Clinical trial NCT04322682
Conditions: Corona Virus Infection
Sponsor: Montreal Heart Institute
Start date: 2020-03-23; Completion date: 2021-01-21
Enrollment: 4506 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3, randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of colchicine in adult patients diagnosed with COVID-19 infection and have at least one high-risk criterion. Approximately 6000 subjects meeting all inclusion and no exclusion criteria will be randomized to receive either colchicine or placebo tablets for 30 days.

Detailed description:
The primary objective of this study is to determine whether short-term treatment with colchicine reduces the rate of death and lung complications related to COVID-19. The secondary objective is to determine the safety of treatment with colchicine in this patient population.

Approximately 6000 patients will be enrolled to receive either colchicine or placebo (1:1 allocation ratio) for 30 days. Follow-up assessments will occur at 15 and 30 days following randomization for evaluation of the occurrence of any trial endpoints or other adverse events.

Safety and efficacy will be based on data from randomized patients. An independent data and safety monitoring board (DSMB) will periodically review study results as well as the overall conduct of the study, and will make recommendations to the study Executive Steering Committee (ESC) to continue, stop or modify the study protocol.

Arms: arm 1: Patients will receive study medication colchicine 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced. arm 2: Patients will receive a placebo per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced.
Interventions: intervention 1: Colchicine intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Patients in this arm will receive study medication colchicine 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced. intervention 2: Patients will receive the placebo 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced.

Protocol documents:
Prot_000.pdf: 
 
 
Protocol #: MHIPS‐2020‐001 
COLCHICINE CORONAVIRUS SARS‐CoV2 TRIAL (COLCORONA) 
NCT #: NCT04322682 
 
 
Protocol Amendment 
Version 29‐May‐2020 


MHICC 
PROTOCOL MHIPS-2020-001 
May 29th, 2020  
 
 
CLINICAL RESEARCH PROTOCOL 
 
 
Protocol # MHIPS-2020-001  
 
COLCHICINE CORONAVIRUS SARS-CoV2 TRIAL (COLCORONA)  
 
 
 
 
 
May 29th, 2020 
 
 
 
 
 
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 
TIME PERIOD AND NUMBER OF PATIENTS: ............................................................ 10 
1 
INTRODUCTION .................................................................................................................... 11 
1.1 
Background ................................................................................................................................... 11 
1.2 
Background on colchicine ................................................................................................. 12 
1.3 
Colchicine Dosage ................................................................................................................... 13 
2 
STUDY OBJECTIVES ........................................................................................................... 13 
3 
STUDY DESIGN ...................................................................................................................... 13 
3.1 
Study Schedule .......................................................................................................................... 14 
3.2 
Enrollment ..................................................................................................................................... 14 
3.3 
Screening Evaluations and Randomization ......................................................... 14 
3.4 
Active Treatment Period .................................................................................................... 15 
Table 1 Timetable of Visits and Requirements .................................................. 16 
4 
STUDY POPULATION ........................................................................................................ 17 
4.1 
Source and Number of Patients ................................................................................... 17 
4.2 
Patient Selection Criteria .................................................................................................. 17 
4.2.1 Inclusion Criteria: ................................................................................................................................. 17 
4.2.2 Exclusion Criteria: ................................................................................................................................ 17 
4.3 
Prohibited, Allowable and Concurrent Medications ..................................... 18 
5 
STUDY METHODOLOGY ................................................................................................... 19 
5.1 
Efficacy Outcomes ................................................................................................................... 19 
5.2 
Safety Monitoring .................................................................................................................... 19 
5.2.1 Adverse Event Reporting................................................................................................................. 19 
5.2.2 Other Safety Monitoring .................................................................................................................. 21 
5.3 
Withdrawal of Patients from the Study ................................................................. 22 
5.4 
Study Completion..................................................................................................................... 22 
6 
STUDY MEDICATION......................................................................................................... 22 
6.1 
Medication Dispensing ......................................................................................................... 22 
6.2 
Dosage Regimen ....................................................................................................................... 23 
7 
DATA COLLECTION ............................................................................................................. 23 
8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ...................... 23 
8.1 
Statistical Power and Sample Size Considerations ....................................... 23 
8.2 
Analysis population ................................................................................................................ 23 
8.2.1 Intent to Treat (ITT) population ................................................................................................ 23 
8.2.2 Safety population .................................................................................................................................. 23 
8.3 
Data analysis ............................................................................................................................... 24 


