Clinical trial NCT02551094
Conditions: Coronary Artery Disease Myocardial Infarction
Sponsor: Montreal Heart Institute
Start date: 2015-12-04; Completion date: 2019-07-17
Enrollment: 4745 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study evaluates whether long-term treatment with colchicine reduces rates of cardiovascular events in patients after myocardial infarction. Patients who have suffered a documented acute myocardial infarction within the last 30 days, are treated according to the national guidelines and after having completed any planned percutaneous revascularization procedures associated with their initial infarction will receive either colchicine (0.5 mg per day) or matching placebo (1:1 allocation ratio) for an estimated 2 years period or until the target of 301 primary endpoints has been reached.

Detailed description:
Atherosclerosis is the most common cause of myocardial infarction, stroke and peripheral arterial disease. Research has clearly demonstrated that inflammation plays a key role in the initiation, progression and manifestations of atherosclerosis. Atherosclerotic lesions begin as an accumulation of lipid-laden cells (primarily macrophages) beneath the endothelium, and progress with the further accumulation of cells, connective-tissue elements, lipids and debris through immunological and inflammatory activation. Neutrophils and other inflammatory cells have been shown to invade culprit atherosclerotic lesions in acute coronary syndromes. It is likely that the inflammatory process is responsible for the high rate of cardiovascular events despite significant advances in the treatment of risk factors such as hypercholesterolemia and hypertension. It is vital to improve our understanding of the inflammatory nature of atherosclerotic disease and modify the inflammatory process with targeted therapies. Prospective cohort studies have consistently shown that high sensitivity C-reactive protein (hs-CRP) and several other biomarkers of inflammation are independently associated with increasing risk of future cardiovascular events in different populations. This together with animal models showing that reduced inflammation has anti-atherosclerotic effects, create the impetus to test the hypothesis that treatment of the underlying inflammatory process will contribute to improved cardiovascular clinical outcomes. Colchicine is an inexpensive, yet potent, anti-inflammatory drug approved for acute use in patients with gout and chronic use in patients with Familial Mediterranean Fever. The mechanism of action is through the inhibition of tubulin polymerization and potentially also through effects on cellular adhesion molecules and inflammatory chemokines. Colchicine may also have direct anti-inflammatory effects by inhibiting key inflammatory signaling networks known as the inflammasome and pro-inflammatory cytokines. Through the disruption of the cytoskeleton, colchicine is believed to suppress secretion of cytokines and chemokines as well as in vitro platelet aggregation. Considerable work has highlighted the potential of colchicine in the treatment of cardiovascular diseases mediated by pro-inflammatory processes. More recently colchicine has been evaluated for its effect on cardiovascular events in patients with coronary artery disease (CAD).

Arms: arm 1: 0.5 mg tablet of colchicine taken once a day arm 2: 0.5 mg tablet of placebo taken once a day
Interventions: intervention 1: colchicine intervention 2: colchicine placebo
Intervention descriptions: intervention 1: 0.5 mg tablet taken once a day intervention 2: sugar pill manufactured to mimic colchicine 0.5 mg tablet

Protocol documents:
Prot_001.pdf: 
MHICC 
PROTOCOL MHIPS-003 
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CLINICAL RESEARCH PROTOCOL 
 
 
Protocol # MHIPS-003  
 
COLCHICINE CARDIOVASCULAR OUTCOMES TRIAL (COLCOT)  
 
 
 
Amendment 2a 
Final Version 
 
November 15th, 2018 
 
 
 
 
SPONSOR 
 
MONTREAL HEART INSTITUTE 
 
 
 
 
CONFIDENTIALITY 
 
The Montreal Health Innovations Coordinating Center (MHICC), a division of the Montreal 
Heart Institute (MHI), considers the information contained in this document to be proprietary 
and/or confidential. It is for the use of the investigational team, and the corresponding 
applications to institutional review boards (IRBs) and independent ethics committees (IECs) in 
support of a clinical trial. Accordingly, please do not copy, use, distribute, or disclose to others 
without the written prior approval of MHICC or their designated representatives. 
 
 




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Table of Contents 
INVESTIGATOR’S SIGNATURE ........................................................................................................... 5 
SYNOPSIS ................................................................................................................................................... 6 
GLOSSARY............................................................................................................................................... 10 
TIME PERIOD AND NUMBER OF PATIENTS: ................................................................................ 11 
DESCRIPTION OF MEDICATIONS .................................................................................................... 11 
1 
INTRODUCTION ............................................................................................................................ 12 
1.1 
Background .............................................................................................................................. 12 
1.2 
Background on colchicine ....................................................................................................... 14 
1.3 
Colchicine Dosage .................................................................................................................... 15 
2 
STUDY OBJECTIVES .................................................................................................................... 15 
3 
STUDY DESIGN .............................................................................................................................. 15 
3.1 
Study Schedule ......................................................................................................................... 16 
3.2 
Enrollment ................................................................................................................................ 16 
3.3 
Screening Evaluations ............................................................................................................. 16 
3.4 
Randomization and Active Treatment Period ...................................................................... 17 
Table 1 
Timetable of Visits and Procedures ................................................................................... 19 
4 
STUDY POPULATION ................................................................................................................... 20 
4.1 
Source and Number of Patients .............................................................................................. 20 
4.2 
Patient Selection Criteria ........................................................................................................ 20 
4.2.1 
Inclusion Criteria: ............................................................................................................... 20 
4.2.2 
Exclusion Criteria: .............................................................................................................. 20 
4.3 
Prohibited, Allowable and Concurrent Medications ............................................................ 22 
5 
STUDY METHODOLOGY ............................................................................................................ 23 
5.1 
Efficacy Outcomes ................................................................................................................... 23 
5.2 
Safety Monitoring .................................................................................................................... 23 
5.2.1 
Adverse Event Reporting.................................................................................................... 24 
5.2.2 
Other Safety Monitoring .................................................................................................... 25 
5.3 
Withdrawal of Patients from the Study ................................................................................. 26 
5.4 
Study Completion .................................................................................................................... 27 
6 
STUDY MEDICATION .................................................................................................................. 27 
6.1 
Medication Dispensing ............................................................................................................ 27 
6.2 
Dosage Regimen ....................................................................................................................... 27 
7 
DATA COLLECTION .................................................................................................................... 27 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS................................................. 27 
8.1 
Statistical Power and Sample Size Considerations ............................................................... 28 
8.2 
Analysis population ................................................................................................................. 28 
8.2.1 
Intent to Treat (ITT) population ........................................................................................ 28 
8.2.2 
Safety population ................................................................................................................. 28 
8.3 
Data analysis ............................................................................................................................ 28 
8.3.1 
Analysis of efficacy outcomes ............................................................................................. 28 


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8.3.2 
Analysis of safety outcomes ................................................................................................ 29 
8.3.3 
Interim analysis ................................................................................................................... 29 
9 
STUDY COORDINATION ............................................................................................................. 29 
REFERENCES .......................................................................................................................................... 31 
LIST OF APPENDICES .......................................................................................................................... 35 
Appendix A 
Detailed Study Safety Parameters ............................................................................. 36 
Appendix B 
PMS-Colchicine 0.6mg Product Monograph ........................................................... 38 
Appendix C 
Administrative Procedures for the Reporting of Adverse Events .......................... 49 
1 
ADVERSE EVENTS DURING THE TRIAL ................................................................................ 49 
1.1 
Pre-existing condition .............................................................................................................. 49 
1.2 
Adverse Event (AE) ................................................................................................................. 49 
1.3 
Related Adverse Event ............................................................................................................ 49 
1.4 
Serious Adverse Event (SAE) ................................................................................................. 50 
1.5 
Life-Threatening Adverse Event ............................................................................................ 50 
1.6 
Unexpected Adverse Event ..................................................................................................... 50 
1.7 
Clinical Laboratory Adverse Event ....................................................................................... 51 
1.8 
Treatment-Emergent Signs and Symptoms (TESS) ............................................................. 51 
1.9 
Post-treatment Adverse Event ................................................................................................ 51 
2 
HANDLING OF ADVERSE EVENTS .......................................................................................... 51 
2.1 
Treatment-Emergent Signs and Symptoms .......................................................................... 51 
2.2 
Serious Adverse Events ........................................................................................................... 51 
2.3 
Intensity .................................................................................................................................... 51 
2.4 
Relationship to Study Drug – Physician’s Assessment ......................................................... 51 
2.5 
Clinical Outcome ..................................................................................................................... 51 
3 
CAPTURING AVDERSE EVENTS ............................................................................................... 52 
3.1 
Pre-Existing Condition ............................................................................................................ 52 
3.2 
Lack of Efficacy of Study Medication .................................................................................... 52 
3.3 
Clinical Laboratory Adverse Event ....................................................................................... 52 
3.4 
Hospitalization or Surgery/Procedure ................................................................................... 52 
3.5 
Death ......................................................................................................................................... 52 
4 
REPORTING TO THE SPONSOR ................................................................................................ 53 
4.1 
Immediately Reportable Adverse Events .............................................................................. 53 
4.2 
Other Adverse Events ............................................................................................................. 53 
4.3 
Follow-Up Period ..................................................................................................................... 53 
Appendix D 
Other Administrative and Regulatory Procedures ................................................. 54 
Appendix E 
Declaration of Helsinki ............................................................................................... 59 
 


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INVESTIGATOR’S SIGNATURE 
I have read the protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol, with applicable laws and regulations and in accordance with the ethical principles 
outlined in the Declaration of Helsinki. 
 
By signing below, I hereby declare that I am not debarred, disqualified, or otherwise restricted by 
any agency from conducting any research studies. 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
Signature 
 
Date 
 
 
Country: 
 
 
 
 
 
 


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PROTOCOL MHIPS-003 
SYNOPSIS 
TITLE:  COLCHICINE CARDIOVASCULAR OUTCOMES TRIAL (COLCOT) 
INDICATION:  Reduction of cardiovascular risk in patients with atherosclerotic coronary artery 
disease (CAD). 
OBJECTIVES:  The primary objective of this study is to determine whether long-term 
treatment with colchicine reduces the rates of cardiovascular events in patients after myocardial 
infarction (MI). The secondary objective is to determine the safety of long-term treatment with 
colchicine in this patient population. The tertiary objective is to evaluate links between soluble 
and genetic biomarkers and treatment effects.  
 
PATIENT POPULATION:  Males and females, at least 18 years of age, who have suffered a 
documented acute MI within the last 30 days, are treated according to national guidelines, and 
have completed any planned percutaneous revascularization procedures associated with their 
initial infarction. 
Inclusion Criteria: 
 Males and females, at least 18 years of age, capable and willing to provide informed 
consent; 
 Patient must have suffered a documented acute MI  within the last 30 days; 
 Patient must be treated according to national guidelines (including anti-platelet therapy, 
statin, renin-angiotensin-aldosterone system (RAAS) inhibitor (preferably angiotensin-
converting-enzyme (ACE) inhibitor) and beta-blocker when indicated); 
 Patient must have completed any planned percutaneous revascularization procedures 
associated with his/her qualifying MI; 
 Female patient is either not of childbearing potential, defined as postmenopausal for at 
least 1 year or surgically sterile, or is of childbearing potential and practicing at least one 
method of contraception and preferably two complementary forms of contraception 
including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, 
jellies, diaphragm, intrauterine device (IUD)) throughout the study and for 30 days after 
study completion;  
 Patient is judged to be in good general health as determined by the principal investigator; 
 Patient must be able and willing to comply with the requirements of this study protocol. 
Exclusion Criteria: 
 Patient with a poorly controlled medical condition, such as New York Heart Association 
Class III-IV heart failure, a left ventricular ejection fraction of less than 35%, recent 
stroke (within the past 3 months), or any other condition which, in the opinion of the 
investigator, would put the patient at risk if participating in the study; 


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 Patient with a Type 2 index MI (secondary to ischemic imbalance) 
 Patient with a prior coronary artery bypass graft within the past 3 years, or planned; 
 Patient currently in cardiogenic shock or with hemodynamic instability; 
 Patient with a history of cancer or lymphoproliferative disease within the last 3 years, 
other than a successfully treated non-metastatic cutaneous squamous cell or basal cell 
carcinoma and/or localized carcinoma in situ of the cervix; 
 Patient with inflammatory bowel disease (Crohn’s disease or ulcerative colitis) or patient 
with chronic diarrhea; 
 Patient with pre-existent progressive neuromuscular disease or patient with CPK level > 3 
times the upper limit of normal (unless due to MI, which is allowed) as measured within 
the past 30 days and determined to be non-transient through repeat testing; 
 Patient with any of the following known parameters, as measured within the past 30 days, 
and determined to be non-transient through repeat testing:  
- 
hemoglobin < 115g/L,  
- 
white blood cell count < 3.0 X 109/L,  
- 
platelet count <110 X 109/L,  
- 
ALT > 3 times the upper limit of normal (ULN),  
- 
total bilirubin > 2 times ULN (unless due to Gilbert syndrome, which is 
allowed) 
- 
Creatinine > 2 times ULN; 
 Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease; 
 Female patient who is pregnant, or breast-feeding or is considering becoming pregnant 
during the study or for 6 months after the last dose of study medication; 
 Patient with a history of clinically significant drug or alcohol abuse in the last year; 
 Patient is currently using or plans to begin chronic systemic steroid therapy (oral or 
intravenous) during the study (topical or inhaled steroids are allowed);  
 Patient currently taking colchicine for other indications (mainly chronic indications 
represented by Familial Mediterranean Fever or gout). There is no wash-out period 
required for patients who have been treated with colchicine and stopped treatment prior 
to enrolment; 
 Patient with a history of an allergic reaction or significant sensitivity to colchicine; 
 Patient who has used an investigational chemical agent less than 30 days or 5 half-lives 
prior to the Screening visit (whichever is longer); 


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 Patient is considered by the investigator, for any reason, to be an unsuitable candidate for 
the study. 
 
STUDY DESIGN:  This will be a worldwide, randomized, double-blind, placebo-controlled, 
multi-center, event-driven study. Following signature of the informed consent form, 
approximately 4500 subjects meeting all inclusion and no exclusion criteria will be randomized 
to receive either colchicine (0.5 mg/day) or placebo (1:1 allocation ratio) for an estimated 
minimum of 2 years (until the target number of primary endpoint events (301) is reached). 
Follow-up visits, or phone assessments (see Timetable), will occur at 1, 3 and 6 months 
following randomization, and every 3 months thereafter for evaluation of the occurrence of any 
trial endpoints or other adverse events.   
 
OUTCOMES:  The primary endpoint will be the time from randomization to the first event of 
cardiovascular death, resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for 
angina requiring coronary revascularization. The secondary endpoints will consist of times to 
total mortality to components of the primary endpoint, and to the composite of cardiovascular 
death, resuscitated cardiac arrest, acute MI, or stroke. Recurrent cardiovascular events will also 
be evaluated. Exploratory endpoints expressed as time to event will include deep venous 
thrombosis and pulmonary embolus, atrial fibrillation, heart failure hospitalization, and coronary 
revascularization. Additionally, associations between biomarkers (stored samples) and treatment 
effects will be evaluated as exploratory endpoints.  
 
STATISTICAL RATIONALE AND ANALYSIS:  COLCOT is designed as an event-driven 
trial with all main analyses conducted on an intention-to-treat basis. A sample size of 
approximately 4500 randomized patients with 2250 patients in each treatment group or, in terms 
of events, a total number of 301 positively adjudicated events (i.e. components of the primary 
endpoint), would yield adequate power. The sample size calculation is based on the primary 
endpoint and assumes a 30% risk reduction with colchicine, translated by a hazard ratio of 0.700. 
However, to account for a non-compliance rate of around 8% in the colchicine group, a more 
conservative hazard ratio of 0.724 (0.08 x 1 + 0.92 x 0.7) was used in the calculation 
(corresponding to a 27% relative risk reduction). Using a two-sided test at the 0.05 significance 
level, the trial would have 80% power if it continues until 301 positively adjudicated primary 
events occur in the combined treatment groups. The total number of patients to randomize, 4500, 
is chosen so that the expected number of adjudicated events after 24 months of follow-up is 301. 
It assumes an event rate of 7% in the placebo group at 24 months, an 18-month recruitment 
period during which patients are uniformly recruited, a 24-month minimum follow-up and a 1% 
yearly lost to follow-up (and withdrawal of consent) rate. 
All suspected cardiovascular endpoints will be adjudicated by a Clinical Endpoint Committee 
(CEC) comprised of experienced members. A fully independent 5-member Data and Safety 
Monitoring Board (DSMB) will be established and will review unblinded safety data as detailed 
in the DSMB charter. In light of the LoDoCo Trial (Low Dose Colchicine for Secondary 
Prevention of Cardiovascular Disease) which showed a statistically significant benefit of 
colchicine with only 500 patients, an interim analysis is planned after approximately 50% of 


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primary endpoints have been positively adjudicated (i.e. after approximately 150 positively 
adjudicated events). The DSMB charter will pre-specify the methods of interim efficacy analyses 
and the rules for early study termination, approved by all board members. The stopping rules for 
efficacy and futility will be based on the O’Brien-Fleming alpha-spending function or on a 
similar conservative approach so that the impact on the final alpha level will be negligible. The 
DSMB will have the option of recommending early study termination because of overwhelming 
efficacy, early termination for futility, or continuation of the trial as planned. 
The primary analysis of efficacy will be based on the intent to treat principle. The primary 
endpoint will be compared between the two treatment groups using a log rank test. Patients with 
no event will be censored at the time last known to be event free. Secondary endpoints will be 
analyzed similarly. Cox proportional hazard models will also be contemplated to adjust for 
important baseline characteristics. Hazard ratios along with 95% confidence intervals will be 
provided. 
ANTICIPATED TOTAL NUMBER OF RANDOMIZED PATIENTS:  Approximately 4500 
patients in total will be randomized in this study.  
 
ANTICIPATED NUMBER OF RANDOMIZED PATIENTS PER SITE:  Enrollment will be 
competitive. It is estimated that approximately 20-100 patients will be randomized at each of the 
study sites. 
 
PHASE:  3 
 
STUDY LOCATION:  Worldwide 


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GLOSSARY  
 
ACE  
- 
Angiotensin-Converting-Enzyme 
ACS  
-  
Acute Coronary Syndrome 
AE 
 
- 
Adverse event  
ALT 
 
-  
Alanine aminotransferase 
ANCOVA 
- 
Analysis of Covariance 
AST 
 
- 
Aspartate aminotransferase 
BUN  
- 
Blood urea nitrogen 
CAD  
-  
Coronary artery disease 
CEC 
 
- 
Clinical Endpoint Committee  
eCRF  
-  
electronic Case Report Form 
CPK  
- 
Creatine phosphokinase 
CRP 
 
- 
C-reactive protein 
CYP3A4 
- 
cytochrome P450 3A4 
DSMB  
- 
Data and Safety Monitoring Board 
EC 
 
-  
Ethics Committee 
GGT  
- 
Gamma-glutamyl transferase 
hs-CRP 
- 
High sensitivity C-reactive protein 
ICF 
 
 
Informed Consent Form 
ICH 
 
- 
International Council for Harmonisation 
IL 
 
- 
Interleukin 
IMPI  
- 
Investigational Medicinal Product Information 
ITT 
 
-  
Intent-to-treat 
IUD 
 
- 
Intrauterine device 
IRB 
 
-  
Institutional Review Board 
LDH  
- 
Lactate dehydrogenase 
LDL 
 
- 
Low-density lipoprotein 
MDR  
- 
Medication dispensing record 
MHI 
 
- 
Montreal Heart Institute 
MHICC  
- 
Montreal Health Innovations Coordinating Center 
MI 
 
- 
Myocardial infarction 
PCI 
 
- 
Percutaneous coronary intervention  
P-gp 
 
- 
P-glycoprotein 
PO (po) 
- 
Per os 
PRN  
- 
pro re nata (as necessary) 
RAAS  
- 
Renin-angiotensin-aldosterone system 
RBC  
-  
Red blood cells 
SAE 
 
- 
Serious adverse event 
SOPs  
- 
Standard operating procedures 
SUSAR 
- 
Suspected Unexpected Serious Adverse Reaction 
TESS  
- 
Treatment-Emergent Signs and Symptoms 
WMA  
- 
World Medical Association 


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TIME PERIOD AND NUMBER OF PATIENTS:  
  
A. Anticipated Starting Date of Study: 3Q15 
  
B. Anticipated Completion Date: 3Q19 
  
C. Anticipated Number of Patients for Site: 20 – 100 (competitive recruitment)  
D. Anticipated Number of Sites:  approximately 200 
  
E. Anticipated Number of Randomized Patients for the Study: 4500 
  
 
DESCRIPTION OF MEDICATIONS 
 
Generic Name 
 Strength and 
Dosage Form 
 
Therapeutic 
Classification 
 
 
  
 
 
 
Colchicine  
 0.5 mg tablet 
 
Anti-inflammatory 
 
 
  
 
 
 
 
 
 
 Placebo to match 0.5 
mg tablet 
 
 
 
NA 
 
 
  


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1 
INTRODUCTION 
 
1.1 
Background   
 
Unmet need in atherosclerotic diseases 
 
Cardiovascular diseases are the first cause of death globally, according to the most recent 2013 
World Health Organization report (1). An estimated 17.3 million people died from 
cardiovascular diseases in 2008, representing 30% of all global deaths. Of these deaths, an 
estimated 7.3 million were due to coronary heart disease and 6.2 million were due to stroke (2). 
In Canada, someone dies from heart disease or stroke every 7 minutes (3). In 2008 
cardiovascular diseases accounted for 29% of all deaths in Canada, of which 54% were due to 
ischemic heart disease, 20% to stroke and 23% to myocardial infarction (3). Additionally, heart 
disease and stroke carry an economic burden in Canada of more than $20.9 billion every year in 
physician and hospital costs as well as lost wages and decreased productivity (4).  
 
