TIMI 3 flow in any treated vessel at any time during procedure (also included in 
post-PCI TIMI flow) 
o Uncovered dissection (grade 3 or higher in vessel >1.5 mm in diameter)  
o Shock during procedure  
o Acute pulmonary edema requiring intubation  
o Dysrhythmia requiring defibrillation 
All electronic data is de-identified and resides on password-protected computer. All hard 
copy of data are secured in a locked cabinet in a locked office. 
 
5 KEY STUDY OUTCOMES 
 
5.1 Primary outcomes: 
 
The primary outcome of the overall trial will be peri-procedural myonecrosis using 
cardiac biomarkers (Troponin I) as defined by the 3rd Universal Definition [1] as follows 
(biomarkers are evaluated at 6 to 8 hours and 22 to 24 hours post-PCI):  
 In subjects with normal baseline cardiac biomarkers, peak post-procedure cardiac 
biomarker above the 99th percentile upper reference limit  
 In subjects with elevated baseline cardiac biomarkers and the biomarker levels are 
stable or falling, there should be a new cardiac biomarker elevation by >20% from 
the most recent pre-procedural level 
 
The primary endpoint of the inflammatory marker substudy will be 1) change in soluble 
interleukin-6 level between baseline and 1 hour post-PCI 
   
5.2 Secondary outcomes:  
1) The secondary outcomes of the inflammatory marker substudy will be change in 
neutrophil surface L-selectin (CD62L) between baseline and peak level post-PCI.  
Measurement of other relevant inflammatory markers (such as cell-associated beta-2 
integrin CD11b, intercellular/vascular cell adhesion molecule-1, myeloperoxidase, 
NGAL, elastase, soluble L- and E-selectin, white blood cell count, and neutrophil count), 
as well as, neutrophil extracellular traps (NETs), neutrophil-derived microparticles, and 
extent of neutrophil-platelet aggregates at 1 hour post-procedure, 6 to 8 hours post-PCI 
and 22 to 24 hours post-PCI. A subset of patients will have neutrophil metabolism and 
mean number of neutrophils adherent to TNFα-stimulated endothelial cells assessed at 
baseline and 1 hour post-procedure. 
2) In the overall trial: 
a) Occurrence of major adverse cardiac events with composite of the earliest occurrence 
of death from any cause, non-fatal MI (defined by the 3rd universal definition of MI) [1], 


 
 
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or target vessel revascularization (bypass surgery or repeat PCI of the target vessel) 
assessed at 30 days, 6 months, and yearly for 5 years. Peri-PCI MI is a component of 
non-fatal MI and will be defined using the Universal Definition [1] (any elevation 5 times 
the 99th percentile upper limit of normal). No definition currently exists to define post-
PCI myocardial necrosis or MI when biomarkers are elevated prior to procedure. In 
patients with elevated baseline levels of troponin or creatine kinase-MB, peri-procedural 
MI will be defined as a subsequent increase of more than 2-fold in troponin or creatine 
kinase-MB from baseline value.   
b) Peri-procedural MI will also be defined by the expert consensus document from the 
Society for Cardiovascular Angiography and Interventions on a new definition of 
clinically relevant MI after coronary revascularization as follows [2]: 
 Subjects with normal baseline cardiac biomarkers  
o Peak post-procedure Troponin >70x upper limit of normal or CKMB >10x 
upper limit of normal  
o A lower threshold (Troponin >35x upper limit of normal, CKMB >5x) will be 
used in subjects with new pathologic Q-waves in >2 contiguous leads (or new 
persistent left bundle branch block)  
 In subjects with elevated baseline cardiac biomarkers and stable or falling 
biomarker levels, there should be a new Troponin or CKMB elevation by an absolute 
increment of >70x (for Troponin) or >10x (for CKMB) upper limit of normal from 
the most recent pre-procedural level 
 In subjects with elevated baseline cardiac biomarkers and the biomarker levels have 
not been shown to be stable or falling, there should be a further rise in Troponin or 
CKMB by an absolute increment >70x (for Troponin) or >10x (for CKMB) upper 
limit of normal plus new ST-segment change plus signs consistent with a clinically 
relevant MI (e.g. new onset or worsening heart failure or sustained hypotension)  
c) The primary outcome of peri-procedural myonecrosis using CKMB as the biomarker  
 
5.3. Sample Size   
A) A total sample size of 400 subjects is needed to demonstrate a 40% reduction in 
proportion of subjects with peri-procedural myonecrosis (from 30% in the placebo group 
to 18% in the colchicine group) using a Chi squared test (80% power, 0.05 significance 
level). This trial is designed to study the effect of colchicine on all-comers to the cath lab. 
A greater effect is expected on both surrogate and clinical endpoints in the ACS 
compared with elective PCI population. Our sample size is based on the lowest relative 
risk reduction observed with anti-inflammatory therapy in elective PCI [3]. We 
approximate that 50% of the patients enrolled will either not have PCI performed after 
coronary angiography (majority) or will be excluded due to requirement of the use of any 
of the medications listed in the exclusion criteria prior to post-PCI blood collection 
(minority).  We, therefore, estimate a total sample size of 800 be enrolled in this study to 
meet the 400 PCI sample size. 
B) Sample size for the inflammatory marker substudy is calculated based on mean 
interleukin-6 level of 12pg/mL and standard deviation of 12pg/mL one hour after PCI in 
predominantly ACS patients reported by Aggarwal et al [4], and an estimated decrease in 
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conservative estimate relative to the 60% reduction of CRP noted in Nidorf’s study 
examining the effect of colchicine in stable CAD patients on aspirin and high-dose statin 
therapy [5].  Furthermore, in Aggarwal’s study, interleukin-6 levels increased by 58% 
from pre-procedural levels [4]. Based on the above assumptions, and a two-sided two 
sample t-test, the number of patients needed in each group to achieve 80% power at the 
0.05 significance level is estimated to be 100.  A minority of subjects (~16%) may 
experience no change in IL-6 after PCI [6]. To adjust for this possible floor effect, the 
sample size needed would also be 120 subjects in each group. If a 35% or 30% decrease 
in post-PCI IL-6 level is observed with colchicine, 129 or 175 subjects will be needed in 
each group, respectively (80% power, 0.05 significance). 
If sample size for the inflammatory marker substudy was calculated with surface CD62L 
(the secondary endpoint) as endpoint, it would be based on the mean (± standard 
deviation) peak post-PCI surface expression of neutrophil CD62L of 9906 ± 6737 MFI  
(39% rise from pre-PCI) from our pilot AHA-funded project. Based on our volunteer data 
examining the effects of surface expression of CD62L after a 1.8 mg loading dose and 
earlier in vitro data, we would estimate a decrease in post-PCI CD62L level by ~25% 
with colchicine. Using a two-sided two sample t-test, the sample size using 80% power 
and 0.05 significance level would be ~120 subjects in each group. If a 23% or 20% 
decrease in post-PCI CD62L level is observed with colchicine, 138 or 182 subjects will 
be needed in each group, respectively (80% power, 0.05 significance). 
C) Other secondary endpoints: Sample size for neutrophil-endothelial cell adhesion assay 
is based on in vitro data by our group that demonstrated reductions in neutrophil-
endothelial adhesiveness with addition of colchicine (108 ± 11 to 31 ± 5 adherent 
neutrophils/200x field) [7]. Based on a conservative estimate of 20% reduction and a 
two-sided two sample t-test, the sample size to achieve 95% power (0.05 significance) is 
~10 subjects in each group.  
Sample size for neutrophil-platelet aggregates is based on data by our group from the 
peri-procedural glycemic control trial (mean leukocyte platelet aggregation 10.57 ± 
4.10%) [8]. Based on a ~30% reduction and a two-sided two sample t-test, the sample 
size to achieve 95% power (0.05 significance) is ~45 subjects in each group. Since these 
subjects must meet dual anti-platelet therapy criteria and the probability of one subject 
satisfying these criteria in the colchicine group is 0.5, increasing the sample size by 10% 
(100 subjects) will make the probability of achieving at least 45 subjects in each group 
(placebo/colchicine) ~68%. Increasing the sample size to 107 subjects will make the 
probability of achieving at least 45 subjects in each group (placebo/colchicine) ~90%. 
Subjects in the inflammatory marker substudy that meet dual anti-platelet therapy criteria 
will undergo neutrophil-platelet aggregate evaluation.  
 