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8.3.1 Analysis of efficacy outcomes ..................................................................................................... 24 
8.3.2 Analysis of safety outcomes ......................................................................................................... 24 
8.3.3 Interim analysis ...................................................................................................................................... 24 
9 
STUDY COORDINATION ................................................................................................. 25 
REFERENCES .................................................................................................................................... 26 
LIST OF APPENDICES ............................................................................................................... 29 
Appendix A  Detailed Study Safety Parameters ................................................. 30 
Appendix B  PMS-Colchicine 0.6mg Product Monograph ............................ 31 
Appendix C  Administrative Procedures for the Reporting of Adverse 
Events 
 ..................................................................................................................................... 42 
1 
ADVERSE EVENTS DURING THE TRIAL .............................................................. 42 
1.1 
Pre-existing condition .......................................................................................................... 42 
1.2 
Adverse Event (AE) ................................................................................................................ 42 
1.3 
Related Adverse Event ......................................................................................................... 42 
1.4 
Serious Adverse Event (SAE) ......................................................................................... 43 
1.5 
Life-Threatening Adverse Event .................................................................................. 43 
1.6 
Unexpected Adverse Event .............................................................................................. 43 
1.7 
Clinical Laboratory Adverse Event ............................................................................. 44 
1.8 
Treatment-Emergent Signs and Symptoms (TESS) ..................................... 44 
1.9 
Post-treatment Adverse Event ...................................................................................... 44 
2 
HANDLING OF ADVERSE EVENTS ........................................................................... 44 
2.1 
Treatment-Emergent Signs and Symptoms ........................................................ 44 
2.2 
Serious Adverse Events ...................................................................................................... 44 
2.3 
Intensity.......................................................................................................................................... 44 
2.4 
Relationship to Study Drug – Physician’s Assessment .............................. 44 
2.5 
Clinical Outcome ....................................................................................................................... 45 
3 
CAPTURING AVDERSE EVENTS ................................................................................. 45 
3.1 
Pre-Existing Condition ......................................................................................................... 45 
3.2 
Lack of Efficacy of Study Medication ........................................................................ 45 
3.3 
Clinical Laboratory Adverse Event ............................................................................. 45 
3.4 
Hospitalization or Surgery/Procedure.................................................................... 45 
3.5 
Death ................................................................................................................................................. 46 
4 
REPORTING TO THE SPONSOR ................................................................................. 46 
4.1 
Immediately Reportable Adverse Events ............................................................. 46 
4.2 
Other Adverse Events ........................................................................................................... 46 
4.3 
Follow-Up Period ...................................................................................................................... 46 
Appendix D  Other Administrative and Regulatory Procedures ............ 47 
Appendix E  Declaration of Helsinki ............................................................................ 52 
 


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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 
SYNOPSIS 
TITLE:  COLCHICINE CORONAVIRUS SARS-CoV2 TRIAL (COLCORONA) 
INDICATION:  Reduction of complications in patients with COVID-19 infection. 
OBJECTIVES:  The primary objective of this study is to determine whether short-term 
treatment with colchicine reduces the rate of death and lung complications related to COVID-19. 
The secondary objective is to determine the safety of treatment with colchicine in this patient 
population. The exploratory objective is to evaluate links between soluble and genetic 
biomarkers and treatment effects.  
 
PATIENT POPULATION:  Males and females, at least 40 years of age, who have been 
diagnosed with a COVID-19 infection and have at least one high-risk criterion. 
Inclusion Criteria: 
 Males and females, at least 40 years of age, capable and willing to provide informed 
consent; 
 Patient must have received a diagnosis of COVID-19 infection within the last 24 hours; 
 Outpatient setting (not currently hospitalized or under immediate consideration for 
hospitalization); 
 Patient must possess at least one of the following high-risk criteria: 70 years or more of 
age, obesity (BMI ≥ 30 kg/m2), diabetes mellitus, uncontrolled hypertension (systolic 
blood pressure ≥150 mm Hg), known respiratory disease (including asthma or chronic 
obstructive pulmonary disease), known heart failure, known coronary disease, fever of 
≥38.4°C within the last 48 hours, dyspnea at the time of presentation, bicytopenia, 
pancytopenia, or the combination of high neutrophil count and low lymphocyte count; 
 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 must be able and willing to comply with the requirements of this study protocol. 
 
Exclusion Criteria: 
 Patient currently hospitalized or under immediate consideration for hospitalization; 
 Patient currently in shock or with hemodynamic instability; 


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 Patient with inflammatory bowel disease (Crohn’s disease or ulcerative colitis), chronic 
diarrhea or malabsorption; 
 Patient with pre-existent progressive neuromuscular disease; 
 Estimated Glomerular filtration rate (eGFR) using the MDRD equation for all subjects 
being considered for enrollment, with a cut-off of < 30 mL/m in/1.73m2. 
 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 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 undergoing chemotherapy for cancer; 
 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 study. Following signature of the informed consent form, approximately 6000 
subjects meeting all inclusion and no exclusion criteria will be randomized to receive either 
colchicine or placebo (1:1 allocation ratio) for 30 days. Follow-up phone or video assessments 
will occur at 15 and 30 days following randomization for evaluation of the occurrence of any 
trial endpoints or other adverse events.   
 
OUTCOMES:  The primary endpoint will be the composite of death or the need for 
hospitalization due to COVID-19 infection in the 30 days following randomization. The 
secondary endpoints will consist of the components of the composite primary endpoint; and the 
need for mechanical ventilation in the 30 days following randomization. Exploratory endpoints 
will include associations between both biomarkers and viral load (stored samples) and treatment 
effects.   
 
STATISTICAL RATIONALE AND ANALYSIS: All main analyses in COLCORONA will 
be conducted on an intention-to-treat basis. A sample size of approximately 6000 randomized 
patients with 3000 patients in each treatment group will be required to detect a 25% risk 
reduction with colchicine with a power of 80% given a primary endpoint event rate of 7% in the 
placebo group and a two-sided test at the 0.05 significance level.  
A fully independent 6-member Data and Safety Monitoring Board (DSMB) will be established 
and will review unblinded safety data as detailed in the DSMB charter. An interim analysis is 
planned after approximately 50% of randomized patients have completed 30 days of follow-up. 