Atherosclerosis is the most common cause of myocardial infarction, stroke and peripheral 
arterial disease. Research has clearly demonstrated that inflammation plays a key role in the 
initiation, progression and manifestations of atherosclerosis. Atherosclerotic lesions begin as an 
accumulation of lipid-laden cells (primarily macrophages) beneath the endothelium, and progress 
with the further accumulation of cells, connective-tissue elements, lipids and debris through 
immunological and inflammatory activation (5). Neutrophils and other inflammatory cells have 
been shown to invade culprit atherosclerotic lesions in acute coronary syndromes (6). It is likely 
that the inflammatory process is responsible for the high rate of cardiovascular events despite 
significant advances in the treatment of risk factors such as hypercholesterolemia and 
hypertension. It is therefore vital that we improve our understanding of the inflammatory nature 
of atherosclerotic disease, and modify the inflammatory process with targeted therapies. 
 
Inflammation and atherosclerosis 
 
Atherosclerosis had previously been considered to be a disease in which lipid debris passively 
accumulate in the arterial wall (7). However, during the past three decades, evidence derived 
from multiple lines of examination, has highlighted the important role of inflammation in the 
pathogenesis of atherosclerosis. It is now widely recognized that atherosclerosis is an 
inflammatory, dynamic, and complex disease involving multiple cell types, especially 
inflammatory cells including macrophages, lymphocytes and neutrophils as well as endothelial 
cells and smooth muscle cells (8-11).  
 
The monocyte/macrophage is an important early cellular component of atherogenesis. One of the 
first steps in the transition from normal artery to atherosclerotic plaque is the recruitment of 
circulating mononuclear phagocytes through the expression of adhesion molecules on the surface 


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of endothelial cells. Once bound to adhesion molecules, monocytes respond to pro-inflammatory 
protein mediators, known as chemokines, which coordinate the migration of these leukocytes 
into the vascular intima (12). The monocytes that have accumulated in the arterial wall mature 
into macrophages, proliferate, multiply, and produce many more inflammatory mediators. The 
process of monocyte recruitment, migration and maturation continues throughout the 
development of the atherosclerotic lesion (13). 
 
After taking up residence in the vascular intima, the monocytes develop into macrophages that 
engulf massive amounts of modified low-density lipoproteins (LDL), becoming “foam cells”.  
Cholesterol deposits at the atherosclerotic site result in intima thickening and aberrant 
proliferation of smooth muscle cells. Mediators of inflammation activate the release of proteases, 
which promote the degradation of the arterial extracellular matrix, making plaques and their 
fibrous cap vulnerable to rupture and thrombosis. These progressive modifications thus lead to 
the formation of an atherothrombotic plaque in the arterial wall that can cause lumen stenosis, 
angina, myocardial infarction and stroke. The acute complications of plaques, including acute 
coronary syndromes, strokes and cardiovascular deaths, result from the rupture of the fibrous 
cap, superimposed thrombus formation and arterial lumen occlusion (7).  
 
It is well established, although often underestimated, that patients with chronic extra-cardiac 
inflammatory diseases such as rheumatoid arthritis or psoriatic arthritis have a higher risk of 
cardiovascular disease (adjusted relative risk of 2.0 for myocardial infarction) and related 
mortality compared to the general population (14,15). This risk could be associated with classic 
cardiovascular risk factors (smoking, hypertension, dyslipidemia, diabetes, excess weight); 
however, systemic inflammation may also be independently involved in this increased 
cardiovascular risk (16) and could lead to myocardial infarction, cerebrovascular disease and 
heart failure (14-18). Furthermore, prospective cohort studies have consistently shown that hs-
CRP (high sensitivity C-reactive protein) and several other biomarkers of inflammation are 
independently associated with increasing risk of future cardiovascular events in different 
populations (19,20). Taken together these data, along with those of multiple animal models 
(showing that reduced inflammation has anti-atherosclerotic effects), create the impetus to test 
the hypothesis that treatment of the underlying inflammatory process will contribute to improved 
cardiovascular clinical outcomes in patients with atherosclerosis (20, 21, 22).  
 
Phase 2 clinical trials have shown that the p-selectin antagonist inclacumab and an anti-
inflammatory serpin both reduce myocardial damage after percutaneous coronary intervention 
performed for an acute myocardial infarction (23, 24). Other reported data have suggested that a 
5-lipoxygenase inhibitor appeared to reduce levels of leukotrienes and hs-CRP and slow 
atherosclerosis progression (25). These results using intermediate endpoints support the 
hypothesis stated above. 
 
 


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1.2 
Background on colchicine 
 
Colchicine is an inexpensive, yet potent, anti-inflammatory drug that is approved for acute use in 
patients with gout and chronic use in patients with Familial Mediterranean Fever, at doses 
between 0.3 mg and 2.4 mg/day (see product monograph in Appendix B). The active compound, 
initially extracted from the plant autumn crocus (Colchicum autumnale), has been used for 
centuries and is one of the oldest drugs still currently available. The mechanism of action by 
which colchicine exerts its effects is through the inhibition of tubulin polymerization (26) and 
potentially also through effects on cellular adhesion molecules and inflammatory chemokines 
(27). Even when used at low doses, colchicine can be found in white blood cells, blocking 
tubulin polymerization and subsequent microtubule generation and stability. Through its action 
on tubulin, colchicine can interfere with many functions of white blood cells including migration 
and degranulation.  Direct inhibition of the migration of neutrophils is considered colchicine’s 
main mechanism of action in gout (28). 
 
Colchicine may also have direct anti-inflammatory effects (29) by inhibiting key inflammatory 
signaling networks known as the inflammasome and pro-inflammatory cytokines. It has been 
shown to inhibit membrane expression of adhesion molecules on T cells and endothelial cells 
(27). Additionally, evidence suggests that colchicine exerts a direct anti-inflammatory effect by 
inhibiting the synthesis of tumor necrosis factor alpha and IL-6, monocyte migration, and the 
secretion of matrix metalloproteinase-9 (30, 31). Through the disruption of the cytoskeleton, 
colchicine is believed to suppress secretion of cytokines and chemokines as well as in vitro 
platelet aggregation (32, 33). 
 
In the past several years, considerable work has highlighted the potential of colchicine in the 
treatment of cardiovascular diseases mediated by pro-inflammatory processes. In the COPE 
(COlchicine for acute PEricarditis) (34), CORE (COlchicine for Recurrent pericarditis) (35) and 
CORP (COlchicine for Recurrent Pericarditis) (36) trials, colchicine was demonstrated to be 
effective for the treatment and prevention of recurrent pericarditis. The COPPS (COlchicine for 
the Prevention of the Post-pericardiotomy Syndrome) trial demonstrated colchicine to be safe 
and efficacious in the prevention of post-pericardiotomy syndrome (37) and atrial fibrillation 
(38) following cardiac surgery. Colchicine was also demonstrated to be safe and effective in the 
prevention of early atrial fibrillation recurrence after pulmonary vein isolation, an effect that was 
strongly associated with a significant decrease in inflammatory mediators including IL-6 and hs-
CRP (39). 
 
More recently, colchicine has been evaluated for its effect on cardiovascular events in patients 
with coronary artery disease (CAD). In the LoDoCo Trial, 532 patients with clinically stable 
CAD were randomly assigned to receive treatment with colchicine (0.5 mg/day) or no colchicine 
in addition to usual care for a minimum of 2 years (40). Following a mean follow-up of 36 
months, colchicine-treated patients experienced significantly fewer cardiovascular events 


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(composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or 
noncardioembolic ischemic stroke) as compared with placebo (5.3% vs. 16.0%; hazard ratio: 
0.33; CI 0.18-0.59; p< 0.0001). The effect was largely driven by a reduction in acute coronary 
syndromes unrelated to stent disease. A favorable trend in mortality was also demonstrated. Ten 
patients in the control group died compared with 4 patients in the colchicine group. Of the 10 
control patients, 5 died of presumed cardiac cause: 2 following an out-of-hospital cardiac arrest, 
2 from cardiogenic shock following acute MI and 1 following bypass surgery. All 4 of the 
colchicine patients died of non-cardiac causes. The results of this relatively small trial suggest 
that colchicine may be a safe and effective agent for the prevention of major cardiovascular 
events in this population, and that its mechanism of action may be through inhibiting the 
inflammatory pathway identified in unstable atherosclerotic plaques. Further work is required to 
better understand the potential beneficial effects of colchicine in this setting. 
 
1.3 
Colchicine Dosage 
 
Pharmascience Inc. is the manufacturer of the 0.5 mg colchicine tablet and matching placebo 
used in COLCOT. Pharmascience Inc. currently manufactures and markets 0.6 mg colchicine 
tablets in Canada.   
 
To potentially improve colchicine tolerability in long-term exposure for cardiovascular 
treatment, a new colchicine coated 0.5 mg tablet is used in COLCOT. Considering the positive 
results obtained with the low-dose colchicine 0.5 mg immediate release formulation, marketed as 
Colgout and sourced from the Australian market in the LoDoCo trial (40), Pharmascience’s 
colchicine coated 0.5 mg formulation will be designed to provide a similar exposure to Colgout 
colchicine immediate release (IR) 0.5 mg tablet. 
 
2 
STUDY OBJECTIVES 
 
The primary objective of this study is to determine whether long-term treatment with colchicine 
reduces rates of cardiovascular events in patients after myocardial infarction (MI). The 
secondary objective is to determine the safety of long-term treatment with colchicine in this 
patient population. The tertiary objective is to evaluate links between soluble and genetic 
biomarkers and treatment effects.  
 
3 
STUDY DESIGN 
 
This will be a worldwide, randomized, double-blind, placebo-controlled, multi-center, event-
driven study. Following signature of the informed consent form, approximately 4500 subjects 
meeting all inclusion criteria and no exclusion criteria will be randomized to receive either 
colchicine (0.5 mg/day) or placebo (1:1 allocation ratio) for an estimated minimum of 2 years 
(until the target number of primary endpoint events (301) is reached). Follow-up visits or phone 
assessments will occur at 1, 3 and 6 months following randomization, and every 3 months 


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thereafter for evaluation of the occurrence of any trial endpoints or other adverse events. Patients 
will also be receiving standard medical care for control of dyslipidemia, hypertension, angina 
and diabetes. All suspected cardiovascular endpoints will be adjudicated by a Clinical Endpoint 
Committee (CEC), consisting of experienced members. A fully independent 5-member Data and 
Safety Monitoring Board (DSMB) will be established and will review unblinded data as detailed 
in the DSMB charter. There will be one formal interim analysis for efficacy and futility after 
approximately 50% of the primary endpoints have been positively adjudicated. The DSMB 
charter will pre-specify the methods of interim efficacy analyses and the rules for early trial 
termination, which will be approved by all board members.   
 
3.1 Study Schedule 
 
The schedule of visits for this study is outlined in Table 1. However, a patient may be seen at any 
time for safety concerns. The time window between scheduled visits is +/- 2 weeks from the 
anticipated scheduled dates so as to facilitate patient scheduling. Close adherence to the patient 
visit schedule is required in order to respect the estimated minimum 2 years of active treatment 
as per the protocol. 
 
3.2 Enrollment 
 
Study site personnel will obtain informed consent from patients who volunteer to participate in 
the study prior to the conduct of any study-specific procedures. The patient will be considered 
“enrolled” into the study at the time an informed consent is provided. 
 
Biomarkers samples collection will be optional for sites and performed only at sites, selected by 
the sponsor, where the biomarkers sample collection, storage, and transport to the Beaulieu-
Saucier Pharmacogenomics Centre of the Montreal Heart Institute is possible. The informed 
consent form will reflect this option and patients will specifically be asked to consent to this 
biomarker evaluation.  
 
Patients who have already signed the informed consent form for the main study will be asked to 
participate in an optional pharmacogenomic sub-study. If they agree, they will be asked to sign 
the pharmacogenomic informed consent form and a signed copy will be provided to them. 
Frozen blood samples will be kept for future analysis of responses to colchicine and genes 
involved in cardiovascular and related diseases. 
 
3.3 Screening Evaluations 
 
Screening evaluations will include a review of the patient’s medical/surgical history and 
assessment of concomitant medications to determine if the patient qualifies for the study. 
Patients who meet all inclusion criteria and no exclusion criteria will be randomized to receive 
the study drug or placebo. All patients must be randomized within 30 days of the index MI.  
 


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There is no wash-out period required for patients who have been treated with colchicine and 
stopped treatment prior to enrolment.  
 
3.4 Randomization and Active Treatment Period 
 
Patients who meet all inclusion criteria and no exclusion criteria will be scheduled for Visit 2 
(randomization). The screening visit and Visit 2 may be performed on the same day. Under these 
circumstances, procedures to be performed at both Screening Visit and Visit 2 will only be 
performed once. Women of childbearing potential must have a negative urine pregnancy test 
result at Visit 2 in order to qualify. Qualifying patients will be randomized to receive placebo or 
colchicine 0.5 mg/day administered in a blinded manner. Blinded randomization will be 
performed through an automated Interactive Web Response System (IWRS). 2250 patients will 
be randomized to active treatment and 2250 patients will be randomized to placebo for a total of 
4500 randomized patients. All patients will receive study medication per os (PO) once daily. If a 
dose is missed, it should not be replaced. Throughout the study, patients will alternate between 
study visits and phone contacts. At study visits and phone contacts, patients will be assessed for 
potential study endpoints and other adverse events (AEs). Patients will be dispensed study 
medication throughout the study. At each study visit and during each phone contact, patients will 
be 1) questioned in a non-specific manner for the occurrence of AEs and any change in 
concomitant medications; and 2) encouraged to comply with the study protocol including 
adherence to study medication.   
 
Routine chemistry and hematology parameters review will be done at Visit 2 and on a yearly 
basis as well as at the End of Study. 
 
At Visit 3, a mandatory blood draw will be collected and analyzed locally to evaluate hepatic and 
renal parameters.   
 
Blood draws for biomarker samples are optional forsites, depending on their ability to collect, 
store, and transport samples to the Beaulieu-Saucier Pharmacogenomics Centre of the Montreal 
Heart Institute. At these sites only, patients who agree to and have signed the biomarkers 
informed consent form will participate in the optional biomarkers sub-study.  
 
An initial optional blood draw for biomarkers will be performed at Visit 2 and at Visit 5. An 
additional blood draw for biomarkers will be performed at Visit 9. All patients that have not yet 
reached Visit 9 should be offered to participate in the additional blood draw, regardless of 
previous participation to the initial blood draw for biomarkers at Visit 2 and Visit 5.  
 
At Visit 2, an optional blood draw for the pharmacogenomic sub-study may be performed at sites 
that have the ability to collect, store and transport samples to the Beaulieu-Saucier 
Pharmacogenomics Centre of the Montreal Heart Institute. At these sites only, patients who 
agree to and have signed the pharmacogenomic informed consent form will participate in the 
optional pharmacogenomic sub-study.  


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Any patient already enrolled in the trial at the time of implementation of the sub-study will be 
offered to participate in the pharmacogenomic sub-study at their next in-person visit. 
 
At the End of Study visit, patients with a minimum of 12 months between the initial 
pharmacogenomics sample collected and the End of Study Visit will be asked to provide a 
second pharmacogenomic sample to evaluate the contributing role of clonal hematopoiesis in 
cardiovascular disease and to determine if anti-inflammatory treatment affects age-related clonal 
hematopoiesis development and clinical outcomes.  
 
Please refer to Table 1 and Appendix A for Timetable of Visits and Procedures. 
 


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Table 1 Timetable of Visits and Procedures 
(Note: all visits are to be +/- 2 weeks from anticipated timepoint) 
Visits 
1  
Screening 
Visit 
2a              
Randomization/ 
Baseline 
3 
Visit  
4     
Phone 
contact 
5, 7, 9… 
Visit 
6, 8, 10… 
Phone 
contact 
End of 
Study 
Months 
 
0 
1 
3 
6, 12, 18… 
9, 15, 21… 
 
Informed consent 
X 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
Phone contact 
 
 
 
X 
 
X 
 
Review Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Urine 
pregnancy 
test 
(only 
women 
of 
childbearing potential) 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Waist circumference, height, and weight 
measurements 
 
X 
 
 
 
 
 
Review parameters for routine chemistry and 
hematology (local, once per year) 
 
X  
X b 
 
X 
 
X 
Blood draw for biomarkers (optional) 
 
X 
 
 
X (V5 and V9)c 
 
 
Blood draw for pharmacogenomics evaluation 
(optional)  
 
X d 
 
 
 
 
X e 
Record potential study endpoints and other AEs  
 
X 
X 
X 
X 
X 
X 
Review concomitant meds  
X 
X 
X 
X  
X 
X  
X 
Study medication dispensing 
 
X f 
X 
 
X 
 
 
Study medication return 
 
 
X g 
 
X 
 
X 
 
a) Screening Visit and Visit 2 may be performed on the same day; under these circumstances, procedures to be performed at both Screening Visit and Visit 2 will be performed once. 
b) At V3, mandatory chemistry parameters will be evaluated locally: ALT, AST, GGT, total bilirubin, alkaline phosphatase, serum creatinine and uric acid. 
c) Biomarkers collection will occur at Randomization visit and at visit 5. The additional biomarkers collection can be offered only to patients that have yet to perform Visit 9 at the time of 
implementation of the sub-study at the site.  
d) Blood draw for pharmacogenomics evaluation can be collected at the next in-person visit if randomization visit has already occurred at the time of the implementation of the sub-study at the site.  
e) Blood draw for pharmacogenomics evaluation at the End of Study visit will only be collected for patients who provided a baseline sample at least 12 months prior to the End of Study visit. 
f) It is recommended that the patient takes his/her first dose on site during the visit. 
g) Patient should bring back their 1st bottle of medication for a compliance check, but should return home with the same opened bottle (and 2nd unopened bottle assigned at V3).


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4 
STUDY POPULATION 
 
4.1 Source and Number of Patients 
 
A total of 4,500 patients will be randomized at approximately 200 study sites worldwide.  
 