6. DATA ANALYSIS AND DATA MONITORING 
Categorical variables will be presented as proportions, normally distributed continuous 
variables as mean ± standard deviation, and skewed continuous variables as median 
[interquartile range] (distributions assessed for normality using histogram, quantile-
quantile plot and Shapiro-Wilk test). Categorical endpoints will be compared between 
placebo and colchicine groups using tests of proportions (exact and asymptotic), and 
continuous endpoints will be compared between placebo and colchicine groups using t-


 
 
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test. Non-parametric alternatives (e.g. Wilcoxon test) and mathematical transformations 
(e.g. Box-Cox) will be considered as needed for skewed distributions. Statistical 
significance will be tested using a 2-sided alpha level of 0.05 with appropriate multiple 
testing correction (Bonferroni or Benjamini-Hochberg) when needed.  
To not incur excess bias by deviating from classification according to assigned treatment, 
an intention-to-treat approach will be utilized as a primary analytic approach. A 
secondary analysis will be performed utilizing a non-intention-to-treat approach, where 
subjects are classified according to the treatment actually received and subjects who do 
not receive treatment are excluded. We believe crossover and pre-procedure withdrawal 
will be relatively low. Adopting both approaches, however, will allow for assessment of 
the robustness of findings. 
Pre-specified subgroup analyses will be performed in subjects presenting with versus 
without ACS and with versus without in-lab complications, as defined below. 
In-lab complications: 1) Vessel closure any time during procedure (main vessel or side 
branch); 2) Perforation; 3) Distal embolization; 4) Plaque shift with side branch 
compromise (>70% residual stenosis in side branch at conclusion of procedure); 5) 
<TIMI 3 flow in any treated vessel at any time during procedure (also included in post-
PCI TIMI flow); 6) Uncovered dissection (grade 3 or higher in vessel >1.5 mm in 
diameter); 7) Shock during procedure; 8) Acute pulmonary edema requiring intubation; 
or 9) Dysrhythmia requiring defibrillation 
A) To delineate changes in neutrophil activation during acute vascular injury using a PCI 
model, markers of neutrophil activity will be assessed by comparison of post- versus pre-
PCI samples in the placebo group using paired t-test or paired sample Wilcoxon signed 
rank test. In addition, to account for all 4 time points (1 pre- and 3 post-PCI), a significant 
change in markers over time will be determined in the placebo group by estimating speed 
of change using slope in a linear mixed effects regression model at a 0.05 level of 
significance cut-off. Markers will then be categorized descriptively as increasing versus 
not increasing post- compared to pre-PCI. 
Univariate and multivariate predictors of markers that demonstrate a significant increase 
post- compared with pre-PCI (as defined above) will be determined using baseline 
demographic, clinical, and procedural covariates of interest. Major covariates of interest 
may include age, sex, race, abdominal circumference, diabetes mellitus, chronic kidney 
disease, MI within 7 days of PCI, ejection fraction <40%, pre-procedural TIMI 0 or 1 
flow, multivessel CAD, visible thrombus or ulcerated lesions, SYNTAX score >23, and 
presence of one of the in lab complications as defined above. Based on our biomedical 
knowledge and experience in variable selection and statistical modeling, we will balance 
model richness against a danger to overfit. First, a screening procedure based on the 
correlation between the outcome and each variable will be used to choose the variables in 
the multivariate model, and then a stepwise variable selection method including both 
forward and backward methods will be employed to search for an optimal model gauged 
by the Akaike information criterion. We will also conduct the principal component 
analysis for parsimonious modeling, which uses the correlation matrix to identify a small 
number of components capturing most of the variability and include them in the 
multivariate logistic regression model.  


 
 
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To determine changes in subsequent cellular interactions, neutrophil adhesion to 
endothelial cells and neutrophil-platelet aggregates will be assessed post- compared with 
pre-PCI samples in the placebo group using paired t-test or paired sample Wilcoxon 
signed rank test.  
Finally, a mediation analysis will be performed in a logistic regression model to test the 
hypothesis that an increase in markers of neutrophil activation is associated with peri-
procedural myonecrosis, and that this association is mediated by neutrophil-endothelials 
cell and neutrophil-platelet adhesion.  
Similar analyses will be performed in the evaluation of the change in NETs and 
neutrophil-derived microparticles post- versus pre-PCI. A mediation analysis will be 
performed in a logistic regression model to test the hypothesis that an increase in these 
neutrophil extracellular fragments is associated with peri-procedural myonecrosis, and 
that this association is mediated by tissue factor pathway inhibitor/thrombin generation.   
B) To determine the effect of colchicine on changes in markers of neutrophil activation 
and subsequent cellular interactions during acute vascular injury, pre- to post-PCI 
changes will be examined between the placebo and colchicine groups using two-sample t 
test or Wilcoxon rank sum test. To further study the time-varying pattern of treatment 
effect, with the observations at pre-PCI and multiple post-PCI time points, a repeated 
measurements or longitudinal data analysis modeling will be used by incorporating both 
individual-specific terms and the treatment by time interaction. The Analysis of Variance 
Analysis will be conducted using the Generalized Estimating Equations or Quasi-
Likelihood approach. Alternatively, proportion of subjects with significantly increased 
markers of neutrophil activity post- compared to pre-PCI (defined above using estimated 
slope of change) will be compared between the placebo and colchicine groups using tests 
of proportions. Finally, an interaction with pre-procedural use of colchicine versus 
placebo will also be evaluated to determine whether or not colchicine modulates the 
mediation analyses described above. 
C) To explore the association between markers of neutrophil activation and outcomes 
after acute vascular injury, the association between tertiles of markers of neutrophil 
activity at baseline and dichotomous outcome of peri-procedural myonecrosis will be 
assessed using logistic regression modeling and presented as odds ratio and 95% 
confidence interval. Similar analyses will be performed to evaluate the association 
between tertiles of markers of neutrophil activity at baseline and dichotomous outcome of 
peri-procedural MI, as well as long-term composite of all-cause mortality, non-fatal MI, 
and target vessel revascularization. 
However, the capacity for neutrophil activity to increase in the setting of acute vascular 
injury may be more pertinent than baseline activity. Therefore, using the estimated speed 
of change in neutrophil activity over time from pre- to post-PCI, markers of neutrophil 
activity will be categorized as increasing or non-increasing (no change or decreasing) 
based on analysis of slope and a 0.05 level of significance cut-off. The association 
between increasing versus non-increasing markers of neutrophil activity and peri-
procedural myonecrosis will be evaluated using logistic regression modeling (increasing 
marker as main predictor, peri-procedural myonecrosis as dichotomous outcome). Similar 
analyses will be performed to evaluate the association between increasing versus non-


 
 
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increasing markers of neutrophil activity and peri-procedural MI, and long-term 
composite of all-cause mortality, non-fatal MI, and target vessel revascularization. 
Logistic regression models will be built hierarchically to include main covariates. As 
above, age, sex, race, abdominal circumference, diabetes mellitus, chronic kidney 
disease, MI within 7 days of PCI, ejection fraction <40%, pre-procedural TIMI 0 or 1 
flow, multivessel CAD, visible thrombus or ulcerated lesions, SYNTAX score >23, and 
presence of one of the in lab complications as defined above. Based on our biomedical 
knowledge and experience in variable selection and statistical modeling we will balance 
model richness against a danger to overfit as described above. 
Finally, to explore the effects of colchicine on peri-procedural myonecrosis in a PCI 
model, the rate of peri-procedural myonecrosis and peri-procedural MI in subjects 
randomized to the placebo vs colchicine groups will be assessed using the tests of 
proportions. This association will also be assessed using logistic regression modeling and 
will include the main covariates described above.  
D) The low-dose colchicine regimen in the current proposal has been studied and 
demonstrates an excellent side effect profile.  A Data Safety Monitoring Committee 
(DSMC) will be formed to review ongoing safety data.  This committee will be a group 
consisting of three physicians and, when needed, one biostatistician. The DSMC 
meetings will include an initial open meeting for discussion with the Principal 
Investigator and the presentation of reports by the study coordinator followed by a closed 
meeting of voting DSMC members. The DSMC will review blinded safety data three 
times a year (or more often as necessary) to ensure the safe and proper treatment of 
subjects. The committee will also review recruitment data, study subject withdrawals, 
data on drug tolerability, and protocol violation data to determine whether any substantial 
deviations from the initial study plan might alter the original risk benefits analysis. If the 
frequency and/or severity of adverse events are thought to be study related, or if other 
logistical issues related to study drug tolerability, are thought to compromise the integrity 
of the study protocol, the DSMC can make recommendations for protocol modification or 
early termination of the study. After each meeting, the committee will prepare a brief 
report to be submitted to the Principal Investigator that will recommend: 1) study 
continuation without modification, 2) study continuation with modification, or 3) study 
discontinuation. A recommendation of study modification or study discontinuation will 
lead to an immediate cessation of study enrollment, but in the event of a recommendation 
of study modification, study enrollment may be allowed to resume once the human 
subjects safety issues and/or other logistical issues have been adequately addressed to the 
satisfaction of the DSMC and IRB. In the event of identification of any relevant safety 
findings that may change the original risk benefit analysis for the human subjects in the 
study, these findings will be forwarded to the IRB committee and will be incorporated 
into a revised protocol and consent form. All current participants and future participants 
will be required to sign the revised consent form.  The Principal Investigator will be 
responsible for reporting of adverse events to the DSMC and IRB according to standard 
definitions. 
 