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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 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. Futility will be assessed by computing 
conditional power. 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 chi-square test. Secondary 
endpoints will be analyzed similarly.  
ANTICIPATED TOTAL NUMBER OF RANDOMIZED PATIENTS:  Approximately 6000 
patients in total will be randomized in this study.  
 
PHASE:  3 
 
STUDY LOCATION:  Worldwide   


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GLOSSARY  
 
ACE  
- 
Angiotensin Converting Enzyme 
ACE2  
- 
Angiotensin Converting Enzyme 2 
AE 
 
- 
Adverse event  
ALT 
 
-  
Alanine aminotransferase 
AST 
 
- 
Aspartate aminotransferase 
BUN  
- 
Blood urea nitrogen  
BMI                -           Body mass index 
eCRF                           electronic Case Report Form 
eGFR                           estimated Glomerular Filtration Rate 
CPK  
- 
Creatine phosphokinase 
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 
MDR  
- 
Medication dispensing record 
MHI 
 
- 
Montreal Heart Institute 
MHICC  
- 
Montreal Health Innovations Coordinating Center 
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 
WBC               -           White Blood Cells 
WMA  
- 
World Medical Association 
 


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TIME PERIOD AND NUMBER OF PATIENTS:  
  
A. Anticipated Starting Date of Study: 1Q20 
  
B. Anticipated Completion Date: 3Q20 
  
C. Anticipated Number of Patients per Site: Centralized recruitment and follow-up; certain 
remote sites responsible for local recruitment and follow up. Competitive enrolment across 
participating sites. 
D. Anticipated Number of Sites: Centralized recruitment and follow-up; certain remote sites 
responsible for local recruitment and follow up. Over 100 sites worldwide. 
 
  
Generic  
Name 
 Strength and 
Dosage Form 
 
Therapeutic 
Classification 
 
  
 
 
Colchicine  
 0.5 mg tablet 
 
Immuno-modulatory 
 
  
 
 
 
 
 
 Placebo to match 0.5 
mg tablet 
 
 
 
NA 
 
 
  


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1 
INTRODUCTION 
 
1.1 
Background   
 
COVID-19 disease 
 
COVID-19 is due to an infection by the beta-coronavirus SARS-CoV2 (1). The outbreak of 
COVID-19 disease started in December 2019 in Wuhan, Hubei Province, China (1,2), has spread 
to other parts of China and Asia, and is now a pandemic that has reached Europe and North 
America. The number of confirmed cases has reached 170,000, including >6500 deaths, as of 
March 16, 2020. Patients initially present with fever with or without respiratory symptoms, but a 
large number of patients later develop various degrees of pulmonary abnormalities on chest 
imaging (3). Although the vast majority of patients only have a common, mild form of illness, 
approximately 15% of the patients fall into the severe group, with requirement of assisted 
ventilation and oxygenation (3). These patients suffer from acute respiratory distress syndrome. 
Pathologic findings reveal edema and prominent proteinaceous exudates, vascular congestion, 
and inflammatory clusters with fibrinoid material and multinucleated giant cells (4).  
 
This single-strand RNA virus depends on angiotensin converting enzyme 2 (ACE2) for its entry 
into cells (5). ACE2 is primarily produced in Clara cells and type II alveolar epithelial cells (6). 
 
Host response to viral infection 
 
Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a 
cytokine storm syndrome (7). Identification and treatment of this dysregulated (exaggerated) 
inflammatory response using existing, approved therapies with proven safety profiles has been 
advocated to address the immediate need to reduce the rising mortality (7,8).  
 
A characteristic common to both the 1918 Spanish flu pandemic and the current COVID-19 
pandemic is that children are largely protected from severe complications of the infection (9).  
Unlike macrophages from adults, ex vivo responses of children macrophages to endotoxin and 
interleukin-1 are dominated by an interleukin-10-dependent anti-inflammatory pattern (10, 11). 
Recent research has shown that DNA methylation stably reduces the expression of IL-10 in Th1 
cells (12). In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in 
a mouse model of colitis and in patients with inflammatory bowel disease, resulting in 
dysregulated activation of the NLRP3 inflammasome and production of IL-1β (13). Thus, these 
observations suggest that the protection against complications of pandemic influenza and 
COVID-19 in children might be explained by their ability to rapidly mount an IL-10-dependent 
anti-inflammatory response. Therefore, we hypothesize that targeting the NLRP3 inflammasome 


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may reduce COVID-19-related complications in adults at risk or with evidence of cytokine 
activation. 
 
 
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 (14) and 
potentially also through effects on cellular adhesion molecules and inflammatory chemokines 
(15). 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 (16). 
 
Colchicine may also have direct anti-inflammatory effects (17) 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 
(15). 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 (18, 19). Through the disruption of the cytoskeleton, 
colchicine is believed to suppress secretion of cytokines and chemokines as well as in vitro 
platelet aggregation (20, 21). 
 