4.2 Patient Selection Criteria 
 
4.2.1 Inclusion Criteria: 
 
All of these criteria must be met: 
 Males and females of at least 18 years of age capable and willing to provide 
informed consent; 
 Patient must have suffered a documented acute myocardial infarction (MI) within 
the last 30 days; 
 Patient must be treated according to national guidelines (including anti-platelet 
therapy, 
statin, 
renin-angiotensin-aldosterone 
system 
(RAAS) 
inhibitor 
(preferably ACE inhibitor) and beta-blocker when indicated); 
 Patient must have completed any planned percutaneous revascularization 
procedures associated with his/her qualifying MI; 
 Female patient is either not of childbearing potential, defined as postmenopausal 
for at least 1 year or surgically sterile, or is of childbearing potential and 
practicing at least one method of contraception and preferably two 
complementary forms of contraception including a barrier method (e.g. male or 
female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine 
device (IUD)) throughout the study and for 30 days after study completion; 
 Patient is judged to be in good general health as determined by the principal 
investigator; 
 Patient must be able and willing to comply with the requirements of this study 
protocol. 
4.2.2 Exclusion Criteria: 
 
 Patient with a poorly controlled medical condition, such as New York Heart 
Association Class III-IV heart failure, a left ventricular ejection fraction of less 
than 35%, recent stroke (within the past 3 months), or any other condition which, 
in the opinion of the investigator, would put the patient at risk if participating in 
the study; 


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 Patient with a Type 2 index MI (secondary to ischemic imbalance); 
 Patient with a prior coronary artery bypass graft within the past 3 years, or 
planned; 
 Patient currently in cardiogenic shock or with hemodynamic instability; 
 Patient with a history of cancer or lymphoproliferative disease within the last 3 
years other than a successfully treated non-metastatic cutaneous squamous cell or 
basal cell carcinoma and/or localized carcinoma in situ of the cervix; 
 Patient with inflammatory bowel disease (Crohn’s disease or ulcerative colitis) or 
patient with chronic diarrhea; 
 Patient with pre-existent progressive neuromuscular disease or patient with CPK 
level > 3 times the upper limit of normal (unless due to MI, which is allowed) as 
measured within the past 30 days and determined to be non-transient through 
repeat testing; 
 Patient with any of the following known parameters as measured within the past 
30 days, and determined to be non-transient through repeat testing:  
 hemoglobin < 115g/L,  
 white blood cell count < 3.0 X 109/L,  
 platelet count <110 X 109/L,  
 ALT > 3 times the upper limit of normal (ULN),  
 total bilirubin > 2 times ULN (unless due to Gilbert syndrome, which is 
allowed), 
 Creatinine > 2 times ULN; 
 Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic 
disease;  
 Female patient who is pregnant, or breast-feeding or is considering becoming 
pregnant during the study or for 6 months after the last dose of study medication; 
 Patient with a history of clinically significant drug or alcohol abuse in the last 
year; 
 Patient is currently using or plans to begin chronic systemic steroid therapy (oral 
or intravenous) during the study (topical or inhaled steroids are allowed);  


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 Patient currently taking colchicine for other indications (mainly chronic 
indications represented by Familial Mediterranean Fever or gout); there is no 
wash-out period required for patients who have been treated with colchicine and 
stopped treatment prior to enrolment; 
 Patient with a history of an allergic reaction or significant sensitivity to 
colchicine; 
 Patient who has used an investigational chemical agent less than 30 days or 5 
half-lives prior to the Screening visit (whichever is longer); 
 Patient is considered by the investigator, for any reason, to be an unsuitable 
candidate for the study. 
 
4.3 Prohibited, Allowable and Concurrent Medications  
 
Colchicine is a substrate of intestinal and hepatic cytochrome P450 3A4 (CYP3A4), which 
catalyzes demethylation of colchicine to inactive metabolites. Consistent with the current 
understanding of colchicine metabolism, certain drugs increase the potential for colchicine 
toxicity via modulation of the efflux transporter P-glycoprotein (P-gp) and CYP3A4 activity. As 
such, during the duration of the trial, the concomitant use of erythromycin and clarithromycin is 
prohibited.  Toxicity has also been reported in a patient who began to regularly consume a liter 
of grapefruit juice daily while being treated chronically with colchicine, and therefore the 
concomitant consumption of large quantities of grapefruit juice (more than 750 mL per day) is to 
be avoided.   
 
All other medications (including oral or parenteral hormonal contraceptive agents), except for 
chronic systemic steroids (oral or intravenous), are allowed as long as they are stabilized prior to 
study entry and maintained as stable throughout the course of the trial.   
 
During the course of the study, patients will be receiving standard medical care for control of 
dyslipidemia, hypertension, angina and diabetes, as applicable and at the discretion of the 
treating physician. Every effort must be made to keep these medications stable throughout the 
course of the trial. It is also recommended that investigators carefully monitor the following 
potentially significant drug interactions: HMG-CoA Reductase Inhibitors (such as Atorvastatin, 
Fluvastatin, Pravastatin, Simvastatin), other Lipid Lowering Drugs (such as Fibrates, 
Gemfibrozil), Digitalis Glycosides (such as Digoxin (P-gp substrate), and Cyclosporine (P-gp 
substrate).  
 
Study medication changes made during the course of the trial will be documented (from the time 
of randomization and onwards).  
 


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The use of concomitant medication from the time of randomization and onwards will be recorded 
in the eCRF (with the exceptions of concomitant medication taken “when necessary” (PRN) or 
medication given for procedures such as coronarography). 
 
5 
STUDY METHODOLOGY 
 
5.1 Efficacy Outcomes 
 
The primary endpoint will be the time from randomization to the first event of cardiovascular 
death, resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for angina requiring 
coronary revascularization. 
 
The secondary endpoints will consist of times to total mortality, to components of the primary 
endpoint, and to the composite of cardiovascular death, resuscitated cardiac arrest, acute MI, or 
stroke. Recurrent cardiovascular events will also be evaluated. 
 
Exploratory endpoints expressed as time to event will include deep venous thrombosis and 
pulmonary 
embolus, 
atrial 
fibrillation, 
heart 
failure 
hospitalization, 
and 
coronary 
revascularization.  
 
All events will be adjudicated by an independent Clinical Endpoint Committee (CEC) and all 
definitions of the endpoints will be outlined in the CEC charter. 
 
Biomarkers endpoints: 
Frozen samples received from participating sites will be kept for future use for evaluation of 
biomarkers related to cardiovascular disease and the response to treatment possibly including, 
but not limited to lipids, markers of inflammation and markers of oxidative stress. 
 
Additional exploratory endpoints will include the changes in these biomarkers from baseline 
(Visit 2) to Visit 5, as well as a cross-sectional comparison at Visit 9 in these biomarkers. Frozen 
samples will be kept at the Beaulieu-Saucier Pharmacogenomics Centre of the Montreal Heart 
Institute.  
 
5.2 Safety Monitoring 
 
Drug safety will be assessed by an evaluation of types, frequencies, severities and duration of 
any reported AEs. Patients will be monitored for signs and symptoms of drug toxicity.  
 
Appendix B includes the product monograph of pms-colchicine 0.6 mg tablets, the product 
currently marketed by Pharmascience Inc. in Canada for gout therapy. Investigators should 
consult this information and their locally approved prescribing information (if available) to seek 
guidance regarding potential colchicine toxicity and its potential signs and symptoms.      
 


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For all toxicities that require the study therapy to be temporarily or permanently discontinued, 
relevant clinical and laboratory tests will be repeated as clinically needed until there is final 
resolution, stabilization of the toxicity, or another cause for the abnormality is determined.  
 
5.2.1 Adverse Event Reporting 
 
Information regarding AEs will be collected from the first dose of study medication (at Visit 2) 
through and including the last visit. Any AEs prior to the first dose of study medication will be 
recorded in the medical history and kept in the patients’ chart.  
 
In addition to standard reporting of Serious Adverse Events (SAEs) as defined and outlined in 
Section 5.2.1.1 below, information regarding SAEs that occur within 30 days following the last 
study visit, and reported to the investigational site, will be collected. Each patient will be 
observed and queried in a non-specific fashion at each visit during the study for any new or 
continuing symptoms since the previous visit.   
 
All SAEs will be recorded on the appropriate eCRF section. The only other AEs to be recorded 
on the eCRF are those that are either related to the gastrointestinal system, that are judged related 
to the study medication by the investigator or laboratory abnormalities judged clinically 
significant by the investigator. Information collected will include the onset, duration, severity, 
relationship to study drug, and the management as outlined in Appendix C.  
 
5.2.1.1 Serious Adverse Events 
 
Serious Adverse Events (SAE) are those that meet any of the following International Council for 
Harmonisation (ICH) criteria: 
  
 Is fatal or immediately life-threatening; 
 Results in persistent or significant disability/incapacity; 
 Requires or prolongs inpatient hospitalization; 
 Is a congenital anomaly/birth defect in the offspring of the patient; 
 Is a cancer; 
 Is an overdose (intentional or accidental); 
 Is judged to be medically important. 
 
Medically important events may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above. Serious Adverse Events are to be reported if they are 
known to occur within 30 days following the last study visit.  
 
Medical and scientific judgment should be exercised in deciding whether other AEs meet these 
criteria and are immediately reportable to the sponsor or designee. 
 


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In the event of a serious or life-threatening adverse event, or in the event of death, immediately 
report the event on the appropriate SAE form in the eCRF.  
 
FOR ANY SAFETY QUESTIONS OR CONCERNS, PLEASE CONTACT: 
MHICC Medical Monitor 
Phone: +1-514 207-1365 (24/7 availability) 
Email: colcot_safety@mhicc.org 
 
If any SAE occurs, the study treatment may be interrupted or discontinued at the Investigator’s 
discretion. If an acute medical emergency occurs, the investigator should make every effort to 
reach the contact person listed above, before breaking the randomization code, via the automated 
Interactive Web Response System (IWRS). However, the investigator may break the 
randomization code (via IWRS) at any time if this is required for proper treatment of the patient 
and even if the contact person could not be reached.  
 
The MHICC Medical Monitor or his designated representative is responsible to report any 
Suspected Unexpected Serious Adverse Reaction (SUSAR) to the regulatory authorities and to 
copy Pharmascience Inc. at time of submission. Reports to the Health Authorities must be made 
within 7 calendar days, (for death and life-threatening events) and within 15 calendar days (for 
other serious events) after being informed of an SAE by the investigator.  
 
5.2.1.2 Lack of Efficacy of study medication 
  
Any signs or symptoms defined as lack of efficacy or collected as efficacy parameters (i.e.: study 
endpoints including cardiovascular mortality, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, or urgent hospitalization for angina requiring coronary revascularization) will not be 
reported as SAEs, but must be included as an Adverse Event in the database.  
 
5.2.1.3 Adverse Event Follow-Up 
 
Record all reportable serious and non-serious AEs on the appropriate eCRF including the onset, 
duration, severity, relationship to the study drug, and ultimate management. All AEs reported 
during the treatment phase should be recorded and followed until the AE has subsided, or 
stabilized or until the end of the study, whichever occurs first. The study will be stopped at any 
time if new knowledge is gained and the risk-benefit ratio is no longer favorable for the 
participating patients and Pharmascience Inc. will then be informed immediately but no later 
than 3 business days if such decision is made. 
 
5.2.2 Other Safety Monitoring 
 
5.2.2.1 Laboratory Evaluations 
 


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Chemistry and hematology test results (refer to Appendix A) obtained at patient admission for 
the index MI may be used to assess patient eligibility at screening. If additional tests are required 
to assess patient eligibility, they should be analyzed locally.  
 
At Visit 3, a mandatory blood sample will be collected and analyzed locally to assess hepatic and 
renal parameters to include ALT, AST, GGT, total bilirubin, alkaline phosphatase, serum 
creatinine and uric acid.  
 
In participating sites, optional biomarker blood samples will be collected at Visit 2, at Visit 5 and 
at Visit 9 and kept at the Montreal Heart Institute for up to five (5) years following completion of 
the trial for possible future evaluation of biomarkers related to cardiovascular disease. These 
samples may be used to assess (but not limited to) lipids, markers of inflammation and markers 
of oxidative stress. 
 
In participating sites, optional blood samples for the pharmacogenomic sub-study will be 
collected at Visit 2 and at the End of Study visit from patients who have signed the 
pharmacogenomic informed consent form. Any patient already enrolled in the trial at the time of 
implementation of the sub-study will be offered to participate in the pharmacogenomic sub-study 
at their next on-site visit. Blood samples for pharmacogenomic evaluation may be kept at the 
Beaulieu-Saucier Pharmacogenomics Centre of the Montreal Heart Institute for up to 20 years 
following completion of the trial to conduct future analysis of responses to colchicine and genes 
involved in cardiovascular and related diseases. If, upon reception of the pharmacogenomic 
samples at the Beaulieu-Saucier Pharmacogenomics Centre of the Montreal Heart Institute, the 
sample cannot be analyzed because of DNA degradation, a second blood draw will be requested. 
 
5.3 Withdrawal of Patients from the Study 
 
Patients have the right to withdraw from the study at any time during the course of the study. 
However, every effort should be made, within the bounds of safety, patient choice and the 
provisions of informed consent, to have each patient complete the study up to and including the 
last protocol-specified study visit. If the study medication jeopardizes the patient’s health or if 
the patient wishes to discontinue for any reason, study medication can be discontinued but the 
patient should be encouraged to remain in the study for the follow-up visits up to the End of 
Study visit. If the patient does not wish to pursue the protocol follow-up visits, the option for a 
last contact at the end of the study to obtain their vital status should be proposed. Patients who 
are not compliant during the active treatment period should be counseled on the importance of 
complying with study requirements and be allowed to remain in the study.  No patient who has 
withdrawn their consent from the study during the active treatment period should be replaced. 
 
In the case of an adverse event or safety concern, the study medication may be withheld 
temporarily, or the dose reduced, as per investigator judgment. Investigators should consult the 
pms-colchicine product monograph (Appendix B) and discuss the patient condition with the 
MHICC medical monitor in order to determine the appropriate dose reduction algorithm or study 
medication discontinuation plan.  


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Patients withdrawn at any time from the study during the active treatment period should 
complete all last protocol-specified visit procedures (End of Study Visit, the reason for 
withdrawal from the study, the date of the last visit and the date of the last dose of double-blind 
medication will be clearly documented in the eCRF). 
 
5.4 Study Completion 
 
The study will end when the total number of targeted primary endpoint events (301) is reached. 
At this point, each patient will be requested to perform the End of Study visit, which entails the 
completion of procedures up to and including the End of Study visit.   
 
Completion of the study by a patient should be clearly indicated in the eCRF, along with the date 
of the last visit and the date of the last dose of double-blind medication.  
 
6 
STUDY MEDICATION 
 
Pharmascience Inc. will provide both colchicine and placebo in bottles of 100 tablets of 0.5 mg 
each. At the time of randomization, the randomization number will be recorded on the 
appropriate eCRF section. Blinded medication will be provided as 0.5 mg colchicine tablets or 
matching placebo tablets. A detailed set of dispensing instructions will be included with the drug 
shipment.  
 
6.1 Medication Dispensing 
 
Study medication may be dispensed by the designated pharmacist or a qualified investigative site 
representative, according to a detailed set of dispensing instructions. 
 
6.2 Dosage Regimen 
 
At randomization, patients will be dispensed colchicine tablets or placebo to match colchicine 
tablets. Patients will be instructed to take tablets once daily and according to the detailed set of 
dispensing instructions outlined on the label. At all Follow-Up visits, compliance to the required 
dosage will be assessed, as per the judgment of the principal investigator and the clinical staff. 
 
7 
DATA COLLECTION 
 
Electronic Case Report Forms (eCRF) for all patients will be supplied by MHICC. These are to 
be completed as instructed. Original source documents and other study documentation will be 
maintained at the study site. Risk-based monitoring will be performed by the MHICC or its 
designated representative. 
 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 


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8.1 Statistical Power and Sample Size Considerations  
 
COLCOT is designed as an event-driven trial with all main analyses conducted on an intention-
to-treat basis. A sample size of approximately 4500 randomized patients with 2250 patients in 
each treatment group or, in terms of events, a total number of 301 positively adjudicated events 
(i.e. components of the primary endpoint), would yield adequate power.   
The sample size calculation is based on the primary endpoint and assumes a 30% risk reduction 
with colchicine, translated by a hazard ratio of 0.700. However, to account for a non-compliance 
rate of approximately 8% in the colchicine group, a more conservative hazard ratio of 0.724 
(0.08 x 1 + 0.92 x 0.7) was used in the calculation (corresponding to a 27% relative risk 
reduction). Using a two-sided test at the 0.05 significance level, the trial would have 80% power 
if it continues until 301 positively adjudicated primary events occur in the combined treatment 
groups. 
The total number of patients to randomize, 4500, is chosen so that the expected number of 
adjudicated events after 24 months of follow-up is 301. It assumes an event rate of 7% in the 
placebo group at 24 months, an 18-month recruitment period during which patients are uniformly 
recruited, a 24-month minimum follow-up and a 1% yearly lost to follow-up (and withdrawal of 
consent) rate. 
The final analysis of the primary endpoint will be conducted at a significance level slightly 
below the 0.05 level to account for the interim analysis. However, since this will have a 
negligible impact on power, the sample size calculation was calculated using a significance level 
of 0.05. 
8.2 Analysis population 
 
8.2.1 Intent to Treat (ITT) population 
 
All patients randomized will be included in the ITT population. Patients will be assigned to 
treatment groups as randomized for analysis purposes. 
 
8.2.2 Safety population 
 
All patients who received at least one dose of study medication will be included in the safety 
analysis population. Patients will be assigned according to the true treatment received for 
analysis purposes. 
 
8.3 Data analysis 
 
8.3.1 Analysis of efficacy outcomes 
 


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All suspected cardiovascular endpoints that are part of the primary, secondary and exploratory 
efficacy endpoints will be adjudicated by a clinical adjudication committee of experienced 
trialists and the statistical analysis will be conducted using positively adjudicated data.  
The primary endpoint will be compared between the two treatment groups using a log rank test. 
Patients with no event will be censored at the time last known to be event free. Cox proportional 
hazard models will also be contemplated to adjust for important baseline characteristics. Hazard 
ratios along with 95% confidence intervals will be provided. Secondary and exploratory 
endpoints expressed as time to event will be analyzed similarly. 
Blood samples for biomarkers will be collected as outlined in Table 1. The changes from 
baseline to Visit 5 will be analyzed using an analysis of covariance (ANCOVA) model adjusting 
for baseline value and estimates of treatment effect will be presented with 95% confidence 
intervals. The biomarkers at Visit 9 will be analyzed using an analysis of variance (ANOVA) 
model and estimates of treatment effect will be presented with 95% confidence intervals. 
Efficacy analyses will be carried out according to the intention to treat principle and performed 
using the ITT population. All statistical tests will be two-sided and conducted at the 0.05 
significance level, with the exception of the primary analysis that will be conducted at a slightly 
lower level to account for the interim analysis. Statistical analyses will be done using SAS 
version 9.3 or higher. 
 
8.3.2 Analysis of safety outcomes 
 
Safety of colchicine will be evaluated by presenting descriptive statistics for various safety 
endpoints broken down by group. This will be done for the population of patients who received 
at least one dose of study medication (safety population). 
 
8.3.3 Interim analysis 
 
A fully independent 5-member DSMB will be established and will review unblinded data as 
detailed in the DSMB charter. In light of the LoDoCo study which showed a statistically 
significant benefit of colchicine with only 500 patients, an interim analysis is planned after 
approximately 50% of primary endpoints have been positively adjudicated (i.e. after 
approximately 150 positively adjudicated events). The DSMB charter will formally pre-specify 
the methods of interim efficacy analyses and rules for early trial termination, as approved by all 
board members. The stopping rule for efficacy and futility will be based on the O’Brien-Fleming 
alpha-spending function or on a similar conservative approach so that the impact on the final 
alpha level will be negligible. The DSMB will at this stage have the options of recommending 
early study termination because of overwhelming efficacy, early termination for futility, or 
continuation of the trial as planned. 
 
9 
STUDY COORDINATION 
 


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The MHICC will be responsible for processing and quality control of the data. Project 
management will be carried out as described in the MHICC standard operating procedures 
(SOPs) for clinical studies. The handling of data, including data quality control, will comply with 
all applicable regulatory guidelines, MHICC SOPs and the study Data Management Plan. 