Missing Data 
 


 
 
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Missing Outcomes. The impact of missing data on the results of the primary analysis 
will be investigated by inferring a relationship between the covariates and the 0-1 
indicator that defines whether or not the outcome of a subject is observed. This analysis 
will help to elucidate characteristics likely to cause outcomes to be missing and test 
whether the covariate-response relationship obtained from the subjects with non-missing 
outcomes represents the larger population. 
Missing Covariates. The relationship between the 0-1 indicators that defines whether or 
not the covariate is observed and variables will be examined using logistic regression 
techniques. Should a substantial proportion of cases (> 10%) be missing for a critical 
independent variable and evidence found of nonrandomness, missing data will be 
incorporated using multiple imputation methods and Inverse Probability Weighting. 
 
7. DATA STORAGE AND CONFIDENTIALITY 
All patient data will be kept strictly confidential, except when published for purposes of 
reporting data. In that case, the patients are never identified. As noted previously, all 
electronic data will be de-identified and resides password-protected computers.  All hard 
copy of data will be secured in a locked cabinet in a locked office on Manhattan VA 
Hospital property. All biological specimens will be encoded with no identifying 
information and stored at NYU School of Medicine Research Building that can only be 
traced back to the individual by the research team. There is a minimal risk of loss of 
confidentiality though every precaution will be taken to avoid this.  The statistician will 
have access to only the de-identified data for analysis. 
8. REFERENCES 
1. Thygesen K, Alpert JS, Jaffe AS, et al; Joint ESC/ACCF/AHA/WHF Task Force for 
the Universal Definition of Myocardial Infarction. Third Universal Definition of 
Myocardial Infarction. Circulation. 2012;126:2020-35.  
2. Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically 
relevant MI after coronary revascularization an expert consensus document from the 
society for cardiovascular angiography and interventions (SCAI). J Am Coll Cardiol. 
2013;62:1563-70.  
3. Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, Mussardo M, 
Montorfano M, Ricciardelli B, Colombo A. Impact of a single high loading dose of 
atorvastatin on periprocedural myocardial infarction: Results from the NAPLES II trial. 
Journal of the American College of Cardiology. 2009;54:2157-2163.  
4. Aggarwal A, Schneider DJ, Terrien EF, Gilbert KE, Dauerman HL. Increase in 
interleukin-6 in the first hour after coronary stenting: an early marker of the inflammatory 
response. Journal of Thrombosis and Thrombolysis. 2003;15:25-31.  
5. Nidorf M, Thompson PL. Effect of colchicine (0.5mg twice daily) on high-sensitivity 
C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary 
artery disease. American Journal of Cardiology. 2007;99:805-807.  


 
 
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6. Biasucci LM, Vitelli A, Liuzzo G, et al. Elevated levels of IL-6 in unstable angina. 
Circulation.1996;94:874-7.  
7. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. Colchicine 
alters the quantitative and qualitative display of selectins on endothelial cells and 
neutrophils. Journal of Clinical Investigation. 1995;96:994-1002  
8. Shah B, Berger JS, Amoroso NS, et al. Periprocedural glycemic control in patients 
with diabetes mellitus undergoing coronary angiography with possible PCI. Am J 
Cardiol. 2014;113:1474-80.  

Prot_003.pdf: 
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STUDY PROTOCOL 
 
 
 
 
 
Anti-inflammatory therapy during percutaneous 
coronary intervention 
 
New York University School of Medicine 
Department of Internal Medicine, Division of Cardiology 


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I. Introduction 
1.  Purpose of the study 
We hypothesize that colchicine may effectively reduce inflammation and peri-procedural 
MI in patients not acutely loaded with high-dose statin prior to PCI.  We further 
hypothesize that colchicine’s effects would be additive in patients undergoing PCI on a 
background of acute high-dose statin pre-treatment. We aim to determine the effects of 
colchicine 1.2mg administered 1 to 2 hours prior to coronary angiography, followed by a 
0.6mg dose 1 hour later, on post-procedural markers of inflammation and cardiac 
biomarkers.     
2. Background and Significance 
ACS and PCI are inflammatory events. Inflammatory cells in coronary plaque are 
increased in patients with ACS, along with a consequent increase in systemic 
inflammatory markers.  Shu et al observed significantly higher levels of interleukin-6 
(IL-6), high-sensitivity C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-
9) in patients with ACS versus stable angina.  Furthermore, markers were significantly 
more elevated in patients with stable angina than in normal controls (1).  
PCI further induces an inflammatory response by disrupting coronary plaque and 
coronary artery endothelium during balloon inflations. Robertson et al noted increases of 
matrix MMP-9 and IL-6 locally in the culprit coronary artery of ACS patients during 
PCI, along with a systemic inflammatory response (2). In one study evaluating 25 
patients predominantly with ACS undergoing PCI, IL-6 increased as early as 1 hour after, 
compared with before, PCI (3). Sardella et al observed a significantly greater level of 
cell-associated beta2-integrin, a subunit that plays a role in leukocyte recruitment and 
adhesion at sites of endothelial injury, in ACS patients versus age-matched healthy 
volunteers, with a significant further increase detected immediately after balloon 
deflation during primary PCI (4). The inflammatory response to PCI has also been 
studied in stable CAD using various markers including pentraxin-3, chemokines CCL2 
and CXCL16, CRP, VACM-1, and IL-6 (5-6). One study suggests that uncomplicated 
diagnostic coronary angiography may in itself be sufficient to trigger a systemic 
inflammatory response in patients with stable CAD (6).  
The inflammatory state at the time of PCI predicts clinical outcomes. Kwaijtaal et al 
demonstrated the prognostic value of IL-6, CRP, and IL-10 measured 6 weeks after PCI 
in predicting late cardiac events (relative risk 3.9, 2.5, and 2.5, respectively) (7).  Chan et 
al further demonstrated that rates of peri-procedural MI increase with pre-procedural 
CRP (8), and high levels of CRP have been associated with adverse outcomes after PCI 
(8-10).  Interleukin-1 (IL-1) is another inflammatory cytokine involved in tissue 
inflammation and ischemia reperfusion injury, while IL-1 receptor antagonist 
competitively blocks the binding of IL-1 to its receptor (11-12) and correlates with 
severity of inflammation even when IL-1 levels are low (13). Patti et al demonstrated 
circulating IL-1 receptor antagonist to be an independent predictor of cardiac events in an 
unselected group of patients with symptomatic CAD undergoing PCI (14). Lastly, 
pentraxin-3, produced at sites of inflammation and stored in neutrophil specific granules 
to be readily released upon activation, is a strong predictor of late lumen loss after PCI 
(15-17). 