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) (22), CORE (COlchicine for Recurrent pericarditis) (23) and 
CORP (COlchicine for Recurrent Pericarditis) (24) trials, colchicine was demonstrated to be 
effective for the treatment and prevention of recurrent (most likely viral) pericarditis.  
 
Colchicine has also 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 (25). Following a mean follow-up of 36 months, 
colchicine-treated patients experienced significantly fewer cardiovascular events (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< 


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0.0001). More recently, we have shown in the COLchicine Cardiovascular Outcomes Trial 
(COLCOT-1) and published in the New England Journal of Medicine that colchicine at the low 
dose of 0.5 mg per day significantly reduced the risk of first and total ischemic cardiovascular 
events by 23% and 34% respectively compared to placebo in 4745 patients with a recent 
myocardial infarction (26). Through a median follow-up of 23 months in COLCOT-1, diarrhea 
was reported by 9.7% and 8.9% (P=0.35) and nausea in 1.8% and 1.0% (P=0.02) of patients in 
the colchicine and placebo groups, respectively. There were more pneumonias (0.9% vs 0.4%, 
P=0.03) reported as serious adverse events in the colchicine group. This difference in numbers of 
pneumonias could be due to the play of chance, or could reflect altered immunological 
responses. 
 
Interestingly, colchicine was shown in one study to reduce hyperoxic lung injury in neonatal rats 
(27). Indeed, colchicine had favorable effects on alveolarization as well as inflammation and 
oxidative stress markers in this animal model of broncho-pulmonary dysplasia (27). 
 
Of note, the mechanism of action of colchicine is very different than that of non-steroidal anti-
inflammatory drugs. The latter agents inhibit cyclooxygenase and may occasionally shift the use 
of arachidonic acid towards lipoxygenase, resulting in the production of pro-inflammatory 
leukotrienes. 
  
1.3 
Colchicine Dosage 
 
Pharmascience Inc. was the manufacturer of the 0.5 mg colchicine tablet and matching placebo 
used in COLCOT-1. Pharmascience Inc. currently manufactures and markets 0.6 mg colchicine 
tablets in Canada. Tablets of 0.5 mg will be used in the COLCORONA trial.  
 
 
2 
STUDY OBJECTIVES 
 
The primary objective of this study is to determine whether short-term treatment with colchicine 
reduces the rate of death and lung complications related to COVID-19. The secondary objective 
is to determine the safety of treatment with colchicine in this patient population. The exploratory 
objective is to evaluate links between soluble and genetic biomarkers, viral load and treatment 
effects.  
 
 
3 
STUDY DESIGN 
 
This will be a worldwide, randomized, double-blind, placebo-controlled, multi-center study. 
Following signature of the informed consent form, approximately 6000 subjects meeting all 
inclusion and no exclusion criteria will be randomized to receive either colchicine or placebo 
(1:1 allocation ratio) for 30 days. Follow-up phone or video assessments will occur at 15 and 30 


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days following randomization for evaluation of the occurrence of any trial endpoints or other 
adverse events.   
 
 
3.1 Study Schedule 
 
The schedule of visits for this study is outlined in Table 1. However, a patient may be evaluated 
at any time for safety concerns.  
 
3.2 Enrollment 
 
Informed consent will be obtained 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. 
 
Biomarker samples collection including viral load and viral genome analysis will be optional for 
participants. 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 the optional pharmacogenomic sub-study of COLCORONA. If they agree, they 
will be asked to sign the pharmacogenomic informed consent form and a signed copy will be 
provided to them. Patient DNA samples will be used for analysis of responses to colchicine and 
genes involved in COVID-19 disease severity, inflammatory, respiratory, cardiovascular, and 
related diseases. 
 
3.3 Screening Evaluations and Randomization 
 
Screening evaluations will include a review of the patient’s medical 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 2 days of the diagnosis of COVID-19 infection.  
 
There is no wash-out period required for patients who have been treated with colchicine and 
stopped treatment prior to enrolment.  
 
Women of childbearing potential must have a negative urine pregnancy test result at the time of 
randomization in order to qualify. Qualifying patients will be randomized to receive placebo or 
colchicine administered in a blinded manner. Blinded randomization will be performed through 
an automated Interactive Web Response System (IWRS). 3000 patients will be randomized to 
active treatment and 3000 patients will be randomized to placebo for a total of 6000 randomized 
patients. 
 


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3.4 Active Treatment Period 
 
All patients will receive study medication (either colchicine 0.5 mg or matching placebo) per os 
(PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, 
it should not be replaced. Throughout the study, patients will undergo two videovisits and/or 
phone contacts (at 15 and 30 days) to assess for potential study endpoints and other adverse 
events (AEs). Patients will be dispensed study medication for the entire follow-up period of 30 
days. At each videovisit and/or 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.   
 
Review of routine chemistry and hematology parameters will be done at Visit 2 where available 
in the patient’s record.  
 
Nasal swab samples for biomarker are optional for the participants. The informed consent form 
will reflect this option and patients will specifically be asked to consent to this biomarker 
evaluation. Analysis of biomarkers (including inflammation biomarker), viral load and viral 
genome analysis with be performed with the sample.  
 