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REFERENCES 
 
1.  World Health Organization Fact Sheet No 317, updated March 2013, 
http://www.who.int/mediacentre/factsheets/fs317/en/ 
 
2. Global atlas on cardiovascular disease prevention and control. Geneva, World Health 
Organization, 2011. 
 
3. Statistics Canada. (2011c, October). Mortality, summary list of causes 2008. Heart and Stroke 
Foundation. 
 
4. Statistics- Heart and Stroke Foundation of Canada 
(w.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm). 
 
5. Hansson GK.  Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 
352:1685-1695. 
 
6. Naruko T, Ueda M, Haze K, et al. Neutrophil infiltration of culprit lesions in acute coronary 
syndromes. Circulation 2002;106:2894-900. 
 
7. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005;111(25): 
3481-3488. 
 
8. Small DM. Cellular mechanism for lipid depositition in atherosclerosis (first of two parts). N 
Engl J Med 1977;297:873-877. 
 
9. Shah PK, Inflammation and plaque vulnerability. Cardiovascular Drugs and Therapy 2009;23: 
31-40. 
 
10. Newby DE. Triggering of acute myocardial infarction: beyond the vulnerable plaque. Heart 
2010;96:1247-1251. 
 
11. Libby P, Ridker PM, Hansson GK. Inflammation in Atherosclerosis: From Pathophysiology 
to Practice. JACC. 2009;54(23): 2129-2138. 
 
12. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in 
inflammation. N Engl J Med. 2006;354:610-621. 
 
13. Swirski FK, Pittet MJ, Kircher MF, et al. Monocyte accumulation in mouse atherogenesis is 
progressive and proportional to extent of disease. Proc Natl Acad Sci USA. 2006. 
 
14. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in 
women diagnosed with rheumatoid arthritis. Circulation 2003;107 :1303-1307. 
 


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15. Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in 
rheumatoid arthritis: a population-based study over 46 years, Arthritis Rheum 2005;52:412-420. 
 
16. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death 
in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005;52:722-732. 
 
17. Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease 
prevalence in rheumatoid arthritis. J Rheumatol 2003;30:36-40. 
 
18. Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of 
cardiovascular events in rheumatoid arthritis cohort not explained by traditional risk factors. 
Arthritis Rheum 2001;44:2737-2745. 
 
19. Rader DJ. Inflammatory markers of coronary risk. N Engl J Med. 2000;343:1179-1182. 
 
20. Ridker PM. Inflammation, C-reactive protein, and cardiovascular disease: moving past the 
marker versus mediator debate. Circ Res 2014;114(4):594-595. 
 
21. Duchatelle V, Kritikou EA, Tardif JC. Clinical value of drugs targeting inflammation for the 
management of coronary artery disease. Can J Cardiol. 2012;28(6):678-686. 
 
22. Tardif JC, McMurray JJ, Klug E, et al. Aggressive Reduction of Inflammation Stops Events 
Trial I. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomized, 
double-blind, placebo-controlled trial. Lancet 2008;371:1761-1768. 
 
23. Tardif JC, Tanguay JF, Wright SS, et al. Effects of P-selectin antagonist inclacumab on 
myocardial damage after percutaneous coronary intervention for non-ST elevation myocardial 
infarction. Results of the SELECT-ACS Trial. J Am Coll Cardiol 2013;61:2048-2055. 
 
24. Tardif JC, L’Allier PL, Grégoire J, et al. A randomized controlled phase 2 trial of the viral 
serpin Serp-1 in patients with acute coronary syndromes undergoing percutaneous coronary 
intervention. Circ Cardiovasc Interv 2010; 3:543-548. 
 
25. Tardif JC, L’Allier PL, Ibrahim R, et al. Treatment with 5-lipoxygenase inhibitor VIA-2291 
(atreleuton) in patients with recent acute coronary syndrome. Circ Cardiovasc Imaging 
2010;3:298-307. 
 
26. Ravelli RBG, Gigant B, Curmi PA, et al. Insight into tubulin regulation from a complex with 
colchicine and a stathmin-like domain. Nature. 2004;428:198-202. 
 
27. Perico N. Ostermann D, Bontempeill M, et al. colchicine interferes with L-selectin and 
leukocyte function associated antigen-1 expression on human T lymphocytes and inhibits T cell 
activation. J Am Soc Nephrol 1996;7:594-601. 
 


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28. Matsukawa A, Yoshimura T, Maeda T, et al. Analysis of the cytokine network among tumor 
necrosis factor alpha, interleukin-1beta, interleukin-8 and interleukin-1 receptor antagonist in 
monosodium urate crystal-induced rabbit arthritis. Lab Investig J Techn Methods Pathol. 
1998;78(5):559-569. 
 
29. Pope RM, Tschopp J. The role of interleukin-1 and the inflammasome in gout: implications 
for therapy. Arthritis Rheumat. 2007;56(10):3183-3188. 
 
30. Cerquaglia C, Diaco M, Nucera G, et al. Pharmacological and clinical basis of treatment of 
familial Mediterranean fever (FMF) with colchicine or analogues: an update. Curr Drug Targ 
Inflamm Allergy. 2005;4:117-124. 
 
31.  Wesley II RB, Meng X, Godin D, Galis ZS. Extracellular matrix modulates macrophage 
functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage 
traits by human peripheral blood monocytes in vitro. Arterioscler Thromb Vasc Biol. 
1998;18:432-440. 
 
32.  Chao FC, Shepro D, Tullis JL, Belamarich FA, Curby WA. Similarities between platelet 
contraction and cellular motility during mitosis: role of platelet microtubules in clot retraction. J 
Cell Sci. 1976;20:569-588.  
 
33.  Sneddon JM. Effect of mitosis inhibitors on blood platelet microtubules and aggregation. J 
Physiol. 1971.;214:145-158. 
 
34. Imazio M, Bobbio M, Cecchi E, et al.   Colchicine in addition to conventional therapy for 
acute pericarditis: results of the Colchicine for acute Pericarditis (COPE) trial. Circulation. 
2005;112(13):2012-2016. 
 
35. Imazio M, Bobbio M, Cecchi E, et al. Colchicine as first-choice therapy for recurrent 
pericarditis: results of the CORE (Colchicine for Recurrent pericarditis) trial. Arch Intern Med. 
2005. 165(17): 1987-1991. 
 
36. Imazio M, Brucato A, Cemin R, et al. Colchicine for recurrent pericarditis (CORP): a 
randomized trial. Ann Intern Med. 2011;155(7):409-414. 
 
37. Imazio M, Brucato A, Rovere ME, et al. Colchicine prevents early postoperative pericardial 
and pleural effusions. Am Heart J. 2011;162(3):527-532. 
 
38. Imazio M, Brucato A, Ferrazzi P et al. Colchicine reduces postoperative atrial fibrillation: 
results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial 
fibrillation substudy. Circulation. 2011;124(21):2290-2295. 
 
39. Deftereos S, Giannopoulos G, Kossyvakis C, et al. Colchicine for Prevention of Early Atrial 
Firbrillation Recurrence After Pulmonary Vein Isolation. JACC. 2012;60(18):1790-1796. 


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40. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-Dose Colchicine for 
Secondary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2013;61:404-410. 


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LIST OF APPENDICES 
 
Appendix 
Title 
A 
Detailed Study Safety Parameters 
B 
PMS-Colchicine 0.6mg Product Monograph 
C 
Administrative Procedures for the Reporting of Adverse Events 
D 
Other Administrative and Regulatory Procedures 
E 
Declaration of Helsinki  
 
 


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Appendix A 
Detailed Study Safety Parameters 
 
1. Medical/Surgical History 
 
The following elements of medical/surgical history will be recorded at the Screening Visit: 
 
 age 
 ethnic origin 
 sex 
 smoking history 
 history of diabetes 
 history of hypertension 
 history of dyslipidemia 
 prior MI 
 prior PCI 
 prior CABG 
 prior stroke 
 prior heart failure 
 prior atrial fibrillation 
 
2. Physical Appearance 
 
1. weight 
2. height  
3. waist circumference 
 
3. Mandatory Laboratory Parameters to Assess at V3 
 
Chemistry 
AST (Aspartate aminotransferase) 
 
 
ALT (Alanine transaminase) 
 
 
GGT (Gamma-glutamyl transferase) 
 
 
Alkaline phosphatase 
 
 
Total Bilirubin 
 
 
Serum creatinine 
 
 
Uric acid  
 
 
 
 
 
 
 
 
 


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4. Clinical Laboratory Parameters To Review (if available at yearly visits) 
 
 
Determinations 
 
Hematology 
RBC 
 
 
Hemoglobin 
 
 
Hematocrit 
 
 
WBC 
 
 
Platelet Count 
 
 
Differential 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
 
 
 
Chemistry 
Glucose 
 
 
AST 
 
 
ALT 
GGT 
 
 
Alkaline phosphatase 
 
 
LDH (Lactate dehydrogenase) 
 
 
CPK (Creatine phosphokinase) 
 
 
BUN (Blood urea nitrogen) 
 
 
Serum Creatinine 
Creatinine Clearance 
 
 
Uric Acid 
 
 
Total bilirubin 
HbA1C (Glycated hemoglobin) 
 
 
 


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Appendix B 
PMS-Colchicine 0.6mg Product Monograph 
 


 
 
 
 
 
 
 
 
 
 
 
PRESCRIBING INFORMATION 
 
 
 
 
 
 
Pr pms-COLCHICINE 
 
 
Colchicine Tablets, USP 
 
 
 
0.6 mg 
 
 
 
 
 
 
 
Gout Therapy 
 
 
 
 
 
 
 
 
 
 
 
PHARMASCIENCE INC. 
6111 Royalmount Ave., Suite 100 
Montreal, Québec 
H4P 2T4 
 
 
www.pharmascience.com 
Date of Revision: 
July 05, 2016 
 
 
 
Control No.: 196333 


pms-COLCHICINE Prescribing Information 
Page 2 of 10 
 
 
Pr pms-COLCHICINE 0.6 mg per Tablet 
Gout Therapy 
Preparations with No Effect on Uric Acid Metabolism 
 
Structural Formula: 
 
 
 
Molecular formula: C22H25NO6 
 
Molecular Mass: 399.4 g/mol 
 
 
 
PHARMACOLOGY 
 
Colchicine is an alkaloid extracted from plants of the genus Colchicum (Colchicum automnale) and is 
a water soluble pale yellow powder which blackens with exposure to light. 
 
Oral colchicine intake undergoes an entero-hepatic cycle. It is absorbed rapidly by the Gastro- 
Intestinal Tract. The drug and its metabolites are distributed in the leukocytes, the kidneys, the liver, 
the spleen and the intestine. 
 
Peak plasma concentration is obtained from 0.5 to 2 hours after ingestion. The half-life of this drug is 
approximately 20 minutes in the plasma and 60 hours in the leucocytes. The drug is 50% bound to 
proteins. The interleucocyte concentrations are higher than the concentration in the plasma. 
 
Its metabolism is not well understood. Colchicine is metabolized in the liver and is excreted mainly in 
the feces, 10-20% of the drug finds its way in the urine. The colchicine binding results in its 
accumulation in tissues as soon as the daily dosage exceeds 1 mg, which, in turn, could result in toxic 
effects. A serious renal ailment could prolong the half-life for its elimination. 
 
Colchicine crosses the placenta and passes into the breast milk. 
 
Although its exact mode of action in the relief of gout is not completely understood, colchicine is 
known to decrease the inflammatory response to urate crystal deposition by inhibiting migration of 
leukocytes, to interfere with urate deposition by decreasing lactic acid production by leukocytes, to 
interfere with kinin formation and to diminish phagocytosis and the subsequent anti-inflammatory 
response. 


pms-COLCHICINE Prescribing Information 
Page 3 of 10 
 
 
The anti-inflammatory effect of colchicine is relatively selective for acute gouty arthritis. It is neither 
analgesic nor a uricosuric and will not prevent progression to chronic gouty arthritis. It does have a 
prophylactic, suppressive effect that helps to reduce the incidence of acute attacks. . 
 
Comparative bioavailability study 
 
A pivotal, single center, randomized, single dose, double-blinded, two-sequence, two-treatment, 
crossover design study was conducted in 34 healthy male volunteers under fasting conditions 
comparing pms-COLCHICINE 0.6 mg tablets (Pharmascience Inc.) to COLCHICINE-ODAN 0.6 mg 
tablets  (Odan  Laboratories  Ltd.).  A summary  of  the  pharmacokinetic  data  is  presented  in  the 
following tables. 
 
SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA 
 
Colchicine 
(1 x 0.6 mg tablet – Fasting Conditions) 
From measured data uncorrected for 
potency Geometric Mean 
Arithmetic Mean (CV %) 
Parameter 
Test* 
Reference† 
% Ratio of 
Geometric Means 
90 % Confidence Interval 
AUC0-72 
(pg·h/mL) 
15457.6 
16029.3 (25.8) 
16324.5 
16713.6 (21.8) 
94.69 
89.53 – 100.14 
AUCI 
(pg·h/mL) 
17827.6 
18487.9 (26.2) 
18702.9 
19154.7 (22.1) 
95.32 
90.25 – 100.67 
Cmax 
(pg/mL) 
2068.1 
2208.7 (35.4) 
2130.8 
2216.6 (27.9) 
97.06 
88.39 – 106.57 
Tmax
§
 
(h) 
1.05 
(0.50 – 2.50) 
1.00 
(0.75 – 2.03) 
T½
€ 
(h) 
29.91 (17.5) 
29.68 (15.8) 
* pms-COLCHICINE 0.6 mg tablets, Pharmascience Inc., Montreal, Quebec, Canada 
† Colchicine 0.6 mg tablets, Odan Laboratories Ltd., Montreal, Quebec, Canada 
§ Median (range) 
€ Arithmetic mean (CV%) 


pms-COLCHICINE Prescribing Information 
Page 4 of 10 
 
 
INDICATIONS 
 
 Gout: prophylaxis and treatment of gout flares in adults. Colchicine is effective in relieving the 
pain of acute attacks, especially if therapy is begun early in the attack and in adequate dosage. 
Many therapists use colchicine as interval therapy to prevent acute attacks of gout. 
 Familial Mediterranean Fever (familial recurrent polyserositis). 
 
 
 
CONTRAINDICATIONS 
 
 Patients with serious gastrointestinal, hepatic, renal and cardiac disease. 
 Patients with known hypersensitivity to colchicine. 
 Patients with renal or hepatic impairment should not be given pms-COLCHICINE in conjunction 
with P-glycoprotein or strong CYP3A4 inhibitors. 
 Avoid pms-COLCHICINE plus cyclosporine or a strong 3A4 inhibitor if patients have renal or 
hepatic impairment. This can be fatal. 
 
WARNINGS AND PRECAUTIONS 
Warnings: 
 
Drug Interactions 
Colchicine is a substrate for both the cytochrome P450 3A isoform subfamily (CYP3A) and the 
efflux transporter, P-glycoprotein (P-gp). Clarithromycin and other macrolides are known to inhibit 
CYP3A4 and P-gp. When colchicine and clarithromycin are administered together, inhibition of P-gp 
and/or CYP3A4 by clarithromycin may lead to increased exposure to colchicine which could result in 
clinically significant safety concerns. Patients should be monitored for clinical symptoms of 
colchicine toxicity. There have been post-marketing reports of colchicine toxicity with concurrent use 
of colchicine and clarithromycin. 
 
In patients with impaired renal function and/or who are elderly, colchicine and clarithromycin should 
not be used concurrently due to the risk of colchicine toxicity. Deaths have been reported in some of 
these patients. 
 
Colchicine has been shown to induce reversible malabsorption of Vitamin B12, apparently by altering 
the function of ileal mucosa. 
 
Blood dyscrasias: myelosuppression, leucopenia, ganulocytopenia, thrombocytopenia, and aplastic 
anemia have been reported with colchicine used in therapeutic doses. 
 
Pregnancy: Cell division in animals and plants can be arrested by colchicine. In certain species of 
animal under certain conditions it has produced teratogenic effects and has adversely affected 
spermatogenesis. If the drug is used during pregnancy, or if the patient becomes pregnant while 
taking it, the woman should be told of the potential hazard to the fetus. While such effects have not 
been demonstrated in humans, pertinent available information is meager. In view of the above, 
colchicine is not recommended for use in pregnancy. 


pms-COLCHICINE Prescribing Information 
Page 5 of 10 
 
 
 
Neuromuscular Toxicity: Colchicine-induced neuromuscular toxicity and rhabdomyolysis have 
been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly 
patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of 
atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, fenofibrate, fenofibric acid, or 
benzafibrate (themselves associated with myotoxicity) or cyclosporine with colchicine may potentiate 
the development of myopathy. Once colchicine is stopped, the symptoms generally resolve within 1 
week to several months. 
 
Precautions: 
 
Periodic blood tests are suggested since prolonged administration of colchicine could cause blood 
dyscrasias. 
 
Colchicine is a toxic substance and must be given only under physician’s care. Since the 
administration of colchicine is subjected to wide variations, the prescribed dosage must be strictly 
followed. 
 
Use with care in geriatrics or debilitated patients and those with cardiac, renal or gastrointestinal 
disease. Dosage reduction may be necessary in these cases and is indicated if weakness, anorexia, 
nausea, vomiting or diarrhea appears (see Contraindications). 
 
Pregnancy: pms-COLCHICINE is not recommended for use in pregnancy (see Warnings). 
 
Lactation: It is not known if colchicine is distributed into human milk. pms-COLCHICINE should 
not be used by women who are breastfeeding. 
 
Children: Safety and efficacy of colchicine in treatment of FMF have not been established in patients 
≤12 years of age. Colchicine is not recommended in pediatric patients for treatment or prophylaxis of 
gout flares. Keep colchicine out of reach of children. Fatal overdoses, both accidental and intentional, 
have been reported in adults and children who have ingested colchicine. 
 
 
 
ADVERSE EFFECTS 
 
Reactions to colchicine appear to be dose related. The most prominent symptoms are referable to the 
gastrointestinal tract (e.g. nausea, vomiting, abdominal pain, diarrhea) and may be particularity 
troublesome in the presence of peptic ulcer or spastic colon. At toxic doses colchicine may cause 
severe diarrhea, generalized vascular damage, and renal damage, with hematuria and oliguria. 
Muscular weakness, which disappears with discontinuance of therapy, urticaria, dermatitis, and 
purpura have also been reported. Hypersensitivity to colchicine is a very rare occurrence, but it 
should be borne in mind. The appearance of any of the aforementioned symptoms may require 
reduction of dosage or discontinuance of the drug. When given for a prolonged period, colchicine 
may cause agranulocytosis, aplastic anemia, peripheral neuritis and loss of hair. 


pms-COLCHICINE Prescribing Information 
Page 6 of 10 
 
 
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin 
and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. 
Deaths have been reported in some such patients (see Warnings). 
 
Post-marketing Experience 
 
Serious toxic manifestations associated with colchicine include myelosuppression, disseminated 
intravascular coagulation, and impairment of renal, hepatic, circulatory, and central nervous systems. 
 
The following adverse reactions have been reported with colchicine. These have been generally 
reversible upon temporarily interrupting treatment or lowering the dose of colchicine. 
 
Neurological: sensory motor neuropathy 
 
Dermatological: alopecia, maculopapular rash, purpura, rash 
 
Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting 
Hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia 
Hepatobiliary: elevated AST, elevated ALT 
Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, 
rhabdomyolysis 
 
Reproductive: azoospermia, oligospermia 
 
Reporting Side Effects 
You can help improve the safe use of health products for Canadians by reporting serious and 
unexpected side effects to Health Canada. Your report may help to identify new side effects and 
change the product safety information. 
3 ways to report: 
 
Online at MedEffect (http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php);; 
 
By calling 1-866-234-2345 (toll-free); 
 
By completing a Consumer Side Effect Reporting Form and sending it by: 
- 
Fax to 1-866-678-6789 (toll-free), or 
- 
Mail to: Canada Vigilance Program 
Health Canada, Postal Locator 0701E 
Ottawa, ON 
K1A 0K9 
Postage paid labels and the Consumer Side Effect Reporting Form are available at 
MedEffect (http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php). 
 
NOTE: Contact your health professional if you need information about how to manage your side 
effects. The Canada Vigilance Program does not provide medical advice. 


pms-COLCHICINE Prescribing Information 
Page 7 of 10 
 
 
DOSAGE AND ADMINISTRATION 
 
Dosage 
Gout Flares: 
Treatment of gout flares in adults (>18 years old): 
The recommended dose of pms-COLCHICINE is 1.2 mg (2 tablets) at the first sign of the flare 
followed by 0.6mg (1 tablet) one hour later. 
 