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Rates of peri-procedural MI are significantly decreased in patients with CAD undergoing 
PCI who are pre-treated with statins.  The ARMYDA (Atorvastatin for Reduction of 
Myocardial Damage During Angioplasty) study demonstrated decreased peri-procedural 
MI (5% versus 18% in the placebo group, 72% relative risk reduction) with atorvastatin 
pre-treatment (40mg for 7 days) prior to elective PCI in statin-naïve patients with stable 
CAD (18).  The NAPLES (Novel Approaches for Preventing or Limiting Events) II study 
further demonstrated decreased rates of peri-procedural MI (9.5% versus 15.8% in the 
control group, 40% relative risk reduction) with atorvastatin pretreatment (80mg 24 hours 
prior to PCI) in the same patient population (19).  A similar benefit was noted in the ACS 
population with high-dose statin pretreatment a mean of 12 hours prior to PCI and an 
additional dose 2 hours prior to PCI in the ARMYDA-ACS study (30-day incidence of 
major adverse cardiac events 5% versus 17% in the placebo group) (20).   
Elevation of cardiac enzymes following PCI occurs in 6% to 34% of patients (21-26), 
with incremental increases in subsequent death and 
MI noted with incremental increase in post-PCI 
cardiac biomarkers (see figure) (22). The beneficial 
effects of statins prior to PCI are likely to be 
independent of their lipid-lowering actions, given 
that significant changes in lipid levels take days to 
weeks.  One proposed mechanism of benefit of 
peri-procedural statin use is the attenuation of the 
pro-inflammatory state in ACS and PCI (27-28). 
The anti-inflammatory effects of statins induce 
plaque stabilization leading to less micro-embolization and side-branch occlusion during 
PCI, thereby decreasing peri-procedural myocardial necrosis.  
Despite the benefits statins offer, up to 40% of patients are not on statin-therapy prior to 
PCI (29). Statins are often withheld in patients with elevated liver enzymes, not an 
uncommon finding in the high-risk ACS population. In a large meta-analysis, statin 
therapy increased the risk of adverse events by 39% (odds ratio of 1.4) when compared 
with placebo (30).  In this analysis, adverse events such as myalgia and liver function 
elevations were responsible for almost two-thirds of the adverse events reported, and, 
although these events are not urgent, they are enough to account for the gap in statin 
therapy in the population undergoing PCI. Furthermore, statins must also be given 12 to 
24 hours before PCI to take effect (probably due to the kinetics of inhibiting post-
translational modification of the small G proteins Rho and Ras), which limits the number 
of patients for whom statins are a beneficial option. 
Given the significant number of patients not on statin therapy prior to PCI (29), and the 
apparent benefit of anti-inflammatory therapy in patients undergoing PCI, there is a need 
for a more rapid acting anti-inflammatory agent, especially prior to urgent PCI in high-
risk ACS cases.  Colchicine is a treatment of choice in gout and familial Mediterranean 
fever due to its rapid anti-inflammatory effect via inhibition of neutrophils and other 
inflammatory cells.  The anti-inflammatory effects of colchicine are well studied, albeit 
incompletely elucidated (31-34). Our group demonstrated colchicine’s interference with 
neutrophil-endothelial interactions by eliminating the E-selectin-mediated increment in 
endothelial adhesiveness to neutrophils in response to IL-1 and tumor necrosis factor-α 


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in-vitro within 4 hours of administering low, prophylactic, concentrations of colchicine 
(35). At higher, therapeutic, concentrations colchicine also diminished the expression of 
L-selectin on the surface of neutrophils (detectable after 1 hour) (35). Terkeltaub et al 
demonstrated the pharmacokinetic properties, as well as the superior safety profile 
without loss of efficacy of the low-dose colchicine regimen (1.2mg followed by 0.6mg 1 
hour later) that is now standard of care in the treatment of gout (36). The adverse event 
profile was similar to that of the placebo group, with 23% of patients having diarrhea and 
none having severe diarrhea or vomiting (36).  We have recently demonstrated that in 
gout patients, the use of colchicine was associated with a ≥50% decrease in MI rates in a 
cohort of VA patients (37). 
Only one study has evaluated the use of colchicine in the CAD population (38), and no 
study to date has examined the use of colchicine 
in the PCI population.  Nidorf et al showed that 
low-dose colchicine significantly decreased CRP 
levels (relative decrease of 60% compared to 11% 
in the no treatment group) in patients with stable 
CAD already on aspirin and high-dose 
atorvastatin therapy (38).  Due to its rapidity of 
action (peak concentrations in 1 to 2 hours, see 
figure) and excellent safety profile, acute 
administration of colchicine may play a promising role in improving outcomes post-PCI. 
When choosing markers to measure in the current proposal, rapidity of change and 
predictors of clinical outcomes in the setting of PCI was taken into account.  CRP is the 
most extensively studied inflammatory marker in patients with CAD, and pre-procedural 
CRP is associated with peri-procedural MI (8). However, CRP is produced in the liver in 
response to interleukin-6 and other inflammatory cytokines, thereby accounting for the 
need for 24 hours before any change in CRP is noted.  Interleukin-6 is not only the 
primary inducer of CRP, but also a marker that increases as early as 1 hour after PCI (3) 
and a strong predictor of late cardiac events along with CRP (7), making it a prime 
candidate for the primary endpoint in the current proposal.   
Animal studies have shown statin therapy to reduce infarct size when given less than 3 
days prior to ischemia/reperfusion but not when administered 1 to 2 weeks before 
ischemia/reperfusion, suggesting that the cardioprotective effect of statin therapy 
decreases over time (39).  However, the same paper also showed that the cardioprotective 
effect can be restored with acute high dose statin therapy, due to modulation of the 
PI3K/Akt pathway (39). With chronic statin therapy there is upregulation of the 
phosphatase and tensin homolog, a potent inhibitor of the phosphatidyl inositol-3 kinase 
(PI3K)/serine/threonine kinase (Akt) pathways.  However, when given acutely, statins 
directly enhance the PI3K/Akt pathways, resulting in endothelial nitric oxide synthase 3 
and activation of a signal transduction cascade that leads to cardioprotective effects (40).  
The ARMYDA-Recapture study demonstrated benefit with a reload of high-dose statin 
12 hours prior to PCI in patients with stable angina or non-ST segment elevation MI on 
chronic (>30 days) statin therapy (2.4-fold reduction in periprocedural MI) (41). These 
studies provide us with the rationale to stratify the randomization process by patients who 
do or do not receive a load with high-dose statin therapy 24 hours to 3 days prior to PCI, 


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thereby attempting to control the confounding cardioprotective effects exerted by acute 
high-dose statins.  
3. Study Design 
Prospective, randomized, double-blinded, placebo-controlled trial of patients undergoing 
coronary angiography in the Manhattan Veterans Affairs Hospital (primary site is 
Manhattan Veterans Affairs Hospital), Bellevue Hospital Center, and New York 
University (NYU) Langone Medical Center cardiac catheterization laboratories.  Patients 
will be stratified into one of two groups:  
1) Patients who received a load with high-dose statin therapy (an increase in the 
patient’s maintenance regimen or started newly on a statin) 24 hours to 7 days prior to 
the procedure and continued on a daily regimen 
2) Patients who did not receive a load with high-dose statin therapy 24 hours to 7 days 
prior to the procedure  
*The decision to load with high-dose statin therapy prior to PCI is made 
clinically by the treating physician. 
Patients will then be randomized to one of two groups: 
1) Colchicine 1.2mg 1 to 2 hours before coronary angiography, followed by colchicine 
0.6mg 1 hour later 
2) Placebo at the same time points above 
 
II. Subject Population and Selection 
1. Patient Population 
Patients referred for coronary angiography at Manhattan Veterans Affairs Hospital 
(primary site is Manhattan Veterans Affairs Hospital), Bellevue Hospital Center, and 
NYU Langone Medical Center,  
2. Gender of Subjects 
Subjects will include both men and women.  Every effort will be made to include 
equitable numbers of each gender. 
3. Age of Subjects 
Subjects more than 18 years of age will be eligible to participate in the study.  The 
research in question applies to the entire adult population and therefore all adults may 
participate. 
4. Racial and Ethnic Origin 
Subjects of any racial or ethnic background may participate in the study.  There will be 
no enrollment restrictions based on race or ethnic origin. 
5. Inclusion Criteria 
Patients must be more than 18 years of age and referred for coronary angiography. 
6. Exclusion Criteria 


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Patients will be excluded if they meet one of the following criteria: 1) Plan for 
diagnostic-only coronary angiography, 2) On colchicine chronically, 3) History of 
intolerance to colchicine, 4) Glomerular filtration rate <30mL/minute or on dialysis, 5) 
Active malignancy or infection, 6) History of myelodysplasia, 7) High-dose statin load 
<24 hours prior to procedure, 8) Use of oral steroids or non-steroidal anti-inflammatory 
agents other than aspirin within 72 hours or 3 times the agent’s half-life (whichever is 
longer), 9) Use of strong CYP3A4/P-glycoprotein inhibitors (specifically ritonavir, 
ketoconazole, clarithromycin, cyclosporine, diltiazem and verapamil), 10) Unable to 
consent, 11) Participating in a competing study, 12) Pregnant women, or 13) Patients 
requiring emergent cardiac catheterization.  
7. Vulnerable Subjects 
The study will not include vulnerable subjects as defined by current regulations. 
 