At Visit 2, an optional saliva sample for the pharmacogenomic sub-study may be collected.  
Only, patients who agree to and have signed the pharmacogenomic informed consent form will 
participate in the optional pharmacogenomic sub-study. Patient DNA will be extracted from 
saliva and stored at the Beaulieu Saucier Pharmacogenomics Centre at the Montreal Heart 
Institute until all material is used or up to 25 years after study completion.  
 
Please refer to Table 1 and Appendix A for Timetable of Visits and Requirements. 
 


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Table 1 Timetable of Visits and Requirements 
(Note: all visits are to be +/- 2 days from anticipated timepoint) 
Visits 
1  
Screening  
Phone call 
2a              
Randomization/ 
Baseline Phone 
call 
3b   
Phone 
or video 
contact 
4b 
Phone or 
video  
End of 
Study 
Days 
 
0 
15 
30 
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 
 
 
Nasal swab sample for biomarkers (optional) 
 
X 
 
 
Saliva Sample for pharmacogenomics evaluation 
(optional)  
 
X c 
 
 
Record potential study endpoints and other AEs  
 
X 
X 
X 
Study medication dispensing 
 
X  
 
 
 
a) 
Screening Visit 1 and Visit 2 may be performed on the same day; under these circumstances, requirements at both Screening Visit 1and Visit 2 will be performed once. 
b)  Phone contact or video visit. 
c) 
Saliva sample for pharmacogenomics evaluation will be collected using saliva collection kit.  


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4 
STUDY POPULATION 
 
4.1 Source and Number of Patients 
 
A total of 6000 patients will be randomized.  
 
4.2 Patient Selection Criteria 
 
4.2.1 Inclusion Criteria: 
 
All of these criteria must be met: 
 Males and females, at least 40 years of age, capable and willing to provide informed 
consent; 
 Patient must have received a diagnosis of COVID-19 infection within the last 24 hours; 
 Outpatient setting (not currently hospitalized or under immediate consideration for 
hospitalization); 
 Patient must possess at least one of the following high-risk criteria: 70 years or more of 
age, obesity (BMI ≥ 30 kg/m2), diabetes mellitus, uncontrolled hypertension (systolic 
blood pressure ≥150 mm Hg), known respiratory disease (including asthma or chronic 
obstructive pulmonary disease), known heart failure, known coronary disease, fever of 
≥38.4°C within the last 48 hours, dyspnea at the time of presentation, bicytopenia, 
pancytopenia, or the combination of high neutrophil count and low lymphocyte count; 
 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 must be able and willing to comply with the requirements of this study protocol. 
 
4.2.2 Exclusion Criteria: 
None of these exclusion criteria should be met: 
 Patient currently hospitalized or under immediate consideration for hospitalization; 
 Patient currently in shock or with hemodynamic instability; 
 Patient with inflammatory bowel disease (Crohn’s disease or ulcerative colitis) or patient 
with chronic diarrhea; 
 Patient with pre-existent progressive neuromuscular disease; 


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 Estimated Glomerular filtration rate (eGFR) using the MDRD equation for all subjects 
being considered for enrollment, with a cut-off of < 30 mL/m in/1.73m2. 
 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 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 undergoing chemotherapy for cancer; 
 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, clarithromycin, 
cyclosporine and verapamil 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 grapefruit juice is to be eliminated 
during the study.  
 
It is recommended that subjects who are taking other moderate or strong inhibitors of CYP3A4, 
or drugs that compete for the P-gp transporter should be considered for enrollment on a case by 
case basis based on the potential for the accumulation of colchicine and resultant toxicity. 
  
All other medications (including oral or parenteral hormonal contraceptive agents) are allowed as 
long as they are stabilized prior to study entry and maintained as stable throughout the course of 
the trial.   
 
The use of concomitant medications at the time of randomization will be recorded in the eCRF 
(with the exceptions of concomitant medication taken “when necessary” (PRN)). 


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5 
STUDY METHODOLOGY 
 
5.1 Efficacy Outcomes 
 
The primary endpoint will be the composite of death or the need for hospitalization due to 
COVID-19 infection in the first 30 days after randomization. The secondary endpoints will 
consist of the components of the composite primary endpoint; and the need for mechanical 
ventilation in the first 30 days after randomization. Exploratory endpoints will include 
associations between both biomarkers and viral load (stored samples) and treatment effects.   
 
Biomarkers endpoints: 
Samples received from participants will be kept frozen until evaluation of biomarkers, viral load 
and viral genome analysis.  
Samples will be stored and processed at laboratory mandated by 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.      
 
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 randomization 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 


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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. 
 
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: +1-514 264-2631 (24/7 availability) 
Email: colcorona_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 


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Page 21 of 58 
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 in the protocol as lack of efficacy or collected as efficacy 
parameters (endpoints) will be captured as AE 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 
 
Chemistry and hematology test results (refer to Appendix A) obtained for a clinical indication 
may be used to assess patient eligibility at screening.  
 
Optional biomarker nasal swab samples that have already been used for diagnosis of COVID-19 
at screening centers will be collected for the biomarkers, viral load and viral genome analysis. 
The samples will be kept in a laboratory mandated by the Montreal Heart Institute for up to 
twenty five (25) years following completion of the trial for possible future evaluation of 
biomarkers. These samples may be used to assess (but not limited to) markers of inflammation 
and sequencing of the viral RNA. 
 