The maximum recommended dose is 1.8 mg over one-hour period. Wait 12 hours to resume 
prophylactic dose. Wait at least three days to repeat. 
 
The treatment of gout flares with pms-COLCHICINE is not recommended in patients receiving 
prophylactic dose of colchicine and CYP3A4 inhibitors. 
 
Prophylaxis of gout flares in adults (>18 years old): 
The recommended dosage of pms-COLCHICINE is 0.6 mg once or twice daily. The maximum 
recommended dose should not exceed 1.2 mg per day. Use with caution in geriatric patients; reduce 
prophylactic daily dose by 50% in individuals >70 years. 
 
Familial Mediterranean Fever (FMF): 
Treatment of FMF in patients >12 years of age: 
The recommended dosage of colchicine for FMF is 1.2 mg to 2.4 mg daily. 
The dosage should be increased as needed to control disease and as tolerated in increments of 0.3 
mg/day to a maximum recommended daily dose of 2.4 mg. If intolerable side effects develop, the 
dose should be decreased in increments of 0.3 mg/day. The total daily dose of pms-COLCHICINE 
may be administered in one to two divided doses. 
 
Dose Modification for Co-administration of Interacting Drugs 
Concomitant Therapy: 
Co-administration of colchicine with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) 
increases the risk of colchicine-induced toxic effects (Table 1). If patients are taking or have recently 
completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as 
shown on the table below (see Warnings and Drug Interactions). 


pms-COLCHICINE Prescribing Information 
Page 8 of 10 
 
 
Drug 
Noted or 
Anticipated 
Prophylaxis of Gout Flar 
Gout Flares 
es 
Treatment of Gout Flares 
FMF 
Outcome 
Original 
Intended 
Dosage 
Adjusted 
Dose 
Original 
Intended 
Dosage 
Adjusted 
Dose 
Original 
Intended 
Dosage 
Adjusted 
Dose 
Strong CYP3A4 Inhibitors2 
Atazanavir 
Clarithromycin 
Darunavir/ 
Ritonavir3 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir/ 
Ritonavir3 
Nefazodone 
Nelfinavir 
Ritonavir 
Saquinavir 
Telithromycin 
Tipranavir/ 
Ritonavir3 
Significant 
increase in 
colchicine 
plasma levels1; 
fatal colchicine 
toxicity has 
been reported 
with 
clarithromycin, 
a strong 
CYP3A4 
inhibitor. 
Similarly, 
significant 
increase in 
colchicines 
plasma levels is 
anticipated with 
other strong 
CYP3A4 
inhibitors. 
0.6 mg twice a 
day 
0.6 mg once a 
day 
0.3 mg once a 
day 
0.3 mg once 
every other 
day 
1.2 mg 
(2 tablets) 
followed by 
0.6 mg 
(1 tablet) 
1 hour later. 
Dose to be 
repeated no 
earlier than 
3 days. 
0.6 mg 
(1 tablet) x 
1 dose, 
followed by 
0.3 mg 
(1/2 tablet) 
1 hour later. 
Dose to be 
repeated no 
earlier than 
3 days. 
Maximum 
daily dose of 
1.2 – 2.4 mg 
Maximum 
daily dose of 
0.6 mg (may 
be given as 
0.3 mg twice a 
day) 
Moderate CYP3A4 Inhibitors 
Amprenavir3 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir3 
(pro-drug of 
Amprenavir) 
Grapefruit 
Juice 
Verapamil 
Significant 
increase in 
colchicine 
plasma 
concentration is 
anticipated. 
Neuromuscular 
toxicity has 
been reported 
with diltiazem 
and verapamil 
interactions. 
0.6 mg twice a 
day 
0.6 mg once a 
day 
0.3 mg twice a 
day or 0.6 mg 
once a day 
0.3 mg once 
every other 
day 
1.2 mg 
(2 tablets) 
followed by 
0.6 mg 
(1 tablet) 
1 hour later. 
Dose to be 
repeated no 
earlier than 
3 days. 
1.2 mg 
(2 tablets) x 
1 dose. Dose 
to be repeated 
no earlier than 
3 days. 
Maximum 
daily dose of 
1.2 – 2.4 mg. 
Maximum 
daily dose of 
1.2 mg (may 
be given as 
0.6 mg twice a 
day) 
P-gp Inhibitors2 
Cyclosporine 
Ranolazine 
Significant 
increase in 
colchicine 
plasma levels1; 
fatal colchicine 
toxicity has 
been reported 
with 
cyclosporine, a 
P-gp inhibitor. 
Similarly, 
significant 
increase in 
colchicine 
plasma levels is 
anticipated with 
other P-gp 
inhibitors. 
0.6 mg twice a 
day 
0.6 mg once a 
day 
0.3 mg once a 
day 
0.3 mg once 
every other 
day 
1.2 mg 
(2 tablets) 
followed by 
0.6 mg 
(1 tablet) 
1 hour later. 
Dose to be 
repeated no 
earlier than 
3 days. 
0.6 mg 
(1 tablet) x 
1 dose. Dose 
to be repeated 
no earlier than 
3 days 
Maximum 
daily dose of 
1.2 – 2.4 mg 
Maximum 
daily dose of 
0.6 mg (may 
be given as 
0.3 mg twice a 
day) 
Table 1: Colchicine Dose Adjustment for Co-administration with Interacting Drugs if no Alternative Available1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 For magnitude of effect on colchicine plasma concentrations 
2 Patients with renal or hepatic impairment should not be given colchicine in conjunction with strong CYP3A4 or P-gp inhibitors 
3 When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors 
 
Treatment of gout flares with pms-COLCHICINE is not recommended in patients receiving 
prophylactic dose of Colchicine and CYP3A4 inhibitors. 


pms-COLCHICINE Prescribing Information 
Page 9 of 10 
 
 
For patients with severe renal or hepatic impairment, a 3-tablet course is recommended. For these 
patients, wait at least two weeks before repeating the course (see Warnings and Drug Interactions). 
 
Administration: 
 Administer orally with water and maintain adequate fluid intake. 
 May be administered without regard to meals. 
 May need to supplement with Vitamin B12. 
 Avoid grapefruit juice. 
 pms-COLCHICINE is not an analgesic medication and should not be used to treat pain from 
other causes. 
 
 
 
OVERDOSE 
 
There is usually a latent period between overdosage and the onset of symptoms, regardless of the 
route of administration. Deaths have been reported with as little as 7 mg, although higher doses have 
been taken without fatal results. 
 
The exact dose of colchicine that produces significant toxicity is unknown. A review of 150 patients 
who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended 
to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg 
had more severe reactions, such as myelosuppression. There was 100% mortality in those who 
ingested more than 0.8 mg/kg. 
 
Symptoms: The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion 
and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and 
significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life 
threatening complications occur during the second stage, which occurs 24 to 72 hours after drug 
administration, attributed to multi-organ failure and its consequences. Death is usually a result of 
respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ 
injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the 
initial ingestion. 
 
Treatment: Induce emesis or perform gastric lavage. Symptomatic and supportive treatment. No 
specific antidote is known. Colchicine is not effectively removed by dialysis. 
 
For management of a suspected drug overdose, contact your regional 
Poison Control Center immediately. 


Page   10 of 10 
pms-COLCHICINE  Prescribing Information 
 
 
SUPPLIED 
 
Each yellow, round, biconvex tablet debossed with “C” above “0.6” on one side and scored on the 
other side contains: 0.6 mg of Colchicine and the following non-medicinal ingredients: D&C Yellow 
#10,  FD&C  Yellow #6,  magnesium  stearate,  povidone,  sodium  starch  glycolate  and  sucrose. 
Available in HDPE bottle of 100 tablets and in blisters of 30 tablets. 
 
Store at room temperature between 15oC and 30oC. 
Keep out of reach and sight of children. 
 
 
 
PHARMASCIENCE INC. 
6111 Royalmount Ave., Suite 100 
Montreal, Quebec, H4P 2T4 
www.pharmascience.com 
 
 
 
REFERENCES 
 
Colchicine Prescribing Information, Odan Laboratories Ltd, Canada. Date of revision May 4, 2016. Control 
number: 190129 
 
 
 


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Appendix C 
Administrative Procedures for the Reporting of Adverse Events  
 
 
The following administrative procedures for reporting AEs are to be followed during the conduct 
of this clinical trial. 
 
1 
ADVERSE EVENTS DURING THE TRIAL 
 
Each patient will be observed and queried in a non-specific manner by the investigator or study 
coordinator at each visit for any new or continuing AE since the previous visit. Any AEs prior to 
the first dose of study medication will be recorded in the medical history and kept in the patients’ 
chart. All SAEs will be recorded in the appropriate eCRF section. In addition to SAEs, the only 
AEs to be recorded in the eCRF are those that are either related to the gastrointestinal system, 
that are judged related to the study medication by the investigator or that are laboratory 
abnormalities judged clinically significant by the investigator. Information collected will include 
the onset, duration, severity, relationship to study drug, and the management. SAEs are to be 
reported if they are known to occur within 30 days following the last study visit.  
 
The investigator will review the clinical laboratory test results in a timely fashion when received 
from the laboratory.  Those results qualifying as AEs as defined in this appendix will be recorded 
on the AE eCRF section and will be handled according to these AE reporting procedures. 
 
The investigator will review concomitant medications being taken by the patient.   
 
Definitions 
 
1.1 Pre-existing condition 
 
A pre-existing condition is one that is present prior to randomization. A worsening of a pre-
existing condition after taking the first dose of investigational product should be reported as an 
AE. 
 
1.2 Adverse Event (AE) 
 
An AE is defined as any unfavorable and unintended sign (including a clinically meaningful 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. 
 
A medical procedure is not considered and should not be reported as an AE. However, the 
medical condition which led to the procedure should be considered as an AE and be reported as 
such. 
 
1.3 Related Adverse Event 
 
A related AE is one where, according to the Investigator, there is a reasonable possibility that the 
event may have been caused by the study drug. 


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1.4 Serious Adverse Event (SAE) 
 
Serious Adverse Events (SAE) are those that meet any of the following International Council for 
Harmonisation (ICH) criteria: 
 
 Is fatal or immediately life-threatening (NOTE: the term "Life-Threatening" refers 
to an event in which the patient was at immediate risk of death at the time of the 
event; it does not refer to an event which could hypothetically have caused death 
had it been more severe); 
 Results in persistent or significant disability/incapacity; 
 Requires or prolongs patient hospitalization; 
 Is a congenital anomaly/birth defect in the offspring of the patient; 
 Is a cancer; 
 Is an overdose (intentional or accidental); 
 Is judged to be medically important. 
 
Medically important events may not be immediately life-threatening, result in death or 
hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above.  Serious adverse events are to be reported if they are 
known to occur within 30 days following the last study visit.  
 
Medical and scientific judgment should be exercised in deciding whether other AEs meet these 
criteria and are immediately reportable to the sponsor or its designee. 
 
Hospitalization is defined as a patient admission to a hospital for medical treatment or 
observation; a visit to the emergency room for an outpatient consultation is not considered a 
hospitalization. Moreover, the following hospitalizations are not considered SAEs: 
 
 Hospitalizations for diagnostic or elective surgical procedures for a pre-existing 
condition. 
 Hospitalization for therapy of the target disease(s) of the study if the protocol 
explicitly anticipated and defined the symptoms or episodes. 
 Hospitalization for study efficacy measurement, as defined in the protocol. 
 
1.5 Life-Threatening Adverse Event 
 
A life-threatening AE is an AE that, in the opinion of the investigator, places the patient at 
immediate risk of death from the reaction as it occurred. 
 
1.6 Unexpected Adverse Event 
 
An unexpected AE is any AE that is not consistent with findings previously observed and 
described in the current Investigational Medicinal Product Information (IMPI). 


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1.7 Clinical Laboratory Adverse Event 
 
A clinical laboratory abnormality is regarded as an AE if it has been confirmed by at least 1 
repeat test and suggests a disease and/or organ toxicity severe enough to require active 
management.  
 
1.8 Treatment-Emergent Signs and Symptoms (TESS) 
 
A TESS event is any AE that was not present prior to randomization or that worsens in character, 
intensity or frequency while the patient is in an active treatment period. 
 
1.9 Post-treatment Adverse Event 
 
A post-treatment AE is any AE that occurs after treatment is discontinued.   
 
2 
HANDLING OF ADVERSE EVENTS 
 
2.1 Treatment-Emergent Signs and Symptoms 
 
Any condition/diagnosis that meets the definition of a TESS event is captured in the medical 
history and kept in the patient’s chart. 
 
2.2 Serious Adverse Events 
 
All SAEs are to be immediately reported as outlined in Section 5.2.1.1., Serious Adverse Events, 
within 24 hours of the Investigator’s first knowledge of the event. 
 
2.3 Intensity 
 
The following criteria are used to assess the intensity of each AE: 
 
 Mild: The patient is aware of the sign or symptom, but finds it easily tolerated. 
 Moderate: The patient has enough discomfort to cause interference with or change 
in usual activities. 
 Severe: The patient is incapacitated and unable to work or participate in many or 
all usual activities. 
 
2.4 Relationship to Study Drug – Physician’s Assessment 
 
There are 3 categories for the physician’s assessment of the causal relationship between study 
drug and an AE as follows: not related, possibly and probably.  
 
2.5 Clinical Outcome 
 


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The following categories are used to assess the clinical outcome of each AE: 
 
 Recovered – The patient has fully recovered from the AE with or without 
observable residual effects. 
 Not Yet Recovered – the patient is still being treated for the residual effects of the 
original AE.  This does not include treatment for pre-existing conditions including 
the indication for the study drug. 
 Died Due to this Adverse Event 
 Died, Other Causes 
 Unknown 
 Surgery/Procedure 
 
3 
CAPTURING AVDERSE EVENTS 
 
3.1 Pre-Existing Condition 
 
A pre-existing condition should be captured in the medical history and kept in the patient’s chart. 
If the frequency, intensity, or character of the condition worsens during study treatment, and is 
either related to the gastrointestinal system, is judged related to the study medication by the 
investigator or is a laboratory abnormality judged clinically significant by the investigator, it 
must be documented in the appropriate eCRF AE form. 
 
3.2 Lack of Efficacy of Study Medication 
 
Signs or symptoms defined in the protocol as lack of efficacy or collected as efficacy parameters 
(endpoints) will be captured as AEs. 
 
3.3 Clinical Laboratory Adverse Event 
 
A clinical laboratory abnormality should be reported as an AE only if it is considered to be 
clinically significant by the investigator and confirmed by repeat testing.  
 
3.4 Hospitalization or Surgery/Procedure 
 
Any AE that results in hospitalization (admitted and not just an emergency room visit) should be 
reported as an SAE (except study endpoints which are adjudicated by the CEC). Any 
condition/diagnosis responsible for surgery/procedure should be reported as an AE if it meets the 
criteria for an AE. A medical procedure is not considered and should not be reported as an AE. 
The surgery/procedure itself will be reported as a Clinical Outcome of the underlying event. 
Events that prolong any hospitalization are reported as SAEs. 
 
3.5 Death 
 
The cause of death should be reported as an AE.   
 


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4 
REPORTING TO THE SPONSOR 
 
4.1 Immediately Reportable Adverse Events 
 
If an AE meets the definition of Serious, it must be reported IMMEDIATELY in the eCRF. If 
the eCRF is not available, the investigator should send the paper SAE form by fax  
(+1-514-461-1301) as soon as possible and within 24 hours of knowledge of the event. Upon 
return of the availability of the eCRF, the information written on the paper SAE form must be 
recorded in the eCRF. For any questions or concerns, the investigator may call the MHICC 
Medical Monitor at +1-514-207-1365 (24/7). If any SAE occurs the investigator, at his 
discretion, can withdraw the patient from the study while taking the appropriate follow-up 
action. 
 
MHICC Medical Monitor or his designated representative is responsible to report SUSARs to 
Regulatory Authorities and to notify Pharmascience Inc. 
 
4.2 Other Adverse Events 
 
Endpoints, including cardiovascular mortality, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, urgent hospitalization for angina requiring revascularization, deep venous thrombosis and 
pulmonary 
embolus, 
atrial 
fibrillation, 
heart 
failure 
hospitalization, 
and 
coronary 
revascularization are to be reported in the eCRF within 24 hours of awareness of the event.  
 
In addition to SAEs and study endpoints, the only AEs to be recorded on the eCRF are those that 
are either related to the gastrointestinal system, that are judged related to the study medication by 
the investigator or that are laboratory abnormalities judged clinically significant by the 
investigator. Information collected will include the onset, duration, severity, relationship to study 
drug, and the management. 
 
4.3 Follow-Up Period 
 
For SAEs, the patient must remain under observation until the SAE has subsided or stabilized 
and all serious findings have returned to normal or stabilized. Any follow-up information to an 
initial SAE report must be updated in the eCRF. Serious Adverse Events are to be reported if 
they are known to occur within 30 days following the last study visit.  


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Appendix D 
Other Administrative and Regulatory Procedures 
 
This appendix provides information necessary to administer the study in compliance with global 
Good Clinical Practice (GCP) and government regulations.   
 
Your signature on this cover page of the protocol, subsequent amendments, addenda, and the 
Clinical Trial Agreement confirms that: 
 
 You have been given appropriate information on the study drug 
 You have read and understand the protocol and appendices 
 You agree to conduct the study in accordance with the provisions of the protocol and 
applicable regulations 
 You acknowledge the sponsor’s ownership of the data and results obtained from the 
conduct of the protocol 
 You agree to maintain the confidentiality of information as outlined in this protocol 
 
1. ADMINISTRATIVE PROCEDURES 
 
1.1 Ethics and Informed Consent 
 
1.1.1 Declaration of Helsinki 
 
This study will be conducted in accordance with the Declaration of Helsinki. 
 
1.1.2 Ethics Committee (EC) Review and Approval of the Study 
 
An EC that is organized and operates according to GCP and applicable laws and regulations, 
should safeguard the rights, safety, and well-being of all trial patients.  No patient should be 
admitted to a trial before the EC issues its written approval/favorable opinion of the trial. 
 
The investigator is responsible for: 
 
 Promptly reporting to the EC all changes in the research activity, all unlabeled AEs, 
and all unanticipated problems involving risks to human patients or others; 
 Not making any changes in the research without EC approval, except when absolutely 
necessary to eliminate apparent immediate hazards to human patients; 
 Submitting a progress report describing the status of the clinical investigation to the 
EC at appropriate intervals not exceeding 1 year; and 
 Submitting a final report when required by the EC within 3 months following 
completion, termination or discontinuation of the study.  Copies of these reports will 
also be provided to the sponsor or the sponsor’s designated representative. 
 
In general, all communications with the EC regarding the study will be handled by the principal 
investigator or coordinating investigator, (if applicable) of the study.  The sponsor or the 
sponsor’s designated representative may directly contact the EC if necessary, but must not 


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attempt to influence the EC in any way.  A copy of all communications from the EC to the 
investigator regarding its review of an initial approval of the study and its re-approvals at 
intervals must be provided to the sponsor by the investigator. 
 
1.1.3 Informed Consent Form (ICF) 
 
The investigator must fully explain the purpose of the study to the patient or his/her guardian 
prior to entering the patient into the study.  The investigator is responsible for obtaining written 
informed consent from each patient.   
 
The sponsor requires that the informed consent be obtained orally and on a written form prepared 
by the investigator and approved by the EC. The person signing the consent form will receive a 
copy of the signed form. The signed consent form will be filed at the site with the investigator’s 
study files. 
 
The consent form is a written document that includes the informed consent requirements listed 
below. This form may be read to the patient who will afterward have adequate opportunity to 
read it, ask questions, and receive requested information before signing. 
 
1.2 Emergency Information 
 
1.2.1 Patient Emergency Information 
 
At least 1 of the investigators at each site will be available to the patient at all times during their 
participation in the study. The patient will be provided an emergency information card that 
contains all necessary information to contact the investigator in the case of an emergency, along 
with a description of the study medications the patient may have received and possible 
emergency precautions to be taken (if any). The patient will be instructed to carry this card with 
him/her at all times during the trial. 
 