III. Methods and Procedures 
1. Methods and Procedures 
Subjects for study participation will be screened from the population referred for 
coronary angiography at the New York University Medical Center and Bellevue Hospital 
and excluded if they meet any one of the following criteria: 1) planned for diagnostic-
only coronary angiography, 2) on colchicine chronically, 3) history of intolerance or 
allergy to colchicine, 4) glomelular filtration rate <30mL/minute or on dialysis, 5) active 
malignancy, 6) history of myelodysplasia, 7) high-dose statin load <12 hours prior to 
procedure, 8) use of oral steroids or any non-steroid anti-inflammatory agent other than 
aspirin within 72 hours or 3 times the agent’s half-life (whichever is longer), 9) Use of 
strong CYP3A4/P-glycoprotein inhibitors (specifically ritonavir, ketoconazole, 
clarithromycin, cyclosporine, diltiazem and verapamil), 10) unable to consent, 11) 
participating in a competing study, 12) pregnant women, or 13) any condition (e.g., 
psychiatric illness) or situation that, in the investigator's opinion, may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject's ability to adhere with study procedures.   
A. Consent and Randomization Recruitment will be conducted in accordance of the 
policies of the Manhattan VA Hospital, Bellevue Hospital, and NYU IRB and Federal 
guidelines. The attending interventional cardiology physician of all potential subjects will 
be contacted to determine if the subject is willing to be approached about the study. 
Informed consent will be sought and documented from all subjects at the earliest time 
possible, or at least 2 hours before coronary angiography. The rationale, procedures and 
potential risks of the procedures in the study will be explained to each participant by the 
Principal Investigator or his appointed designee.  Each subject will be told that 
participation in the studies described in this proposal is strictly voluntary, that refusal to 
participate will not alter the patient's relationship with their physician, that the studies 
constitute research and that the information obtained will not be specifically helpful to 
the individual patient's care. After the subject has read the consent form, comprehension 
of the key elements of the study procedures and risks will be tested with verbal questions 


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of the consent form content. If the subject is willing to participate, the subject will sign 
the IRB-approved informed consent form.  
A randomization code will be generated by an independent statistician using random 
block sizes and held by the research pharmacist. Study drug and a unique subject 
identifier linked to group assignment will be allocated by the research pharmacist. 
However, the research pharmacist will not release group assignment to the investigative 
team until after all subjects have completed the protocol and the database has been 
locked.  
B. Study Technique 
Patients will then be randomized to one of two groups: 
1) Colchicine 1.2mg 1 to 2 hours before coronary angiography, followed by 
colchicine 0.6mg 1 hour later. 
2) Placebo at the same time points above 
Adjunctive pharmacotherapy: 
1) All subjects will be on aspirin therapy as follows: 1) Maintenance therapy 
(defined as >2 days of 81 mg or 325 mg doses), or 2) aspirin 325 mg load >2 
hours pre-baseline (with daily dose thereafter if load >1 day pre-procedure).  
2) This is a real-world all-comers study, and there is a substantial subset of subjects 
referred for possible PCI who are not on maintenance clopidogrel therapy and 
receive a clopidogrel loading dose <6 hours pre-procedure, including the majority 
of subjects who present with ACS. Therefore, it is appropriate and clinically 
relevant to include all subjects, regardless of timing of clopidogrel administration, 
as long as it is administered pre-procedure. Timing and dose of clopidogrel 
administration will be noted in detail. Secondary analyses will be conducted 
separately in a subgroup adequately loaded with clopidogrel to achieve steady-
state levels pre-procedure, and a subgroup not adequately loaded with clopidogrel 
pre-procedure (see definition below). 
For studies affected by background antiplatelet therapy (i.e. neutrophil-platelet 
aggregation), subjects will have to meet the definition of clopidogrel therapy as 
follows: 1) Maintenance therapy (>7 days of 75 mg), or 2) clopidogrel 600 mg >6 
hours pre-baseline (with 75mg daily thereafter if load >1 day pre-procedure), or 
3) clopidogrel 300 mg >12 hours pre-baseline (with 75 mg daily thereafter if 
load >1 day pre-procedure). 
3) Bivalirudin therapy for a targeted activated clotting time of >250 seconds prior to 
PCI 
Measurement of inflammatory markers via standard venopuncture: 
1) Immediately prior to colchicine or placebo administration as baseline  
2) At end of procedure  (30 minutes to 1 hour post-procedure) 
3) If successful PCI is performed, 6 to 8 hours post-PCI, at the time of routine 
clinical blood collection 
4) If successful PCI is performed, next day morning collection (22 to 24 hours), at 
the time of routine clinical blood collection 


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Approximately, 10cc of blood will be collected in ethylenediaminetetraacetic (EDTA) 
acid or sodium citrate tubes at each time point and stored immediately on ice.  
Approximately 5cc of blood will be prepared using a fluorescence activated cell sorter to 
allow for measurement of cell-associated inflammatory markers.  Approximately 3cc of 
blood will be separated within 30 minutes by centrifugation at 4ºC and 1600g for 10min, 
and samples will be stored at -80 ºC until analysis and thawed only once. The remaining 
2cc of blood will be used to measure white blood cell count and neutrophil count using a 
hematology analyzer. Samples will be labeled with patient unique identifier research 
number assigned at randomization and will only be used for the purpose of this study (no 
blood samples will be stored for other research studies in the future).  Since baseline 
blood samples will be obtained from non-PCI patients due to the lack of a priori 
knowledge of which patients will have PCI and which will be diagnostic only, baseline 
and post-angiography samples will also be analyzed to test an exploratory hypothesis that 
colchicine also reduces markers of inflammation induced by coronary angiography/dye 
administration alone, albeit to a lesser degree.  
Measurement of post-PCI cardiac biomarkers: 
Troponin and creatine kinase-MB are measured at 6 to 8 hours and at 22 to 24 hours post-
PCI via standard venopuncture as part of standard clinical care 
Screening & 
Consent  
Baseline 
Assessment 
(immediately 
prior to drug) 
Standard venipuncture for assays assessed in Aims 1 and 2 
Colchicine 
1.2mg 
Placebo 
1.2mg 
Randomization 
Colchicine 
0.6mg 
Placebo 
0.6mg 
1 hour 
1 hour 
Percutaneous 
Coronary 
Intervention 
(PCI) 
Post-PCI 
Follow-up #1 
Post-PCI 
Follow-up #2 
Post-PCI 
Follow-up #3 
1 hour  
post-PCI 
6 to 8 hours  
post-PCI 
22 to 24 hours  
post-PCI 
Long-term 
Follow-up 
30 days, 6 
months, and 
then yearly for 
5 years 
post-PCI 
Assessment for major adverse cardiac events 
Screening & Randomization 
Drug Administration 
Follow-up 
Procedure 
 Troponin and CKMB 
Schematic of Study Protocol 
Post-PCI follow-ups are defined as time 
from last balloon inflation 
 
Of note, the cardiac catheterization and PCI procedures are part of standard clinical care, 
along with post-PCI measurements of Troponin and CKMB.  Measures of inflammatory 
markers in the blood and administration of colchicine versus placebo are the only 
research-related interventions. 
C. Data Collection   The following baseline variables will be prospectively collected: 
Baseline Variables: 
 Demographics, Height, Weight, Body mass index, Abdominal circumference (race-
ethnicity self-reported, other variables measured) 
 Medical history:  Previous MI, previous PCI, previous coronary artery bypass surgery, 
hypertension, hypercholesterolemia, diabetes mellitus, peripheral vascular disease, 
previous stroke or transient ischemic attack, carotid artery disease (>50% stenosis), 
hepatitis C, and tobacco use (collected from medical records and confirmed by patient)  
       