Optional saliva samples for the pharmacogenomic sub-study will be collected at Visit 2 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 any phone contact or video visit. DNA extracted from the 
saliva samples for pharmacogenomic evaluation may be kept at the Beaulieu-Saucier 
Pharmacogenomics Centre of the Montreal Heart Institute for up to 25 years following 
completion of the trial to complete the pharmacogenomic substudy including the analysis of 
responses to colchicine and genes involved in the severity of COVID-19 disease, inflammation, 
cardiovascular, lung 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 saliva sample will be requested. 
 


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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 visit up to the End of Study 
visit. If the patient does not wish to pursue the protocol follow-up visit, 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.  
 
Patients withdrawn at any time from the study during the active treatment period should 
complete all last protocol-specified visit requirements (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 last randomized patient will have completed his (or her) 30 day 
follow-up phone contact or videovisit. 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 in bottles of 35 tablets as 0.5 mg 
colchicine tablets or matching placebo tablets.  
 
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. Study medication may also 


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be shipped directly to the patient’s home depending on evolving circumstances related to 
COVID-19. 
 
6.2 Dosage Regimen 
 
At randomization, patients will be dispensed colchicine tablets or placebo to match colchicine 
tablets. Patients will be instructed to take one tablet twice daily for the first 3 days and then one 
tablet once a day for the last 27 days and according to the detailed set of dispensing instructions 
outlined on the label.  
 
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 
 
8.1 Statistical Power and Sample Size Considerations  
 
All main analyses in COLCORONA will be conducted on an intention-to-treat basis. A sample 
size of approximately 6000 randomized patients with 3000 patients in each treatment group will 
be required to detect a 25% risk reduction with colchicine with a power of 80% given a primary 
endpoint event rate of 7% in the placebo group and a two-sided test at the 0.05 significance level.  
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 (see below). 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. 


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8.3 Data analysis 
 
8.3.1 Analysis of efficacy outcomes 
 
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 chi-square test. Logistic 
regression models might also be used to compare the primary endpoint between the two 
treatment groups while accounting for important baseline characteristics. Secondary endpoints 
will be analyzed similarly. Exploratory analysis (biomarkers) will include logistic regression 
models with the primary/secondary endpoints as dependent variables and with treatment group, 
biomarker and treatment group x biomarker interaction as independent variables. 
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 9.4 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 Data and Safety Monitoring Board (DSMB) will be established 
and will review unblinded safety data as detailed in the DSMB charter. An interim analysis is 
planned after approximately 50% of randomized patients have completed 30 days of follow-up. 
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 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. Futility will be assessed by computing 
conditional power. 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 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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9 
STUDY COORDINATION 
 
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.  Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients 
with pneumonia in China, 2019. N Engl J Med 2020.doi.org/10.1056/ NEJMoa2001017 
 
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet 2020 doi.org/10.1016/S0140-6736(20)30183-
5. 
 
3. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized 
patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 doi.org/ 
10.1001/jama.2020.1585. 
 
4. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao S-Y. Pulmonary pathology of early phase 2019 novel 
coronavirus (COVID-19) pneumonia in two patients with lung cancer, J Thor Oncology 2020 
doi: https://doi.org/10.1016/j.jtho.2020.02.010. 
 
5. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 
and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181:1-10.  
 
6. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. 
Critical Care 2017; 21:305-307. 
 
7. Mehta P, McAuley DF, Brown M, Emilie Sanchez E, Tattersall RS, Jessica J Manson JJ. 
COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020 March 13  
 https://doi.org/10.1016/ S0140-6736(20)30628-0. 
 
8. Fedson DS. Treating the host response: an alternative way to manage Ebola in Africa and the 
next influenza pandemic. JOGH 2019; 9: doi: 10.7189/jogh.09.010322. 
 
9. Fedson DS. Influenza, evolution, and the next pandemic. Evolution, Medicine, and Public 
Health 2018; 260-269. 
 
10. Barsness KA, Bensard DD, Partrick DA, Calkins CM, Hendrickson RJ, McIntyre RC Jr. 
Endotoxin induces an exaggerated interleukin-10 response in peritoneal macrophages of children 
compared with adults. J Pediatr Surg 2004; 39:912-5. 
 
11. Barsness KA, Bensard DD, Partrick DA, et al. IL-1beta induces an exaggerated pro- and anti- 
inflammatory response in peritoneal macrophages of children compared with adults. Pediatr Surg 
Int 2004; 20:238-42. 
 
12. Hwang W, Lee CG, Lee C, et al. Locus-specific reversible DNA methylation regulates 
transient IL-10 expression in Th1 cells. J Immunol 2018; 200:1865-75.  
 


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13. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 
mediated by metabolic reprogramming of macrophages. Science 2017;356:513-19. 
 
14. 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. 
 
15. 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. 
 
16. 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; 
78:559-569. 
 
17. Pope RM, Tschopp J. The role of interleukin-1 and the inflammasome in gout: implications 
for therapy. Arthritis Rheumat 2007;56(10):3183-3188. 
 
18. 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. 
 
19.  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. 
 