1.2.2 Emergency Code Breaks 
 
The investigator will be provided with a mechanism for emergency determination of a patient’s 
treatment regimen (if required for proper treatment of the patient) in the event that contact with 
MHICC is not possible.  
 
1.2.3 Confidentiality of Patient Information 
 
All patients will be assigned a patient number. Subsequently, patients will be identified in the 
eCRF only by their initials (or coded initials if mandated per local requirements) and that 
number. Any information published as a result of the study will be such that it will not permit 
identification of any patient. The information from this study will be available within the sponsor 
organization and may be shared with the regulatory authorities.  It may also be the subject of an 
audit by a regulatory agency within the local government. The patient’s identity will remain 
protected except as required for legal or regulatory inquiries. 


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1.2.4 Publication of Study Results 
 
All information and data regarding the study drug obtained in connection with the conduct of this 
study are considered confidential. Accordingly, the sponsor (Montreal Heart Institute) retains the 
right to review manuscripts, abstracts, and presentation material related to this protocol and its 
amendments/addenda prior to presentation or submission to a journal. This review will not 
restrict publication of facts or opinions formulated by the investigator.  
 
1.2.5 Roles and Responsibilities 
 
Montreal Heart Institute (MHI) 
The Montreal Heart Institute is the sponsor for this study. 
 
Montreal Health Innovations Coordinating Center (MHICC) 
The MHICC is a division of the Montreal Heart Institute, and has been designated to provide 
clinical coordination for this trial. These activities include overall project management, site 
selection, distribution of study materials, site management including clinical monitoring, 
SUSARs reporting to regulatory authorities, data management, biostatistical analysis and writing 
of the final clinical study report.  
 
Pharmascience Inc. 
Pharmascience Inc. will provide the Montreal Heart Institute with study medication and matched 
placebo for all patients for the duration of this trial according to a Clinical Supply Agreement 
between them and MHI (the Sponsor). 
 
Investigator 
The Investigator is responsible for ensuring this trial is conducted according to the signed 
investigator statement, following ICH/GCP guidelines and all other local regulatory 
requirements; for protecting the rights, safety, and welfare of subjects under the investigator's 
care; and ensure accountability of the investigational product.   
 
It is the responsibility of the investigator(s) that: 
 
 The study is conducted in accordance with the Declaration of Helsinki and according to 
the guidelines in the attached appendices. 
 This study is conducted in compliance with all applicable laws and regulations of the 
local and country where the study is conducted. 
 This study is not initiated until the protocol and a copy of the informed and consent form 
(ICF) have been reviewed and approved by a duly constituted Ethics Committee (EC), 
and that any local institutional requirements are satisfied.  
 Each patient and/or their legal guardian (or caregiver) reads, understands, and signs an 
instrument of informed consent.    


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 The patient be informed that personal information may be examined during audit by 
properly authorized individuals but that personal information will be treated as strictly 
confidential and not be publicly available. 
 The patient log and patient records are retained as detailed in this protocol. 
 
The final responsibility for the content of the informed consent statement remains with the 
investigator and the EC. Indemnification of the investigator, coworkers, and the institution is 
provided as specified in the Clinical Trial Agreement.  
 
2. PROTOCOL AMENDMENTS AND ADDENDA 
 
2.1 Definitions 
 
A protocol amendment is any systematic change (e.g., revision, addition, deletion) that is made 
to the Final Protocol for all sites participating in a clinical study and is identified by consecutive 
Arabic numerals (e.g., Amendment 1, Amendment 2, etc).  Amendments can be made regardless 
of whether the protocol has been signed by the investigator or whether or not the protocol has 
been implemented at a site. 
 
A Protocol Addendum is any systematic change (e.g., revision, addition, deletion) that is made to 
the Final Protocol for one/some site(s) but not all sites from a multicenter clinical study and is 
identified by single sequentially ordered letters (e.g., Addendum A, Addendum B). 
 
An Urgent Protocol Amendment is one that must be instituted quickly, usually to eliminate an 
apparent immediate hazard to subjects and may be implemented prior to eventual EC review 
(within 5 working days) and submission to regulatory authorities. 
 
All amendments/addenda to the protocol must be approved by the principal investigator, the 
sponsor and the EC of the investigator's institution.  The investigator is responsible for 
submitting any proposed change in the approved protocol in writing to the EC for review and 
approval and for sending a copy of the approval to the sponsor or designee. All 
amendments/addenda will be filed with appropriate local regulatory authorities by the sponsor or 
designee. 
 
With 
the 
exception 
of 
urgent 
protocol 
amendments, 
as 
outlined 
below, 
the 
amendment/addendum will apply to all subjects/patients entered into the study (or all 
subjects/patients in affected sites for addenda) after it has gone through the applicable procedure 
described above and been approved by the EC.  Any amendments/addenda proposed in a 
multicenter protocol must be approved by the EC at the individual study site before it can be 
placed in effect at that site. 
 
2.2 Urgent Protocol Amendment 
 
If the amendment eliminates an apparent immediate safety hazard to the patient (urgent protocol 
amendment), it may be implemented immediately.  The sponsor will promptly notify the 


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appropriate regulatory authorities of the amendment while the investigator will notify his/her EC 
of the change in writing within 5 working days of its implementation. 
 
3. STUDY TERMINATION 
 
The study will normally be carried to completion as described in the protocol. However, if in the 
course of the study a severe adverse reaction or intercurrent illness is noted in any patient, 
consideration may be given to abrupt termination of the study for this patient. Such a decision 
may be made by either the principal investigator or by the sponsor, or both. Likewise, the study 
may be terminated due to ethical/safety issues or at the sponsor’s discretion or for regulatory 
issues. 
 


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Appendix E 
Declaration of Helsinki 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
Preamble 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
  
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
 
General Principles 
 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient's best interest when providing 
medical care.” 
 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 


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therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
 
 
 


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Risks, Burdens and Benefits  
 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. 
 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study.            
 
Vulnerable Groups and Individuals 
 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 


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22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions. 
  
Privacy and Confidentiality  
 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in 
a research study unless he or she freely agrees. 
 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 


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anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed.       
 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The 
potential subject’s dissent should be respected. 
 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research  group. 
In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 
 
 


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31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention  
 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention.  
 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 


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to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 

SAP_000.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Protocol number: MHIPS-003 
 
Colchicine Cardiovascular Outcomes Trial 
 
COLCOT 
 
 
 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
04APR2019 
Amendment No. 1  
19AUG2019 
Amendment No. 2  
28AUG2019 
 
 
Prepared by: 
Lucie Blondeau, M.Sc 
Senior Biostatistician 
Montreal Health Innovations Coordinating Center (MHICC) 
4100 Molson, Suite 400 
Montréal, QC  H1Y 3N1 
Phone: 514-461-1300 ext. 2135 / Fax: 514-461-1301 






 
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Revision History 
 
Version 
Date 
 
Author 
Summary of Changes 
Amendment 1 
19AUG2019 
Lucie Blondeau 
Section 3.3 Per Protocol Population 
 
Adding intake of study medication for < 6 months as a criterion to 
be excluded from the PP population. 
 
Adding that the eligibility criteria not met to be used to exclude 
subjects from the PP population will be those considered as 
important by the principal investigator. 
 
Section 4.5 Laboratory Endpoints 
 
Adding a section for WBC and differentials that will be retrieved 
for a sample of subjects at Visit 2 and Visit 7.  
 
Section 5.1.1.1 Serious Adverse Events of Special Interest 
 
Adding AEs that are classified as serious adverse events under 
category “Cancer” to the definition of cancers and specifying the 
types of cancers to be analyzed. Adjusting Section 7 accordingly. 
 
Section 6.3.7 Treatment Compliance 
Specifying that subjects who never took study medication will be 
excluded when reporting some compliance data. 
 
Section 6.4.5 Laboratory Analysis 
 
Adding a statistical analysis for WBC and differentials. Adding the 
corresponding summary tables to Section 7. 
 
Section 6.4.6.2 Effect of Medication Discontinuation (On-
Treatment Analysis) 
 
Adding a sensitivity analysis for the primary endpoint where 
subjects’ follow-up will end at the date of last dose. Adding the 
corresponding summary table to Section 7. 
 
Appendix 1 
 
Adding Table 2 to describe the algorithm to derive end of study 
dates, Table 3 to describe the imputation rules for incomplete 
and/or missing date of last dose and Table 4 to describe the 
derivation of permanent study medication discontinuation. 
 
Minor updates, corrections and clarifications throughout the text, 
including in the abbreviation list. 
 
 
 


 
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Revision History (continued) 
 
Version 
Date 
 
Author 
Summary of Changes 
Amendment 2 
28AUG2019 
Lucie Blondeau 
Section 6.4.1 Primary Analysis 
Moving former section 6.4.6.3 (Effect of Important Baseline 
Characteristics) to the primary analysis section to allow for an 
adjustment for baseline characteristics. 


 
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TABLE OF CONTENTS  
 
1 
Introduction ......................................................................................................................................... 8 
2 
Study Description ................................................................................................................................. 8 
2.1 
Study Design ................................................................................................................................ 8 
2.2 
Study Objectives .......................................................................................................................... 8 
3 
Datasets Analyzed ................................................................................................................................ 9 
3.1 
Intent-To-Treat (ITT) Population ................................................................................................. 9 
3.2 
Safety Population ........................................................................................................................ 9 
3.3 
Per Protocol Population............................................................................................................... 9 
4 
Efficacy Endpoints .............................................................................................................................. 10 
4.1 
Primary Efficacy Endpoint.......................................................................................................... 10 
4.2 
Secondary Efficacy Endpoints .................................................................................................... 10 
4.3 
Exploratory Efficacy Endpoints .................................................................................................. 11 
4.4 
Biomarker Endpoints ................................................................................................................. 11 
4.5 
Laboratory Endpoints (additional endpoints not specified in the protocol) ............................. 11 
5 
Safety Parameters .............................................................................................................................. 11 
5.1 
Adverse Events .......................................................................................................................... 11 
5.1.1 
Serious Adverse Events ......................................................................................................... 12 
5.1.1.1 
Serious Adverse Events of Special Interest .................................................................. 12 
5.1.2 
Related Adverse Events ......................................................................................................... 13 
5.1.3 
Gastrointestinal Adverse Events ........................................................................................... 13 
5.1.4 
Clinical Laboratory Adverse Events ....................................................................................... 13 
6 
Statistical Methodology ..................................................................................................................... 13 
6.1 
Determination of Sample Size ................................................................................................... 13 
6.2 
Statistical Considerations .......................................................................................................... 14 
6.2.1 
Interim Analysis ..................................................................................................................... 14 
6.3 
Study Subjects ........................................................................................................................... 14 
6.3.1 
Subject Disposition ................................................................................................................ 14 
6.3.2 
Protocol Deviations ............................................................................................................... 14 
6.3.3 
Datasets Analyzed ................................................................................................................. 15 
6.3.4 
Demographic and Baseline Characteristics ........................................................................... 15 
6.3.5 
Medical History ..................................................................................................................... 15 
6.3.6 
Concomitant Medications ..................................................................................................... 15 
6.3.6.1 
Medication at Randomization ...................................................................................... 15 
6.3.6.2 
Medication at or After Randomization ......................................................................... 16 
6.3.7 
Treatment Compliance .......................................................................................................... 16 
6.4 
Efficacy Analysis ......................................................................................................................... 17 
6.4.1 
Primary Analysis .................................................................................................................... 17 
6.4.2 
Secondary Analysis ................................................................................................................ 18 
6.4.3 
Exploratory Analysis .............................................................................................................. 18 
6.4.4 
Biomarker Analysis ................................................................................................................ 18 
6.4.5 
Laboratory Analysis ............................................................................................................... 18 
6.4.6 
Sensitivity Analysis ................................................................................................................ 19 
6.4.6.1 
Effect of Major Protocol Deviations ............................................................................. 19 
6.4.6.2 
Effect of Medication Discontinuation (On-Treatment Analysis) .................................. 19 
6.4.6.3 
Robustness Checks ....................................................................................................... 19 


 
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6.4.7 
Analysis of Recurrent Events ................................................................................................. 19 
6.5 
Safety Analysis ........................................................................................................................... 20 
6.5.1 
Treatment Exposure .............................................................................................................. 21 
6.5.2 
Adverse Events ...................................................................................................................... 21 
7 
Summary Tables, Figures and Listings ................................................................................................ 22 
8 
Appendix 1.......................................................................................................................................... 26 


 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CABG 
Coronary Artery Bypass Graft 
CEC 
Clinical Endpoint Committee 
CV 
Cardiovascular 
DOV 
Date of Visit 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
GI 
Gastrointestinal 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICH 
International Conference on Harmonisation 
ITT 
Intent-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHICC 
Montreal Health Innovations Coordinating Center 
MI 
Myocardial Infarction 
PCI 
Percutaneous Coronary Intervention 
PM 
Project Manager 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Study Completion 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient Ischemic Attack 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WLW 
Wei, Lin and Weissfeld 
 
 
 


 
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1 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to present the statistical methodology that will be 
used for the final analysis of Montreal Heart Institute protocol MHIPS-003. This plan also provides a 
description of the tables, figures and listings that will be included in the final statistical report. It is based 
on the protocol dated 15NOV2018 and on the annotated case report form version 2.2. In case of 
differences in terms of descriptions or explanations between the SAP and the protocol, the SAP will 
supersede the protocol. 
 
2 
STUDY DESCRIPTION 
 
2.1 
Study Design 
 
This will be a worldwide, randomized, double-blind, placebo-controlled, multi-center, event-driven 
study. Following signature of the informed consent, approximately 4500 subjects meeting all inclusion 
criteria and no exclusion criteria will be randomized to receive either colchicine (0.5 mg/day) or placebo 
(1:1 allocation ratio) for an estimated minimum of 2 years (until the target number of primary endpoint 
event (301) is reached). Follow-up visits or phone assessments will occur at 1, 3 and 6 months following 
randomization, and every 3 months thereafter for evaluation of the occurrence of any trial endpoints or 
other adverse events (AEs). Subjects will also be receiving standard medical care for control of 
dyslipidemia, hypertension, angina and diabetes. All suspected cardiovascular endpoints will be 
adjudicated by a clinical endpoint committee (CEC), consisting of experienced members. A fully 
independent 5-member Data and Safety Monitoring Board (DSMB) will be established and will review 
unblinded data as detailed in the DSMB charter. There will be one formal interim analysis for efficacy 
and futility after approximately 50% of the primary endpoints have been positively adjudicated. The 
DSMB charter will pre-specify the models of interim efficacy analyses and the rules for early trial 
termination, which will be approved by all board members. Detailed information of the interim analysis 
is presented in the DSMB charter dated 05-JAN-2016. 
 
The schedule of visits for this study is outlined in Table 1 of Section 8. However, a subject may be seen at 
any time for safety concerns. The time window between scheduled visits is +/- 2 weeks from the 
anticipated scheduled dates so as to facilitate subject scheduling. Close adherence to the subject visit 
schedule is required in order to respect the estimated minimum 2 years of active treatment as per the 
protocol. 
 
2.2 
Study Objectives 
 
The primary objective of this study is to determine whether long-term treatment with colchicine 
reduces rates of cardiovascular events in subjects after myocardial infarction (MI).  
 
The secondary objective is to determine the safety of long-term treatment with colchicine in this subject 
population.  
 
The tertiary objective is to evaluate links between soluble and genetic biomarkers and treatment 
effects. 
 
 
 


 
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3 
DATASETS ANALYZED 
 
Subjects who were not eligible for randomization but who have been erroneously randomized into the 
study will be excluded from all analysis populations. The MHICC study project manager (PM) will provide 
the list of all erroneously randomized subjects.  
 
The analysis populations will be approved by the principal investigator prior to unblinding. 
 
3.1 
Intent-To-Treat (ITT) Population  
 
The ITT population will consist of all randomized subjects (i.e. subjects having a randomization number 
on the Demographics electronic case report form (eCRF)). In the ITT population, subjects allocated to a 
treatment group by randomization will be followed up, assessed and analyzed as members of that group 
irrespective of their compliance to the planned course of treatment.  
 
3.2 
Safety Population 
 
The safety population refers to the ITT subjects who used at least one dose of study medication. The 
MHICC study PM will provide a log to identify all subjects who never took study medication. 
 
Subjects will be considered as having used at least one dose of study medication if they have at least 
one bottle number collected on the Visit Information eCRF and if they are not listed on the MHICC study 
PM log. 
 
In the safety population, subjects will be presented according to the treatment allocated by 
randomization. However, subjects who used any dose of the treatment opposite to the one assigned by 
randomization, as well as subjects randomized to placebo who used open-label colchicine, will be 
identified and listed.  
 
Subjects who used any dose of the treatment opposite to the one assigned by randomization will be 
identified from the list of bottle treatment allocated. Information on open-label colchicine will be 
available from the Concomitant Medication eCRF. Open-label colchicine will be identified as 
concomitant medications with preferred term coded “colchicine” or “other cardiac preparations” (for 
pericarditis indication).  
 
3.3 
Per Protocol Population 
 
The per-protocol population refers to the ITT subjects excluding subjects with at least one of the 
following major deviations: 
 
 
Never took any dose study medication; 
 
Took study medication for less than 6 months (i.e. subjects for whom duration of treatment 
exposure, as defined Section 6.5.1, is < 182 days, excluding subjects who died while being on 
medication [i.e. for whom # of days between date of last dose and date of death is ≤ 14 days]); 
 
Use of wrong treatment allocation for more than 30 cumulative days as listed in the MHICC 
study PM log; 
 
Use of open-label colchicine for more than 30 cumulative days; 


 
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 
Use of chronic systemic steroids identified as concomitant medications with therapeutic 
subgroup (ATC2) coded “corticosteroids for systemic use”. Systemic steroids should be used 
more than 30 consecutive days to be classified as chronic.  
 
Use of erythromycin identified as concomitant medications with preferred term coded 
“erythromycin”. 
 
Use of clarithromycin identified as concomitant medications with preferred term coded 
“clarithromycin”. 
 
Eligibility criteria (inclusion/exclusion) not met as listed in the MHICC study PM log and 
considered as important by the principal investigator. 
 
The duration of open label colchicine (end date - start date + 1) will be calculated for each use of open-
label colchicine during the clinical study and the cumulative days will be the total of all these durations. 
If the cumulative days are unknown due to missing information, the worst case scenario will be applied 
and the cumulative days will be considered as more than 30 days.  
 
The duration (end date - start date + 1) of each use of systemic steroid during the clinical study will also 
be calculated. If at least one of the durations is more than 30 days, then this systemic steroid will be 
classified as chronic. If at least one of the consecutive days is unknown due to missing information, the 
worst case scenario will be applied and the systemic steroid will be classified as chronic. 
  
4 
EFFICACY ENDPOINTS 
 
All events that are components of the primary, secondary and exploratory efficacy endpoints will be 
adjudicated by an independent CEC and all definitions of the endpoints will be outlined in the CEC 
charter. 
 
4.1 
Primary Efficacy Endpoint 
 
The primary endpoint will be the time from randomization to the first event of cardiovascular (CV) 
death, resuscitated cardiac arrest, acute myocardial infarction (MI), stroke, or urgent hospitalization for 
angina requiring coronary revascularization. 
 
4.2 
Secondary Efficacy Endpoints 
 
The secondary endpoints will consist of time from randomization to the following events: 
 
 
Death (total mortality); 
 
Cardiovascular death; 
 
Resuscitated cardiac arrest; 
 
Acute MI; 
 
Stroke; 
 
Urgent hospitalization for angina requiring coronary revascularization; 
 
The first event of cardiovascular death, resuscitated cardiac arrest, acute MI or stroke. 
 
 
 


 
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4.3 
Exploratory Efficacy Endpoints 
 
Exploratory endpoints will consist of time from randomization to the following events: 
 
 
The first event between deep venous thrombosis or pulmonary embolus ; 
 
Atrial fibrillation;  
 
Heart failure hospitalization; 
 
Coronary revascularization. 
 