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 Medications:  statin (type and dose), aspirin, thienopyridine, cilostazol, dipyridamole, 
beta blocker, calcium channel blocker, nitrate, ranolazine, hydralazine, ACE inhibitor, 
angiotensin receptor blocker, statin, fibrate, niacin, ezetimibe, diuretic, aldosterone 
receptor blocker, digoxin, antiarrhythmic agent, unfractionated heparin, low molecular 
weight heparin within 12 hours of procedure, insulin, protease inhibitor (collected from 
medical records and confirmed by patient) 
 Laboratory data: BUN, creatinine, glomerular filtration rate, glucose, white blood cell 
count, hemoglobin, total cholesterol, high density lipoprotein, low density lipoprotein, 
triglyceride, hemoglobin A1c, ejection fraction (normal, mild to moderately reduced, or 
severely reduced left ventricular systolic function) (collected from medical records) 
 
Procedural data: 
 Time of baseline blood draw and drug administration (recorded in real time) 
 Indication for coronary angiography (determined by research team according to data 
provided in medical records) 
 Time of procedural access and type of arterial access (femoral or radial) (collected from 
catheterization report) 
 Type of contrast agent used (Hexabrix, Visipaque, Isovue) (collected from 
catheterization report) 
 Number of native and graft vessels with greater than 70% stenosis (collected from 
catheterization report) 
 Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) score is a scoring 
system that provides information on atherosclerosis burden in patients undergoing 
revascularization (calculated by at least two cardiologists trained in SYNTAX scores and 
grouped as <17 (low), 17-32 (intermediate), or >33 (high) scores).  
 
 If PCI performed (collected from operator questionnaire administered in real time and 
catheterization report): 
o Segment treated (left main, left anterior descending, left circumflex, right coronary 
artery, saphenous vein graft, arterial graft) and single vessel or multivessel 
intervention 
o Single vessel or multivessel intervention 
o Percent diameter stenosis pre- and post-PCI on semi-quantitative coronary 
angiography 
o Type of lesion treated (de novo or restenotic, chronic total occlusion, bifurcation 
lesion, calcification, visible thrombus, lesion length >33 mm), lesion site (ostial, 
proximal, mid-vessel, distal), and number of lesions treated 


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o Type of intervention with devices used (balloon only, balloon plus stent, cutting 
balloon, thrombectomy device, rotational atherectomy device, chronic total 
occlusion crossing device, filter basket, laser) 
o Time of first coronary balloon inflation  
o Number of pre-dilations or use of direct-stenting  
o Type of stent, number of stents, stent diameter and total stent length 
o Stent deployment pressure 
o Use of post-dilations and maximum pressure on post-dilation 
o Use of Intracoronary medications used (e.g. nitroglycerin, nitroprusside, 
glycoprotein IIb/IIIa inhibitors) 
o Pre- and post-TIMI flow grade 
o Procedural success (defined as residual stenosis <20% at the end of procedure) 
 Time of end of procedure 
 Complications  
o Abrupt vessel closure at any time during procedure (main vessel or side branch) 
o Perforation 
o Distal embolization 
o Plaque shift with side branch compromise (>70% residual stenosis in at conclusion 
of procedure) 
o <TIMI 3 flow in any treated vessel at any time during procedure (also included in 
post-PCI TIMI flow) 
o Uncovered dissection (grade 3 or higher in vessel >1.5 mm in diameter)  
o Shock during procedure  
o Acute pulmonary edema requiring intubation  
o Dysrhythmia requiring defibrillation 
All electronic data is de-identified and resides on password-protected computer. All hard 
copy of data are secured in a locked cabinet in a locked office. 
D.  Outcomes   
The primary outcome of the overall trial will be peri-procedural myonecrosis using 
cardiac biomarkers (Troponin I) as defined by the 3rd Universal Definition (42) as follows 
(biomarkers are evaluated at 6 to 8 hours and 22 to 24 hours post-PCI):  
 
In subjects with normal baseline cardiac biomarkers, peak post-procedure cardiac 
biomarker above the 99th percentile upper reference limit  
 
In subjects with elevated baseline cardiac biomarkers and the biomarker levels 
are stable or falling, there should be a new cardiac biomarker elevation by >20% 
from the most recent pre-procedural level 


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The primary outcome of the inflammatory marker subset will be change in soluble 
interleukin-6 level between baseline and 1 hour post-PCI.  
   
Secondary outcomes include:  
1) The secondary outcomes of the inflammatory marker substudy will be as follows:  
Measurement of other relevant inflammatory markers (such as cell-associated L-selectin 
(CD62L), cell-associated beta-2 integrin CD11b, soluble L-selectin, myeloperoxidase, 
elastase, soluble E-selectin, intercellular/vascular cell adhesion molecule-1, white blood 
cell count, and neutrophil count), as well as mean number of neutrophils adherent to 
TNFα-stimulated endothelial cells, extent of neutrophil-platelet aggregates, neutrophil 
extracellular traps (NETs), neutrophil-derived microparticles, tissue factor pathway 
inhibitor, and endogenous thrombin potential at the end of procedure, 6 to 8 hours post-
successful PCI and 22 to 24 hours post-successful PCI. 
2) In the overall trial: 
a) Occurrence of major adverse cardiac events with composite of the earliest occurrence 
of death from any cause, non-fatal MI (defined by the 3rd universal definition of MI) (42), 
or target vessel revascularization (bypass surgery or repeat PCI of the target vessel) 
assessed at 30 days, 6 months, and yearly for 5 years. Peri-PCI MI will be defined using 
the Universal Definition (42) (any elevation 5 times the 99th percentile upper limit of 
normal). No definition currently exists to define post-PCI myocardial necrosis or MI 
when biomarkers are elevated prior to procedure. In patients with elevated baseline levels 
of troponin or creatine kinase-MB, peri-procedural MI will be defined as a subsequent 
increase of more than 2-fold in troponin or creatine kinase-MB from baseline value.   
b) Peri-procedural MI will also be defined by the expert consensus document from the 
Society for Cardiovascular Angiography and Interventions on a new definition of 
clinically relevant MI after coronary revascularization as follows (43): 
 Subjects with normal baseline cardiac biomarkers  
o Peak post-procedure Troponin >70x upper limit of normal or CKMB >10x 
upper limit of normal 
o A lower threshold (Troponin >35x upper limit of normal, CKMB >5x) will be 
used in subjects with new   pathologic Q-waves in >2 contiguous leads (or new 
persistent left bundle branch block)  
 In subjects with elevated baseline cardiac biomarkers and stable or falling 
biomarker levels, there should be a new Troponin or CKMB elevation by an absolute 
increment of >70x (for Troponin) or >10x (for CKMB) upper limit of normal from 
the most recent pre-procedural level 
 In subjects with elevated baseline cardiac biomarkers and the biomarker levels have 
not been shown to be stable or falling, there should be a further rise in CKMB (or 
Troponin) by an absolute increment of >70x for Troponin or >10x (for CKMB) upper 
limit of normal plus new ST-segment change plus signs consistent with a clinically 
relevant MI (e.g. new onset or worsening heart failure or sustained hypotension)  
c) The primary outcome of peri-procedural myonecrosis using CKMB as the biomarker  
 