20.  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.  
 
21.  Sneddon JM. Effect of mitosis inhibitors on blood platelet microtubules and aggregation. J 
Physiol 1971;214:145-158. 
 
22. 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; 
112:2012-2016. 
 
23. 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;165:1987-1991. 
 
24. Imazio M, Brucato A, Cemin R, et al. Colchicine for recurrent pericarditis (CORP): a 
randomized trial. Ann Intern Med 2011;155:409-414. 


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25. 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. 
 
26. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after 
myocardial infarction. N Engl J Med 2019; 381:2497-2505. 
 
27. Ozdemir R, Yurttutan S, Talim B, Uysal B, Erdeve O, Oguz SS, Dilmen U. Colchicine 
protects against hyperoxic lung injury in neonatal rats. Neonatology 2012;102:265–269 
 


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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. Demographics and Medical/Surgical History 
 
The following elements of demographics, 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 obstructive pulmonary disease 
 prior other respiratory disease 
 
2. Physical Appearance 
1. weight 
2. height  
3. BMI ≥ 30 kg/m2 
 
3. Laboratory Parameters to Assess at V1 or V2 (This data is obtained from the patient’s 
medical file). 
 
Chemistry 
AST (Aspartate aminotransferase) 
 
 
ALT (Alanine transaminase) 
 
 
GGT (Gamma-glutamyl transferase) 
 
 
Alkaline phosphatase 
 
 
Total Bilirubin 
 
 
Serum creatinine 
 
 
Uric acid  
 
 
Hematology:  
 
RBC 
Hemoglobin 
Hematocrit 
WBC 
Platelet count 
Differential (Neutrophils, lymphocytes, monocytes, eosinophils)  


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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 


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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. 
 


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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. 
 
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%) 


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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. 
 


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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. 
 
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. 
 


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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. 
 
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 


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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. 
 


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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). 


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Table 1: Colchicine Dose Adjustment for Co-administration with Interacting Drugs if no Alternative Available1 
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) 
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 


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Treatment of gout flares with pms-COLCHICINE is not recommended in patients receiving 
prophylactic dose of Colchicine and CYP3A4 inhibitors. 
 
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. 


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Page 41 of 58 
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 
 


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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. 
 
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 


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An unexpected AE is any AE that is not consistent with findings previously observed and 
described in the pms-Colchicine 0.6 mg monograph included in the protocol. 
 
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 appropriate 
eCRF AE form 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 
 


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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 
 
The following categories are used to assess the clinical outcome of each AE: 
 
 Death related to the adverse event 
 Recovered – The patient has fully recovered from the AE without observable 
residual effects. 
 Recovered with sequelae – The patient has recovered from the AE with 
observable residual effects. 
 Not 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. 
 Recovering 
 Unknown 
 
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 reported as study endpoint should not be reported as an SAE. 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 


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Page 46 of 58 
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.   
 
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 +1-514-264-2631 (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 
 
Study endpoints 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 


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sponsor’s designated representative may directly contact the EC if necessary, but must not 
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 


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audit by a regulatory agency within the local government. The patient’s identity will remain 
protected except as required for legal or regulatory inquiries. 
 
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.  


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 Each patient and/or their legal guardian (or caregiver) reads, understands, and signs an 
instrument of informed consent.    
 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. 
 


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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 
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. 
 


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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 
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 


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sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 
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. 


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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 
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 


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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. 
 
 
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 
 


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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 
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_001.pdf: 
 
 
Protocol #: MHIPS‐2020‐001 
COLCHICINE CORONAVIRUS SARS‐CoV2 TRIAL (COLCORONA) 
NCT #: NCT04322682 
 
 
Statistical Analysis Plan (SAP) 
Amendment No. 1 
Version 25‐Nov‐2020 


 
BS-T1-001-05 
Confidential 
Page 1 of 21 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Protocol number: MHIPS-2020-001 
 
COLCHICINE CORONAVIRUS SARS-CoV2 TRIAL 
 
COLCORONA 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
24-JUN-2020 
Amendment No. 1: 
25-NOV-2020 
 
 
Prepared by: 
Malorie Chabot-Blanchet, M.Sc. 
Biostatistician 
Montreal Health Innovations Coordinating Center (MHICC) 
5000 Bélanger Street 
Montréal, QC  H1T 1C8 
Phone: 514-461-1300 ext. 4043 / Fax: 514-461-1301 
 
 




 
SAP: 25-NOV-2020/Amendment 1 
Protocol number: MHIPS-2020-001 
 
BS-T1-001-05 
Confidential 
Page 3 of 21 
  
Revision History 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
Final  
24-JUN-2020 
Malorie Chabot-
Blanchet 
Initial version 
Amendment 1 
25-NOV-2020 
Malorie Chabot-
Blanchet 
Updated SAP format. 
Updated MHICC address.  
 
Section 1 Introduction.  
Update to annotated CRF version.  
 
Section 3.1 Intent-To-Treat Population 
Change to the identification of subjects for 
whom medication was delivered. 
Added subjects suspected to have eligibility 
issues to be reviewed for inclusion or 
exclusion from the ITT population. 
 