4.4 
Biomarker Endpoints 
 
Frozen samples collected at Visit 2, at Visit 5 and Visit 9, and received from participating sites, will be 
kept for future use for evaluation of biomarkers related to cardiovascular disease and the response to 
treatment possibly including, but not limited to lipids, markers of inflammation and markers of oxidative 
stress. 
 
Additional exploratory endpoints will include the changes in these biomarkers from baseline (Visit 2) to 
Visit 5, as well as a cross-sectional comparison at Visit 9 in these biomarkers. Frozen samples will be kept 
at the Beaulieu-Saucier Pharmacogenomics Centre of the Montreal Heart Institute.  
 
4.5 
Laboratory Endpoints (additional endpoints not specified in the protocol) 
 
Values for white blood cells (WBC) and differentials (basophils, eosinophils, lymphocytes, monocytes 
and neutrophils) assessed at Visit 2 (baseline) and at Visit 7 will be retrieved for a sample of subjects. 
These values will come from local labs and will be expressed as absolute counts. If differentials are only 
available as relative values, they will be converted to absolute counts by multiplying the relative value 
by the absolute counts of WBC. In addition, values entered as less than a specified value will be 
considered as the specified value divided by 2 (e.g. entered value <0.2 will be analyzed as 0.1).  
 
Laboratory endpoints will include the changes in these laboratory values from baseline (Visit 2) to Visit 
7, calculated as the difference between the follow-up value and the baseline value. 
 
5 
SAFETY PARAMETERS 
 
Safety in this study will be assessed by the frequency and intensity of clinical AEs. 
 
5.1 
Adverse Events 
 
An adverse event is any unfavorable and unintended sign (including a clinically meaningful abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational product.  
 
Information regarding AEs will be collected from the first dose of study medication (at Visit 2) through 
and including the last visit. Each subject will be observed and queried in a non-specific manner by the 
investigator or study coordinator for any new or continuing AE since the previous visit. Any AEs prior to 
the first dose of study medication will be recorded in the medical history and kept in the subjects’ chart.   
All serious adverse events (SAEs) will be recorded in the appropriate eCRF section. In addition to SAEs, 


 
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the only AEs to be recorded in the eCRF are those that are either related to the gastrointestinal (GI) 
system, that are judged related to the study medication by the investigator or that are laboratory 
abnormalities judged clinically significant by the investigator. Information collected will include the 
onset, duration, severity, relationship to study drug, and the management. SAEs are also to be collected 
if they are known to occur within 30 days following the following the last study visit.   
 
The investigator will review the clinical laboratory test results in a timely fashion when received from 
the laboratory.  Those results qualifying as AEs as defined in section 5.1.3 will be recorded on the AE 
eCRF section.  
 
Treatment-Emergent Adverse Event (TEAE) will be defined as any AE that was not present prior to 
randomization or that worsens in character, intensity or frequency while the subject is in an active 
treatment period. More specifically, TEAE will be defined as any AE with onset date ≥ date of 
randomization. If a partially or completely missing onset date makes the timing of an AE impossible to 
assess, the AE will be assumed to be treatment-emergent.  
 
5.1.1 
Serious Adverse Events 
 
Serious adverse events are those that meet any of the following the international conference on 
harmonisation (ICH) criteria: 
 
 
Is fatal or immediately life-threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Requires or prolongs inpatient hospitalization; 
 
Is a congenital anomaly/birth defect in the offspring of the subject; 
 
Is a cancer; 
 
Is an overdose (intentional or accidental); 
 
Is judged to be medically significant (including laboratory abnormalities). 
 
Medically significant events may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the outcomes listed in the 
definition above.  
 
5.1.1.1 
Serious Adverse Events of Special Interest 
 
Because of the potential effect of colchicine on cancer, new and worsening cancer will be specifically 
investigated. Incidence of cancer and of cancer, excluding skin cancer other than melanoma, will both be 
investigated.  
 
Cancer will be identified using the Adverse Event eCRF as any adverse event falling in the MedDRA 
System Organ Class (SOC) term “Neoplasms benign, malignant and unspecified (incl cysts and polyps)” or 
classified as a serious adverse event under category “Cancer”. Benign tumors falling in a MedDRA High 
Level Group Term (HLGT) containing the word “benign” will be excluded. 
 
Cancer excluding skin cancer other than melanoma will be defined as above, but cancers falling in the 
MedDRA High Level Term (HLT) “Skin neoplasms malignant and unspecified (excl melanoma)” will be 
excluded. 


 
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5.1.2 
Related Adverse Events 
 
A related AE is one where, according to the Investigator, there is a reasonable possibility that the event 
may have been caused by the study drug. 
 
5.1.3 
Gastrointestinal Adverse Events 
 
A GI AE is one that is related to the gastrointestinal system. 
 
5.1.4 
Clinical Laboratory Adverse Events 
 
A clinical laboratory profile, including chemistry and hematology, will be performed during the study as 
outline in Table 1 of Section 8. Laboratory results will not be collected per se on the eCRF in this study 
but abnormalities in laboratory results will be collected as adverse events.  
 
A clinical laboratory abnormality is regarded as an AE if it has been confirmed by at least 1 repeat test 
and suggests a disease and/or organ toxicity severe enough to require active management. 
 
6 
STATISTICAL METHODOLOGY 
 
6.1 
Determination of Sample Size 
 
COLCOT is designed as an event-driven trial with all main analyses conducted on an intention-to-treat 
basis. A sample size of approximately 4500 randomized subjects with 2250 subjects in each treatment 
group or, in terms of events, a total number of 301 positively adjudicated events (i.e. components of the 
primary endpoint), would yield adequate power.   
The sample size calculation is based on the primary endpoint and assumes a 30% risk reduction with 
colchicine, translated by a hazard ratio of 0.700. However, to account for a non-compliance rate of 
approximately 8% in the colchicine group, a more conservative hazard ratio of 0.724 (0.08 x 1 + 0.92 x 
0.7) was used in the calculation (corresponding to a 27% relative risk reduction). Using a two-sided test 
at the 0.05 significance level, the trial would have 80% power if it continues until 301 positively 
adjudicated primary events occur in the combined treatment groups. 
The total number of subjects to randomize, 4500, is chosen so that the expected number of adjudicated 
events after 24 months of follow-up is 301. It assumes an event rate of 7% in the placebo group at 24 
months, an 18-month recruitment period during which subjects are uniformly recruited, a 24-month 
minimum follow-up and a 1% yearly lost to follow-up (and withdrawal of consent) rate. 
The final analysis of the primary endpoint will be conducted at a significance level slightly below the 0.05 
level to account for the interim analysis. However, since this will have a negligible impact on power, the 
sample size calculation was calculated using a significance level of 0.05. 
 
 
 


 
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6.2 
Statistical Considerations 
 
Baseline, efficacy and safety data will be reported using descriptive statistics. N, mean, standard 
deviation, median, Q1, Q3, minimum and maximum will be provided for continuous variables. Count and 
frequency will be provided for categorical variables. 
 
Basic assumptions of the proposed analyses will be verified prior to the analyses. Subject disposition, 
datasets analyzed, baseline characteristics and efficacy analyses will be carried out on the ITT population 
defined in Section 3.1 according to the intent to treat principle. Safety analyses will be done on the 
safety population defined in Section 3.2. To account for the interim analysis, the statistical test for the 
primary efficacy endpoint will be two-sided and conducted at the 0.0490 significance level. All the other 
statistical tests will be two-sided and conducted at the 0.05 significance level. Statistical analyses will be 
done using SAS version 9.4 or higher. 
 
Incomplete date of birth will be imputed for age calculation as described in Section 6.3.4.  
 
6.2.1 
Interim Analysis 
 
An interim analysis was performed in July 2018 after 50% of the primary endpoints had been positively 
adjudicated (i.e. 150 positively adjudicated events). The DSMB charter specified the methods of interim 
analysis and the rules for early trial termination, as approved by all DSMB members. In short, the 
stopping rule for efficacy was based on the Lan-DeMets procedure with the O’Brien-Fleming alpha-
spending function and the stopping rule for futility was based on conditional power. The interim analysis 
(log-rank test on the primary endpoint) was conducted at the 0.0030 significance level and the p-value 
for the final analysis was calculated as 0.0490. The DSMB reviewed the results of the interim analysis 
and recommended that the trial should continue as planned. Therefore, the final analysis will be 
conducted at the 0.0490 significance level.   
 
The interim analysis was performed by the MHICC unblinded study biostatistician not otherwise 
involved in the study. More details about the interim analysis can be found in the DSMB charter dated 
05-JAN-2016.  
 
6.3 
Study Subjects 
 
6.3.1 
Subject Disposition  
 
Number of subjects completing the study, reasons for discontinuation and survival status at the end of 
the study will be summarized overall and by treatment group for the ITT population. A flow chart and a 
listing of subject disposition will also be provided. 
 
The survival status information for subjects who did not complete the study and are not known to be 
dead will be directly obtained from the Survival Status eCRF. As for the other subjects, they will be 
classified as alive if they completed the study or dead if death information is known. 
 
6.3.2 
Protocol Deviations  
 
A listing of major protocol deviations according to the MHICC study PM log will be provided. 


 
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6.3.3 
Datasets Analyzed 
 
The number of subjects in each datasets will be summarized overall and by treatment group. A listing 
will also be provided. 
 
6.3.4 
Demographic and Baseline Characteristics 
 
Demographic data (age at randomization, sex and ethnic origin) and physical appearance at baseline 
(weight, height, body mass index (BMI) and waist circumference) will be summarized by treatment 
group and overall for the ITT population. BMI will be calculated as weight (kg) / [height (cm) * 0.01]2. 
Delays between randomization and index MI, as well as between randomization and percutaneous 
coronary intervention (PCI) associated with index MI if applicable, will be presented similarly. A listing 
will also be provided.  
 
For the age calculation, incomplete date of birth will be imputed as follows: 
 
1. If the day is missing, it will be imputed to 15. 
2. If the day and month are missing, they will be imputed to July 1st. 
3. If the day, month and year are missing, no imputation will be done, the birth date will remain 
missing.  
 
6.3.5 
Medical History 
 
Medical history details of primary interest will be the following ones: smoking (cigarettes/cigars), history 
of diabetes, history of hypertension, history of dyslipidemia (before index MI), prior myocardial 
infarction, prior PCI, prior coronary artery bypass surgery (CABG), prior Stroke/transient ischemic attack 
(TIA), prior heart failure and history of atrial fibrillation. 
 
Number and proportion of subjects with these specific previous histories will be summarized overall and 
broken down by treatment group for the ITT population. Medical history will also be listed. 
 
6.3.6 
Concomitant Medications 
 
The use of concomitant medication from the time of randomization and onwards will be recorded in the 
eCRF (with the exceptions of concomitant medication taken “when necessary” (PRN) or medication 
given for procedures such as coronarography). The concomitant medications will be collected in the 
eCRF and coded with respect to the level 2 Anatomical Therapeutic Chemical (ATC) classification and 
preferred term using the World Health Organization (WHO) drug dictionary (Version SEP2015).  
 
6.3.6.1 
Medication at Randomization 
 
A medication will be flagged as being ongoing at the time of randomization if: 
 
 
Medication start date < randomization date 
AND 
 
(Medication end date ≥ randomization date OR Medication is ongoing) 


 
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In case of missing or incomplete medication start / end dates, the following rules will be applied: 
 
 
If 1) the medication start date is completely missing, or 2) only the year is specified, it is the 
same as the randomization year and randomization did not occur the first day of the year or 3) 
only the month/year are specified, they are the same as the randomization month/year and 
randomization did not occur the first day of the month, then the medication will be assumed to 
have started before randomization. 
 
If 1) the medication end date is completely missing, or 2) only the year is specified and it is the 
same as the randomization year or 3) only the month/year are specified and they are the same 
as the randomization month/year, then the medication will be assumed to have ended after 
randomization 
 
Otherwise, partial medication start / end dates (month/year or year only) will be compared to 
the randomization date and the medication will be classified accordingly. 
 
Frequency of use of medications at randomization will be presented for the subjects of the ITT 
population by therapeutic class and preferred term, overall and for each treatment arm.   
 
6.3.6.2 
Medication at or After Randomization 
 
Frequency of use of medications ongoing at randomization or started after randomization (i.e. all 
concomitant medications recorded on the eCRF) will be presented for the subjects of the ITT population 
by therapeutic class and preferred term, overall and for each treatment arm.   
 
Listing of concomitant medications will also be provided. 
 
6.3.7 
Treatment Compliance  
 
Compliance (yes/no), permanent medication discontinuation and, among subjects who did not 
permanently discontinued, temporary medication interruption and reduction of medication dosage 
since the previous visit, will be directly obtained from the eCRF at all follow-up visits (starting at Visit 5) 
and will be presented using number and proportion, overall and by treatment group.  
 
Compliance (yes/no) at each visit will similarly be summarized, but excluding subjects who never took 
medication and subjects who permanently discontinue medication. 
 
Number and proportion of subjects who permanently discontinued medication during the study 
(excluding subjects who never took medication) will be presented. Among those who did permanently 
discontinue medication, the duration on study medication (date of last dose of study medication – 
randomization date) in months will be presented, overall and by treatment group. The derivation of 
permanent study medication discontinuation is described in Appendix 1, Table 4. 
 
Compliance and discontinuation will be presented for the ITT population. A listing will also be provided. 
 
 
 


 
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6.4 
Efficacy Analysis 
 
All suspected cardiovascular endpoints that are part of the primary, secondary and exploratory efficacy 
endpoints will be adjudicated by a clinical adjudication committee of experienced trialists and the 
statistical analysis will be conducted using positively adjudicated data (based on the CEC chair’s decision 
Section of the Event Information eCRF).  
 
Suspected events (based on the Event Information Section of the Event Information eCRF) as well as 
adjudicated events will be summarized by treatment group and overall for the ITT population. An overall 
cross-table will also be presented for suspected vs. adjudicated events. A listing of all events will be 
provided. 
 
6.4.1 
Primary Analysis 
 
The primary endpoint of the study, time from randomization to the first event of cardiovascular death, 
resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for angina requiring coronary 
revascularization, will be compared between the two treatment groups using a log rank test and Kaplan-
Meier survival curves will be presented.  
 
The hazard ratio from a Cox proportional hazard model will also be provided, along with a 95% 
confidence interval. A multivariate Cox proportional hazard model could also be contemplated to adjust 
for the following important baseline characteristics: 
 
 
Age; 
 
Sex; 
 
BMI; 
 
Delays between randomization and baseline index MI; 
 
Smoking; 
 
History of diabetes; 
 
History of hypertension; 
 
History of dyslipidemia (before Index MI); 
 
Prior MI; 
 
Prior coronary revascularization (prior PCI or prior CABG); 
 
Prior Heart failure. 
 
The results from univariable Cox models with only the baseline characteristic as the dependent variable 
would be carefully reviewed and baseline characteristics that would 1) show an association (p-
value<0.20) with the primary endpoint, 2) not have levels with too few subjects and 3) not show too 
many missing values would be candidate for inclusion in a stepwise multivariable Cox regression model 
in which the treatment group would be forced. Adjusted hazard ratios along with 95% confidence 
intervals would be provided.  
 
Time to event will be calculated as the difference (in months) between the date of the first adjudicated 
event among the components of the primary endpoint and the date of randomization + 1 day. Death of 
undetermined cause will be classified as CV death for analysis purposes. Subjects with none of the 
events included in the primary endpoint will be censored and time to censoring will be computed as the 
difference (in months) between the last date subject was known to be event free (based on the Study 


 
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Completion eCRF) and the date of randomization + 1 day. The algorithm used to derive the censoring 
dates is described in Appendix 1, Table 2. 
 
The primary analysis will be conducted on the ITT population and the significance level for the 
comparison between treatment groups will be set to 0.0490.  
 
6.4.2 
Secondary Analysis 
 
The secondary endpoints are expressed as time from randomization to event. They will be compared 
between the two treatment groups using a log rank test and Kaplan-Meier survival curves will be 
presented. The hazard ratio from a Cox proportional hazard model will also be provided, along with a 
95% confidence interval. 
 
The secondary analyses will be conducted on the ITT population.  
 
6.4.3 
Exploratory Analysis 
 
The exploratory endpoints are expressed as time from randomization to event and will be compared 
across treatment groups using the same methodology as described in Section 6.4.2. 
 
The exploratory analyses will be conducted on the ITT population.  
 
6.4.4 
Biomarker Analysis 
 
Blood samples for biomarkers will be collected at Visit 2 (baseline) and at Visit 5 in subjects agreeing to 
participate in the optional biomarkers sub-study. An additional blood samples for biomarkers will also 
be performed at Visit 9 in subjects agreeing to participate in this additional blood draw. 
The exact biomarkers to be collected are yet to be determined but they will be analyzed as described 
below. Because many biomarkers are known to have a skewed distribution (ex. hs-CRP), a log-
transformation is likely to be used prior to the analysis. 
The changes from baseline to Visit 5 will be analyzed using an analysis of covariance (ANCOVA) model 
adjusting for baseline value and estimates of treatment effect will be presented with 95% confidence 
intervals. The biomarkers at Visit 9 will be analyzed using an analysis of variance (ANOVA) model and 
estimates of treatment effect will be presented with 95% confidence intervals. 
The biomarker analyses will be conducted on the ITT subjects with available biomarker data. These 
analyses will be produced once the biomarker data will be available. 
 
6.4.5 
Laboratory Analysis 
 
Values for WBC and differentials at Visit 2 (baseline) and at Visit 7 will be retrieved for a sample of 
subjects.  
The change from baseline to Visit 7 will be analyzed using an ANCOVA model adjusting for the baseline 
value. Estimates of treatment effect will be presented with 95% confidence intervals. The ANCOVA 
model will be stratified by study site if the number of subjects per study site is large enough to account 


 
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for the fact that the laboratory data will come from local labs. According to the distribution of the 
laboratory parameters, a log-transformation might be used prior to the analysis.  
The laboratory analyses will be conducted on the ITT subjects with available laboratory data.  
 
6.4.6 
Sensitivity Analysis 
 
6.4.6.1 
Effect of Major Protocol Deviations 
 
To assess the impact of major protocol deviations, the analysis of the primary endpoint described in 
Section 6.4.1 will be repeated on the PP population. 
 
6.4.6.2 
Effect of Medication Discontinuation (On-Treatment Analysis) 
 
To assess the impact of medication discontinuation, the analysis of the primary endpoint described in 
Section 6.4.1 will be repeated but follow-up time will end at the date of their last dose. In other words, 
any primary events occurring after the date of last dose will not be included in the analysis and subjects 
will be censored at the date of last dose if they are event free. 
 
6.4.6.3 
Robustness Checks 
 
The Cox proportional hazards model that is presented in Section 6.4.1 assumes proportional hazards. To 
verify this assumption, the assessment of proportional hazard for the primary endpoint will be done by a 
visual inspection of the plot of log(-log(estimated Survival distribution function)) versus log time and 
through a formal test of the interaction between logarithm of the time variable and group at the 0.05 
significance level.  
 
6.4.7 
Analysis of Recurrent Events 
 
The primary analysis in Section 6.4.1 is based on time to first event among the components of the 
primary endpoint but three other analyses will be done to account for multiple events within subjects. In 
other words, these other analyses will make use of all events, including the ones that occur after the 
first. In cases of multiple events occurring the same day, the order of occurrence will be confirmed by 
the Medical Reviewer and coded accordingly for the statistical analysis. 
 
The cardiovascular events that will be considered for these analyses are the components of the primary 
endpoint, namely:  
 
 
Cardiovascular death; 
 
Resuscitated cardiac arrest (non-fatal); 
 
Acute MI (non-fatal); 
 
Stroke (non-fatal); 
 
Urgent hospitalization for angina requiring coronary revascularization (non-fatal). 
 
The first approach will be based on the Wei, Lin and Weissfeld (WLW) marginal model [1]. The idea 
behind this approach is to model the time from randomization to first, second and subsequent event 
with a Cox proportional hazards model and use a covariance matrix estimate for the regression 


 
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coefficients that accounts for the possible intra-subject correlation. The WLW approach can be applied 
when the events are of different nature and also in presence of death. In this approach, each subject is 
considered to be at risk for all events, regardless of how many events each subject actually experienced. 
This preserves the randomization and permits valid treatment effect estimation [2]. 
 