E. Sample Size   


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A) A total sample size of 400 subjects is needed to demonstrate a 40% reduction in 
proportion of subjects with peri-procedural myonecrosis (from 30% in the placebo group 
to 18% in the colchicine group) using a Chi squared test (80% power, 0.05 significance 
level). This trial is designed to study the effect of colchicine on all-comers to the cath lab. 
A greater effect is expected on both surrogate and clinical endpoints in the ACS 
compared with elective PCI population. Our sample size is based on the lowest relative 
risk reduction observed with anti-inflammatory therapy in elective PCI (19). We 
approximate that 50% of the patients enrolled will either not have PCI performed after 
coronary angiography (majority) or will be excluded due to requirement of the use of any 
of the medications listed in the exclusion criteria prior to post-PCI blood collection 
(minority).  We, therefore, estimate a total sample size of 800 be enrolled in this study to 
meet the 400 PCI sample size. 
B) Sample size for the inflammatory marker subset is calculated based on mean 
interleukin-6 level of 12pg/mL and standard deviation of 12pg/mL one hour after PCI in 
predominantly ACS patients reported by Aggarwal et al (3), and an estimated decrease in 
post-PCI interleukin-6 level by 40% if randomized to colchicine. A 40% decrease is a 
conservative estimate relative to the 60% reduction of CRP noted in Nidorf’s study 
examining the effect of colchicine in stable CAD patients on aspirin and high-dose statin 
therapy (38).  Furthermore, in Aggarwal’s study, interleukin-6 levels increased by 58% 
from pre-procedural levels (3). Based on the above assumptions, and a two-sided two 
sample t-test, the number of patients needed in each group to achieve 80% power at the 
0.05 significance level is estimated to be 100.  A minority of subjects (~16%) may 
experience no change in IL-6 after PCI (44). To adjust for this possible floor effect, the 
sample size needed would also be 120 subjects in each group. If a 35% or 30% decrease 
in post-PCI IL-6 level is observed with colchicine, 129 or 175 subjects will be needed in 
each group, respectively (80% power, 0.05 significance). 
If sample size for the inflammatory marker subset was calculated with surface CD62L 
(the secondary endpoint) as endpoint, it would be based on the mean (± standard 
deviation) peak post-PCI surface expression of neutrophil CD62L of 9906 ± 6737 MFI  
(39% rise from pre-PCI) from our pilot AHA-funded project. Based on our volunteer data 
examining the effects of surface expression of CD62L after a 1.8 mg loading dose and 
earlier in vitro data, we would estimate a decrease in post-PCI CD62L level by ~25% 
with colchicine. Using a two-sided two sample t-test, the sample size using 80% power 
and 0.05 significance level would be ~120 subjects in each group. If a 23% or 20% 
decrease in post-PCI CD62L level is observed with colchicine, 138 or 182 subjects will 
be needed in each group, respectively (80% power, 0.05 significance). 
C) Other secondary endpoints: Sample size for neutrophil-endothelial cell adhesion assay 
is based on in vitro data by our group that demonstrated reductions in neutrophil-
endothelial adhesiveness with addition of colchicine (108 ± 11 to 31 ± 5 adherent 
neutrophils/200x field) (35). Based on a conservative estimate of 20% reduction and a 
two-sided two sample t-test, the sample size to achieve 95% power (0.05 significance) is 
~10 subjects in each group.  
Sample size for neutrophil-platelet aggregates is based on data by our group from the 
peri-procedural glycemic control trial (mean leukocyte platelet aggregation 10.57 ± 
4.10%) (45). Based on a ~30% reduction and a two-sided two sample t-test, the sample 


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size to achieve 95% power (0.05 significance) is ~45 subjects in each group. Since these 
subjects must meet dual anti-platelet therapy criteria and the probability of one subject 
satisfying these criteria in the colchicine group is 0.5, increasing the sample size by 10% 
will make the probability of achieving at least 45 subjects in each group 
(placebo/colchicine) ~68%. Increasing the sample size to 107 (90*1.10%) will make the 
probability of achieving at least 45 subjects in each group (placebo/colchicine) ~90%. 
Subjects in the inflammatory marker substudy that meet dual anti-platelet therapy criteria 
will undergo neutrophil-platelet aggregate evaluation. 
F. Time Period  We estimate a weekly enrollment of at least 2 eligible patients who 
undergo randomization and successful PCI.  We believe there will be very low dropout 
rate due to the excellent side-effect profile and short follow-up which involves blood 
collection during two time points post-PCI when blood is routinely collected for non-
research purposes. Therefore, we believe the study should take approximately 4 years to 
complete. 
G.  Follow-up  Telephone contact will be made at 30 days, 6 months, and yearly for up to 
5 years post-PCI. A subject’s participation is voluntary, and the subject has the right to 
withdraw at any time without penalty or loss of benefit. Should this occur, the reason for 
the withdrawal will be documented. Discontinuation may be due to subject withdrawal 
(refuse all subsequent testing/follow-up) or loss to follow-up. Research team will make 
all reasonable efforts to locate and communicate with subjects who do not complete 
follow-up but have not officially withdrawn from the study, including the following at 
each contact time point: 
1) A minimum of two telephone calls to contact the subject will be attempted 
2) If these attempts are unsuccessful, a letter will be sent to the subject and the VA 
electronic medical record system will be reviewed for the needed data 
3) If the subject misses two consecutive scheduled contact time points, the above-
mentioned attempts at communicating with the subject are unsuccessful, and there is 
no interim data in the VA electronic medical record system the subject will be 
considered lost to follow-up. As a last resort, the Social Security Death Benefit Index 
will be queried for death. 
2. Data Analysis and Data Monitoring 
Categorical variables will be presented as proportions, normally distributed continuous 
variables as mean ± standard deviation, and skewed continuous variables as median 
[interquartile range] (distributions assessed for normality using histogram, quantile-
quantile plot and Shapiro-Wilk test). Categorical endpoints will be compared between 
placebo and colchicine groups using tests of proportions (exact and asymptotic), and 
continuous endpoints will be compared between placebo and colchicine groups using t-
test. Non-parametric alternatives (e.g. Wilcoxon test) and mathematical transformations 
(e.g. Box-Cox) will be considered as needed for skewed distributions. Statistical 
significance will be tested using a 2-sided alpha level of 0.05 with appropriate multiple 
testing correction (Bonferroni or Benjamini-Hochberg) when needed.  
To not incur excess bias by deviating from classification according to assigned treatment, 
an intention-to-treat approach will be utilized as a primary analytic approach. A 
secondary analysis will be performed utilizing a non-intention-to-treat approach, where 
subjects are classified according to the treatment actually received and subjects who do 


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not receive treatment are excluded. We believe crossover and pre-procedure withdrawal 
will be relatively low. Adopting both approaches, however, will allow for assessment of 
the robustness of findings. 
Pre-specified subgroup analyses will be performed in subjects presenting with versus 
without ACS and with versus without in-lab complications, as defined below. 
In-lab complications: 1) Vessel closure any time during procedure (main vessel or side 
branch); 2) Perforation; 3) Distal embolization; 4) Plaque shift with side branch 
compromise (>70% residual stenosis in side branch at conclusion of procedure); 5) 
<TIMI 3 flow in any treated vessel at any time during procedure (also included in post-
PCI TIMI flow); 6) Uncovered dissection (grade 3 or higher in vessel >1.5 mm in 
diameter); 7) Shock during procedure; 8) Acute pulmonary edema requiring intubation; 
or 9) Dysrhythmia requiring defibrillation 
A) To delineate changes in neutrophil activation during acute vascular injury using a PCI 
model, markers of neutrophil activity will be assessed by comparison of post- versus pre-
PCI samples in the placebo group using paired t-test or paired sample Wilcoxon signed 
rank test. In addition, to account for all 4 time points (1 pre- and 3 post-PCI), a significant 
change in markers over time will be determined in the placebo group by estimating speed 
of change using slope in a linear mixed effects regression model at a 0.05 level of 
significance cut-off. Markers will then be categorized descriptively as increasing versus 
not increasing post- compared to pre-PCI. 
Univariate and multivariate predictors of markers that demonstrate a significant increase 
post- compared with pre-PCI (as defined above) will be determined using baseline 
demographic, clinical, and procedural covariates of interest. Major covariates of interest 
may include age, sex, race, abdominal circumference, diabetes mellitus, chronic kidney 
disease, MI within 7 days of PCI, ejection fraction <40%, pre-procedural TIMI 0 or 1 
flow, multivessel CAD, visible thrombus or ulcerated lesions, SYNTAX score >23, and 
presence of one of the in lab complications as defined above. Based on our biomedical 
knowledge and experience in variable selection and statistical modeling, we will balance 
model richness against a danger to overfit. First, a screening procedure based on the 
correlation between the outcome and each variable will be used to choose the variables in 
the multivariate model, and then a stepwise variable selection method including both 
forward and backward methods will be employed to search for an optimal model gauged 
by the Akaike information criterion. We will also conduct the principal component 
analysis for parsimonious modeling, which uses the correlation matrix to identify a small 
number of components capturing most of the variability and include them in the 
multivariate logistic regression model.  
To determine changes in subsequent cellular interactions, neutrophil adhesion to 
endothelial cells and neutrophil-platelet aggregates will be assessed post- compared with 
pre-PCI samples in the placebo group using paired t-test or paired sample Wilcoxon 
signed rank test.  
Finally, a mediation analysis will be performed in a logistic regression model to test the 
hypothesis that an increase in markers of neutrophil activation is associated with peri-
procedural myonecrosis, and that this association is mediated by neutrophil-endothelials 
cell and neutrophil-platelet adhesion.  


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Similar analyses will be performed in the evaluation of the change in NETs and 
neutrophil-derived microparticles post- versus pre-PCI. A mediation analysis will be 
performed in a logistic regression model to test the hypothesis that an increase in these 
neutrophil extracellular fragments is associated with peri-procedural myonecrosis, and 
that this association is mediated by tissue factor pathway inhibitor/thrombin generation.   
B) To determine the effect of colchicine on changes in markers of neutrophil activation 
and subsequent cellular interactions during acute vascular injury, pre- to post-PCI 
changes will be examined between the placebo and colchicine groups using two-sample t 
test or Wilcoxon rank sum test. To further study the time-varying pattern of treatment 
effect, with the observations at pre-PCI and multiple post-PCI time points, a repeated 
measurements or longitudinal data analysis modeling will be used by incorporating both 
individual-specific terms and the treatment by time interaction. The Analysis of Variance 
Analysis will be conducted using the Generalized Estimating Equations or Quasi-
Likelihood approach. Alternatively, proportion of subjects with significantly increased 
markers of neutrophil activity post- compared to pre-PCI (defined above using estimated 
slope of change) will be compared between the placebo and colchicine groups using tests 
of proportions. Finally, an interaction with pre-procedural use of colchicine versus 
placebo will also be evaluated to determine whether or not colchicine modulates the 
mediation analyses described above. 
C) To explore the association between markers of neutrophil activation and outcomes 
after acute vascular injury, the association between tertiles of markers of neutrophil 
activity at baseline and dichotomous outcome of peri-procedural myonecrosis will be 
assessed using logistic regression modeling and presented as odds ratio and 95% 
confidence interval. Similar analyses will be performed to evaluate the association 
between tertiles of markers of neutrophil activity at baseline and dichotomous outcome of 
peri-procedural MI, as well as long-term composite of all-cause mortality, non-fatal MI, 
and target vessel revascularization. 
However, the capacity for neutrophil activity to increase in the setting of acute vascular 
injury may be more pertinent than baseline activity. Therefore, using the estimated speed 
of change in neutrophil activity over time from pre- to post-PCI, markers of neutrophil 
activity will be categorized as increasing or non-increasing (no change or decreasing) 
based on analysis of slope and a 0.05 level of significance cut-off. The association 
between increasing versus non-increasing markers of neutrophil activity and peri-
procedural myonecrosis will be evaluated using logistic regression modeling (increasing 
marker as main predictor, peri-procedural myonecrosis as dichotomous outcome). Similar 
analyses will be performed to evaluate the association between increasing versus non-
increasing markers of neutrophil activity and peri-procedural MI, and long-term 
composite of all-cause mortality, non-fatal MI, and target vessel revascularization. 
Logistic regression models will be built hierarchically to include main covariates. As 
above, age, sex, race, abdominal circumference, diabetes mellitus, chronic kidney 
disease, MI within 7 days of PCI, ejection fraction <40%, pre-procedural TIMI 0 or 1 
flow, multivessel CAD, visible thrombus or ulcerated lesions, SYNTAX score >23, and 
presence of one of the in lab complications as defined above. Based on our biomedical 
knowledge and experience in variable selection and statistical modeling we will balance 
model richness against a danger to overfit as described above. 


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Finally, to explore the effects of colchicine on peri-procedural myonecrosis in a PCI 
model, the rate of peri-procedural myonecrosis and peri-procedural MI in subjects 
randomized to the placebo vs colchicine groups will be assessed using the tests of 
proportions. This association will also be assessed using logistic regression modeling and 
will include the main covariates described above.  
D) The low-dose colchicine regimen in the current proposal has been studied and 
demonstrates an excellent side effect profile.  A Data Safety Monitoring Committee 
(DSMC) will be formed to review ongoing safety data.  This committee will be a group 
consisting of three physicians and, when needed, one biostatistician. The DSMC 
meetings will include an initial open meeting for discussion with the Principal Investigator 
and the presentation of reports by the study coordinator followed by a closed meeting of 
voting DSMC members. The DSMC will review blinded safety data three times a year (or 
more often as necessary) to ensure the safe and proper treatment of subjects. The 
committee will also review recruitment data, study subject withdrawals, data on drug 
tolerability, and protocol violation data to determine whether any substantial deviations 
from the initial study plan might alter the original risk benefits analysis. If the frequency 
and/or severity of adverse events are thought to be study related, or if other logistical 
issues related to study drug tolerability, are thought to compromise the integrity of the 
study protocol, the DSMC can make recommendations for protocol modification or early 
termination of the study. After each meeting, the committee will prepare a brief report to 
be submitted to the Principal Investigator that will recommend: 1) study continuation 
without modification, 2) study continuation with modification, or 3) study discontinuation. 
A recommendation of study modification or study discontinuation will lead to an 
immediate cessation of study enrollment, but in the event of a recommendation of study 
modification, study enrollment may be allowed to resume once the human subjects 
safety issues and/or other logistical issues have been adequately addressed to the 
satisfaction of the DSMC and IRB. In the event of identification of any relevant safety 
findings that may change the original risk benefit analysis for the human subjects in the 
study, these findings will be forwarded to the IRB committee and will be incorporated into 
a revised protocol and consent form. All current participants and future participants will 
be required to sign the revised consent form.  The Principal Investigator will be 
responsible for reporting of adverse events to the DSMC and VA IRB according to 
standard definitions. 
 
3. Data Storage and Confidentiality 
All patient data will be kept strictly confidential, except when published for purposes of 
reporting data. In that case, the patients are never identified. As noted previously, all 
electronic data will be de-identified and resides password-protected computers.  All hard 
copy of data will be secured in a locked cabinet in a locked office on Manhattan VA 
Hospital property. All biological specimens will be encoded with no identifying 
information and stored at NYU School of Medicine Smilow Research Building that can 
only be traced back to the individual by the research team. There is a minimal risk of loss 
of confidentiality though every precaution will be taken to avoid this.  The statistician 
will have access to only the de-identified data for analysis. 
 
IV. Risk/Benefit Assessment 
1. Risk 


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The proposed colchicine regimen for this proposal has been studied in regards to safety 
profile, and the adverse event profile was similar to that of placebo, with 23% of patients 
having diarrhea and none having severe diarrhea or vomiting (36).   There is also a rare 
incidence of hypersensitivity to colchicine that may cause skin rash, hives, and/or 
angioedema. 
Venipuncture is associated with risk of pain, bruising, infection, and less commonly 
development of anemia, lightheadedness or syncope. We will be collecting blood at 4 
well-spaced time points. 
2. Protection against risks 
The study investigators are specialists in Interventional Cardiology with particular 
training in radiation safety.  Subjects will have access to study investigators at all times 
by telephone.  
3. Potential Benefits to the Subjects 
Subjects may experience no direct benefit. 
 
V. Investigators Qualifications and Experience 
Attached are copies of the curriculum vitae for each study investigator.  The investigators 
each have completed training in the protection of human subjects. 
 
VI. Subject Identification, Recruitment, and Consent 
1. Method of Subject Identification and Recruitment 
Subjects will be screened and recruited when they are referred to the Manhattan Veterans 
Affairs Hospital, Bellevue Hospital Center, and NYU Langone Medical Center cardiac 
catheterization laboratory for clinically indicated coronary angiography.  Informed 
consent will be obtained by the study team at least 2 hours prior to coronary angiography.  
Every effort will be made to recruit subjects prior to the day of the catheterization 
whenever practical. 
2. Process of Consent 
Subjects will be provided the required information for informed consent in writing, and 
they will also be given an oral description of the project.  Consent will be obtained by the 
study investigators who have training in obtaining consent from research subjects.   
Completed written consent forms will be stored securely with the other study documents 
by the Principal Investigator. 
3. Subject Capacity and Comprehension 
Only subjects with the capacity to give consent will be included in the study. The subjects 
will be required to state their understanding of each step of the informed consent and to 
demonstrate their understanding by repeating the information provided. 
4. Consent forms 
A study consent form is attached. 


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5. Costs to the Subject 
The subjects will incur no costs as a result of study participation. 
6. Payment for Participation 
The subjects will receive no payment of any sort for participating in the study. 
 


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