The sequence of events (CV death, non-fatal event or censoring) will be defined as in scenario II of [3].  A 
subject who died of a non-CV cause will be censored at the time of death. Namely, the kth event of a 
subject (k=1, 2, …, K) will be defined as the kth occurrence of a non-fatal event or CV death, whichever 
comes first. In this scenario, if a subject dies from a CV death before experiencing a non-fatal event, CV 
death will be counted K times in the combined statistic (estimated treatment effect size considered as 
weighted towards CV death). The number of events per subject that will be used in the analysis, K, will 
be set according to the number of events observed in the trial. The rule that will be considered is to 
choose K  so that the expected number of subjects with K events is at least 5 [3]. To avoid any bias, K will 
be chosen prior to unblinding. 
 
Marginal hazard ratios for a kth occurrence of a non-fatal event or CV death will be provided, along with 
a 95% confidence interval, and tested. A weighted average of these hazard ratios will also be provided, 
along with a 95% confidence interval, and tested in order to examine the global treatment effect across 
the K events.  
 
For illustrative purposes, number of subjects experiencing no event, 1 event, 2 events, etc. among the 
ones above will also be presented.  
 
The second approach will be based on the Andersen and Gill (AG) model [4] with a robust variance 
estimator (sandwich estimator) [5, 6] to account for the dependency of within-subject events.  This 
method is based on a gap-time approach considering the time since a previous event.  Hazard ratio will 
be provided, along with a 95% confidence interval, and tested. 
 
The first and second approaches are based on Cox proportional hazards models for time to event but a 
third approach will be done based on Poisson-type regressions for count data, i.e. the negative binomial 
regression model [7].  Number of events per subject will be used as the outcome and the length of 
follow-up time in months per subject will be used as an offset term in the model.  For illustrative 
purposes, the crude event rate per 100 subjects-months by treatment group will be calculated by 
dividing the total number of events by the total number of follow-up months in each group and then 
multiplying by 100.  The Negative Binomial model assumes that each subject’s events follow an 
individual-specific Poisson rate, and that these rates vary according to a Gamma distribution.  Marginal 
rate ratio will be provided, along with a 95% confidence interval, and tested. 
 
These analyses will be conducted on the ITT population.  
 
6.5 
Safety Analysis 
 
The safety analyses described in this section will be conducted on the safety population. No formal 
statistical testing is planned for the safety parameters. 
 
 
 


 
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6.5.1 
Treatment Exposure 
 
Duration of treatment exposure will be defined as number of months on treatment (computed as date 
of last dose – date of first study drug dispensed + 1). Duration of treatment exposure will be 
summarized by treatment group using descriptive statistics. Duration of treatment exposure will also be 
categorized according to 3-month intervals (≤ 1, ]1-3], ]3-6], ]6-9], etc.) and summarized accordingly 
using frequencies and percentages, by treatment group. The imputation rules applied to incomplete 
and/or missing date of last dose are described in Appendix 1, Table 3.  
 
Listing of treatment exposure will also be provided. 
 
6.5.2 
Adverse Events 
 
Adverse events will be coded by system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary (Version 18.1). 
 
Number and proportion of subjects experiencing at least one treatment-emergent AE, at least one 
severe treatment-emergent AE, at least one treatment-emergent AE leading to study drug dosage 
reduced, at least one treatment-emergent AE leading to study drug temporarily interrupted, at least one 
treatment-emergent AE leading to study drug permanently stopped and at least one treatment-
emergent AE leading to randomization code broken will be presented. In addition, number and 
proportion of subjects experiencing a treatment-emergent AE will be presented by system organ class, 
preferred term and severity for each treatment group for the safety population. In case of missing 
severity, the worst severity will be imputed. 
 
Because adverse events are either categorized as SAE, SAE of special interest, AE related to study drug, 
GI AE or laboratory abnormality in this study, the presentation described above will be done for each 
category of AE.  
 
Adverse events will also be listed. 


 
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7 
SUMMARY TABLES, FIGURES AND LISTINGS 
 
1 Study Subject 
1.1 Subject Disposition 
Table 1.1.1 
Subject Disposition, ITT Population 
Table 1.1.2 
Datasets Analyzed, ITT Population 
 
1.2 Demographic and Baseline Characteristics 
Table 1.2.1 
Summary of Demographics, ITT Population 
Table 1.2.2 
Summary of Physical Appearance, ITT Population 
Table 1.2.3 
Summary of Delays for Index MI and PCI, ITT Population 
 
1.3 Medical History 
Table 1.3.1 
Summary of Medical History, ITT Population 
 
1.4 Concomitant Medications 
Table 1.4.1 
Summary of Medications at Randomization, ITT Population 
Table 1.4.2 
Summary of Medications at or After Randomization, ITT Population 
 
1.5 Treatment Compliance 
Table 1.5.1 
Summary of Treatment Compliance, ITT Population 
Table 1.5.2 
Summary of Treatment Compliance Excluding Subjects who Never Took Medication 
and Subjects who Permanently Discontinued Medication, ITT Population 
Table 1.5.3 
Summary of Study Medication Discontinuation Excluding Subjects who Never Took 
Medication, ITT Population 
 
2 Efficacy Analysis 
2.1 Endpoint Events 
Table 2.1.1 
Summary of Suspected and Adjudicated Events, ITT Population 
Table 2.1.2 
Concordance of Suspected and Adjudicated Events, ITT Population 
 
2.2 Primary Analysis 
Table 2.2.1 
Summary of and Statistical Analysis of Time to First Positively Adjudicated Event of 
Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI, Stroke or Urgent 
Hospitalization for Angina Requiring Coronary Revascularization, ITT Population 
 
2.3 Secondary Analysis 
Table 2.3.1 
Summary of and Statistical Analysis of Time to Positively Adjudicated Death, ITT 
Population 
Table 2.3.2 
Summary of and Statistical Analysis of Time to Positively Adjudicated Cardiovascular 
Death, ITT Population 
Table 2.3.3 
Summary of and Statistical Analysis of Time to Positively Adjudicated Resuscitated 
Cardiac Arrest, ITT Population 
Table 2.3.4 
Summary of and Statistical Analysis of Time to Positively Adjudicated Acute MI, ITT 
Population 
 
 


 
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Table 2.3.5 
Summary of and Statistical Analysis of Time to Positively Adjudicated Stroke, ITT 
Population 
Table 2.3.6 
Summary of and Statistical Analysis of Time to Positively Adjudicated Urgent 
Hospitalization for Angina Requiring Coronary Revascularization, ITT Population 
Table 2.3.7 
Summary of and Statistical Analysis of Time to First Positively Adjudicated Event of 
Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI or Stroke, ITT 
Population 
 
2.4 Exploratory Analysis 
Table 2.4.1 
Summary of and Statistical Analysis of Time to First Positively Adjudicated Event of 
Deep Venous Thrombosis or Pulmonary Embolus, ITT Population 
Table 2.4.2 
Summary of and Statistical Analysis of Time to Positively Adjudicated Atrial 
Fibrillation, ITT Population 
Table 2.4.3 
Summary of and Statistical Analysis of Time to Positively Adjudicated Heart Failure 
Hospitalization, ITT Population 
Table 2.4.4 
Summary of and Statistical Analysis of Time to Positively Adjudicated Coronary 
Revascularization, ITT Population 
 
2.5 Biomarker Analysis 
Table 2.5.1 
Summary of and Statistical Analysis for Change in Biomarker 1, ITT Population 
Table 2.5.2 
Summary of and Statistical Analysis for Biomarker 1 at Visit 9, ITT Population 
Each biomarker will be presented in separate tables similarly as tables 2.5.1 and 2.5.2. 
 
2.6 Laboratory Analysis 
Table 2.6.1 
Summary of and Statistical Analysis for Change in WBC (103/L), ITT Population 
Table 2.6.2 
Summary of and Statistical Analysis for Change in Basophils (103/L), ITT Population 
Table 2.6.3 
Summary of and Statistical Analysis for Change in Eosinophils (103/L), ITT 
Population 
Table 2.6.4 
Summary of and Statistical Analysis for Change in Lymphocytes (103/L), ITT 
Population 
Table 2.6.5 
Summary of and Statistical Analysis for Change in Monocytes (103/L), ITT 
Population 
Table 2.6.6 
Summary of and Statistical Analysis for Change in Neutrophils (103/L), ITT 
Population 
 
2.7 Sensitivity Analysis 
Table 2.7.1 
Summary of and Statistical Analysis of Time to First Positively Adjudicated Event of 
Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI, Stroke or Urgent 
Hospitalization for Angina Requiring Coronary Revascularization, PP Population 
Table 2.7.2 
Summary of and Statistical Analysis of Time to First Positively Adjudicated Event of 
Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI, Stroke or Urgent 
Hospitalization for Angina Requiring Coronary Revascularization, ON-TREATMENT 
ANALYSIS, ITT Population 
 
 


 
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2.8 Analysis of Recurrent Events 
Table 2.8.1 
Summary of and Statistical Analysis of Recurrent Primary Endpoint, ITT Population 
 
3 Safety analysis 
3.1 Treatment Exposure 
Table 3.1.1 
Summary of Treatment Exposure, Safety Population 
 
3.2 Adverse Events  
Table.3.2.1 
Overall Summary of Treatment Emergent SAEs, Safety Population 
Table 3.2.2 
Summary of Treatment Emergent SAEs by Preferred Term, System Organ Class and 
Severity, Safety Population 
Table.3.2.3 
Overall Summary of Treatment Emergent SAEs of New or Worsening Cancer, Safety 
Population 
Table 3.2.4 
Summary of Treatment Emergent SAEs of New or Worsening Cancer by Preferred 
Term, System Organ Class and Severity, Safety Population 
Table.3.2.5 
Overall Summary of Treatment Emergent SAEs of New or Worsening Cancer, 
Excluding Skin Cancer Other than Melanoma, Safety Population 
Table 3.2.6 
Summary of Treatment Emergent SAEs of New or Worsening Cancer, Excluding Skin 
Cancer Other than Melanoma, by Preferred Term, System Organ Class and Severity, 
Safety Population 
Table.3.2.7 
Overall Summary of Treatment Emergent AEs Related to Study Drug, Safety 
Population 
Table 3.2.8 
Summary of Treatment Emergent AEs Related to Study Drug by Preferred Term, 
System Organ Class and Severity, Safety Population 
Table.3.2.9 
Overall Summary of Treatment Emergent Gastrointestinal AEs, Safety Population 
Table 3.2.10 
Summary of Treatment Emergent Gastrointestinal AEs by Preferred Term, System 
Organ Class and Severity, Safety Population 
Table.3.2.11 
Overall Summary of Treatment Emergent Laboratory Abnormality, Safety 
Population 
Table 3.2.12 
Summary of Treatment Emergent Laboratory Abnormality by Preferred Term, 
System Organ Class and Severity, Safety Population 
 
Figures 
Figure 1 
Subject Disposition, ITT Population (Flow Chart) 
Figure 2 
Kaplan-Meier Survival Curves for Time to First Positively Adjudicated Event of 
Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI, Stroke or Urgent 
Hospitalization for Angina Requiring Coronary Revascularization, ITT Population 
Figure 3 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Death, ITT 
Population 
Figure 4 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Cardiovascular 
Death, ITT Population 
Figure 5 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Resuscitated 
Cardiac Arrest, ITT Population 
Figure 6 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Acute MI, ITT 
Population 


 
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Figure 7 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Stroke, ITT 
Population 
Figure 8 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Urgent 
Hospitalization for Angina Requiring Coronary Revascularization, ITT Population 
Figure 9 
Kaplan-Meier Survival Curves for Time to First Positively Adjudicated Event of 
Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI or Stroke, ITT 
Population 
Figure 10 
Kaplan-Meier Survival Curves for Time to First Positively Adjudicated Event of Deep 
Venous Thrombosis or Pulmonary Embolus, ITT Population 
Figure 11 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Atrial Fibrillation, 
ITT Population 
Figure 12 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Heart Failure 
Hospitalization, ITT Population 
Figure 13 
Kaplan-Meier Survival Curves for Time to Positively Adjudicated Coronary 
Revascularization, ITT Population 
Figure 14 
Log-Negative Log of Estimated Survival Distribution Function of Primary Endpoint 
Versus Log Time, ITT Population, ITT Population 
 
Listings 
Listing 1 
Site Identification 
Listing 2 
Subject Disposition 
Listing 3 
Survival Status at End of Study 
Listing 4 
Protocol Deviations 
Listing 5 
Datasets Analyzed 
Listing 6 
Subjects who Used Treatment Opposite to Treatment Allocated by Randomization 
Listing 7 
Demographic and Baseline Characteristic 
Listing 8 
Medical History 
Listing 9 
Concomitant Medications 
Listing 10 
Study Compliance 
Listing 11 
Suspected and Adjudicated Events 
Listing 12 
Treatment Exposure 
Listing 13 
Endpoint Adverse Events 
Listing 14 
Serious Adverse Events 
Listing 15 
Adverse Events Related to Study Drug as per PI Judgement 
Listing 16 
GI Adverse Events 
Listing 17 
Laboratory Abnormalities  


 
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8 
APPENDIX 1 
 
Table 1 Timetable of Visits and Procedures 
               (Note: All visits are to be ± 2 weeks from anticipated timepoint) 
 
Visits 
1  
Screening 
Visit 
2a               
Randomization/ 
Baseline 
3 
Visit  
4     
Phone 
contact 
5, 7, 9… 
Visit 
6, 8, 10… 
Phone 
contact 
End 
of 
Study 
Months 
 
0 
1 
3 
6, 12, 18… 
9, 15, 21… 
 
Informed consent 
X 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
Phone contact 
 
 
 
X 
 
X 
 
Review Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Urine pregnancy test (only women 
of childbearing potential) 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Waist circumference, height, and 
weight measurements 
 
X 
 
 
 
 
 
Review parameters for routine 
chemistry and hematology (local, 
once per year) 
 
X  
X b 
 
X 
 
X 
Blood 
draw 
for 
biomarkers 
(optional) 
 
X 
 
 
X (V5 and 
V9)c 
 
 
Blood draw for 
pharmacogenomics evaluation 
(optional)  
 
X d 
 
 
 
 
X e 
Record potential study endpoints 
and other AEs  
 
X 
X 
X 
X 
X 
X 
Review concomitant meds  
X 
X 
X 
X  
X 
X  
X 
Study medication dispensing 
 
X f 
X 
 
X 
 
 
Study medication return 
 
 
X g 
 
X 
 
X 
 
a) Screening Visit and Visit 2 may be performed on the same day; under these circumstances, procedures to be performed at both Screening 
Visit and Visit 2 will be performed once. 
b) At V3, mandatory chemistry parameters will be evaluated locally: ALT, AST, GGT, total bilirubin, alkaline phosphatase, serum creatinine and 
uric acid. 
c) Biomarkers collection will occur at Randomization visit and at visit 5. The additional biomarkers collection can be offered only to subjects that 
have yet to perform Visit 9 at the time of implementation of the sub-study at the site.  
d) Blood draw for pharmacogenomics evaluation can be collected at the next in-person visit if randomization visit has already occurred at the 
time of the implementation of the sub-study at the site.  
e) Blood draw for pharmacogenomics evaluation at the End of Study visit will only be collected for subjects who provided a baseline sample at 
least 12 months prior to the End of Study visit. 
f) It is recommended that the subject takes his/her first dose on site during the visit. 
g) Subject should bring back their 1st bottle of medication for a compliance check, but should return home with the same opened bottle (and 2nd 
unopened bottle assigned at V3). 
 
 
 


 
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Table 2 Algorithm to derive end of study dates 
 
Calculation of time to event requires the definition of an end of study date. This date is to be used as a 
censoring date in event free subjects, i.e. as the date they were last known to be event free. It is to be 
noted that this date is to be defined differently for mortality and for other types of event.  
 
The end date will be calculated using the following dates in the eCRF forms: 
 
a) Date of study completion [SC Form, Date of completion where study completion = Yes] 
b) Date of death [SC Form, Date of death] 
c) Date of EOS visit [DOVEOS Form, Date of visit] 
d) Date of last contact [SC Form, Date of last contact where study completion = No] 
e) Date survival status [Survival Status Form, Last date patient known to be alive] 
f) Date survival status [Survival Status Form, Date of death] 
 
For the endpoints of death (total mortality) and CV death, the end of study date will be defined as 
follows: 
 
End of study date 
In patients who completed the study as per the SC Form 
Max [(a), (c)] 
In patients who didn’t complete the study and are dead as per the SC Form 
(b) 
In patients who didn’t complete the study and are not dead as per the SC Form 
Max [(c), (d), (e), (f)] 
 
For all other endpoints, including composite endpoints that include CV death as a component, the end 
of study date will be defined as follows: 
 
End of study date 
In patients who completed the study as per the SC Form 
Max [(a), (c)] 
In patients who didn’t complete the study and are dead as per the SC Form 
(b) 
In patients who didn’t complete the study and are not dead as per the SC Form 
Max [(c), (d)] 
 
Note: If the adjudicated date of death is different than the date of death reported on the SC Form, the 
adjudicated date of death is to be used. 
 
 


 
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Table 3 Imputation rules for incomplete and/or missing date of last dose [SC Form, Date of last dose of 
study medication] 
 
It is to be noted that imputation for incomplete and/or missing date of last dose is to be done in subjects 
of the safety population, i.e. in subjects who took at least one dose of study medication. Subjects were 
asked about study medication discontinuation starting from Visit 5.   
 
Step #1: Derive a temporary date of last dose for incomplete and/or missing date as follows: 
 
 
If only day is missing, replace missing day by last day of the month 
 
If both day and month are missing, replace missing day/month by 31DEC 
 
If date is completely missing, replace by the date of the visit at which the subject reports 
“permanent discontinuation since last visit” if available 
 
Step #2: Generate the imputed date of last dose using the following dates: 
 
a) Temporary date of last dose derived at step #1 
b) Date of the visit at which the subject reports “permanent discontinuation since last visit” 
[DOV/DOVEOS Form, Date of visit and Compliance Form, Was the study medication 
permanently discontinued since the last visit at the site?] 
c) Date of death [SC Form, Date of death] 
d) Date of last contact [SC Form, Date of last contact where study completion = No] 
e) Date of study completion [SC Form, Date of completion where study completion = Yes] 
 
and the following imputation rules: 
 
 
Imputed date of last dose 
If temporary date of last dose > date of death 
(c) 
If temporary date of last dose is completely missing 
Max [(c), (d), (e)] 
Otherwise 
Min [(a), (b), (c), (d), (e)] 
 
Note: If the adjudicated date of death is different than the date of death reported on the SC Form, the 
adjudicated date of death is to be used. 
 
 
 


 
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Table 4 Derivation of permanent study medication discontinuation  
 
It is to be noted that permanent study drug medication discontinuation is to be assessed in subjects of 
the safety population, i.e. in subjects who took at least one dose of study medication. Subjects were 
asked about study medication discontinuation starting from Visit 5.   
 
Permanent study medication discontinuation will be derived as follows: 
 
 
For subjects who completed a visit 5 or more, or in whom an EOS visit was done. 
 
Subjects who permanently discontinued study medication will be identified through the Compliance 
Form, using the question “Was the study medication permanently discontinued since the last visit at 
the site?”.  
 
 
For subjects who discontinued the study prior to Visit 5 and in whom no EOS visit was done.  
 
Since the response to the question on permanent study medication discontinuation will be 
unavailable, derivation of permanent study medication discontinuation will be as follows: 
 
 
Imputed 
permanent study 
medication 
discontinuation 
Patient is alive as per the SC Form 
# of days between date of last dose and date of last 
contact / study discontinuation ≤ 3 days 
No 
# of days between date of last dose and date of last 
contact / study discontinuation > 3 days 
Yes 
Patient is dead as per the SC Form 
# of days between date of last dose and date of death ≤ 
14 days 
No 
# of days between date of last dose and date of death > 
14 days 
Yes 
 
Note: If the adjudicated date of death is different than the date of death reported on the SC Form, the 
adjudicated date of death is to be used. 
 
 
 


 
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Protocol number: MHIPS-003 
 
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Page 30 of 30 
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