Section 3.2 Safety Population 
Removed “Did the subject take the IP every 
day since the last visit?” is answered ‘Not 
Applicable (Subject never took any study 
medication since the last visit)’) at Day 15 and 
at EOS as a criterion to be excluded from the 
safety population. 
 
Section 4.2 Secondary Efficacy Endpoints 
Added that time from randomization to end 
of COVID-19 symptoms is defined in the 30 
days following randomization. 
 
Section 4.3 Exploratory Efficacy Endpoints 
Added associations between cytokines and 
treatment effects. 
 
Section 5.1 Adverse Events 
Clarified derivation of treatment-emergent 
AE. 
 
 


 
SAP: 25-NOV-2020/Amendment 1 
Protocol number: MHIPS-2020-001 
 
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Page 4 of 21 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
 
 
 
Section 6.2 Statistical Considerations 
Added for the secondary endpoint “Time 
from randomization to end of COVID-19 
symptoms”: 
- Calculation of the delay between the end 
of symptoms and randomization. 
- Derivation of time to censoring in case of a 
delay ˃ 30 days. 
- Imputation in case of missing event date. 
 
Section 6.3.1 Subject Disposition 
Added subject disposition tables to be 
presented for the ITT population. 
 
Section 6.3.3 Datasets Analyzed 
Removed number of subjects who had their 
biomarkers sample collected from table and 
listing. 
 
Section 6.3.4 Demographic and Baseline 
Characteristics 
Added imputation for incomplete date of 
birth. 
 
Section 6.4.2 Secondary Analysis 
For the secondary endpoint “time from 
randomization to end of COVID-19 
symptoms”: 
- Changed Kaplan-Meier survival curves for 
Kaplan-Meier failure curves. 
- Added subjects for whom the date of first 
symptoms associated to potential COVID-19 
is on the same day as the date of 
randomization to be considered in the 
analysis and added specifications on how to 
deal with incomplete date of first 
symptoms.  
-Updated derivation of time to 
event/censoring. 
-Updated conditions to use the 15 days 
phone contact data in place of the EOS data. 
 
 
 


 
SAP: 25-NOV-2020/Amendment 1 
Protocol number: MHIPS-2020-001 
 
BS-T1-001-05 
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Page 5 of 21 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
 
 
 
Section 6.4.3 Exploratory Analysis 
Added odds ratio to be provided with the 
analysis with the viral load measure. 
Added analyses on the primary endpoint 
with the cytokines. 
 
Section 6.4.4 Subgroup Analysis 
Added subgroup analyses for the primary 
endpoint with the genetic variant 
rs149354567 and the genetic variant 
rs10811106 as subgroup factors. 
 
Section 6.4.5.4 Analyses on compliant 
subjects 
Added sensitivity analyses for the primary 
endpoint on subjects for whom the 
treatment duration is at least 50% of the 
planned duration and on subjects for whom 
the treatment duration is at least 75% of the 
planned duration. 
 
Section 6.5.1 Treatment Exposure 
Updated variables to be presented. 
 
Section 7 Summary Tables, Figures and 
Listings 
Updated to reflect the new analyses. 


 
SAP: 25-NOV-2020/Amendment 1 
Protocol number: MHIPS-2020-001 
 
BS-T1-001-05 
Confidential 
Page 6 of 21 
TABLE OF CONTENTS  
 
1 
Introduction ......................................................................................................................................... 7 
2 
Study Description ................................................................................................................................. 7 
2.1 
Study Design ................................................................................................................................ 7 
2.2 
Study Objectives .......................................................................................................................... 7 
3 
Datasets Analyzed ................................................................................................................................ 8 
3.1 
Intent-To-Treat (ITT) Population ................................................................................................. 8 
3.2 
Safety Population ........................................................................................................................ 8 
4 
Efficacy Endpoints ................................................................................................................................ 8 
4.1 
Primary Efficacy Endpoint............................................................................................................ 8 
4.2 
Secondary Efficacy Endpoints ...................................................................................................... 8 
4.3 
Exploratory Efficacy Endpoints .................................................................................................... 9 
5 
Safety Parameters ................................................................................................................................ 9 
5.1 
Adverse Events ............................................................................................................................ 9 
5.2 
Serious Adverse Events.............................................................................................................. 10 
6 
Statistical Methodology ..................................................................................................................... 10 
6.1 
Determination of Sample Size ................................................................................................... 10 
6.2 
Statistical Considerations .......................................................................................................... 10 
6.2.1 
Interim Analysis ..................................................................................................................... 11 
6.3 
Study Subjects ........................................................................................................................... 12 
6.3.1 
Subject Disposition ................................................................................................................ 12 
6.3.2 
Protocol Deviations ............................................................................................................... 12 
6.3.3 
Datasets Analyzed ................................................................................................................. 13 
6.3.4 
Demographic and Baseline Characteristics ........................................................................... 13 
6.3.5 
Prior and Concomitant Medications ..................................................................................... 13 
6.4 
Efficacy Analysis ......................................................................................................................... 14 
6.4.1 
Primary Analysis .................................................................................................................... 14 
6.4.2 
Secondary Analysis ................................................................................................................ 14 
6.4.3 
Exploratory Analysis .............................................................................................................. 15 
6.4.4 
Subgroup Analysis ................................................................................................................. 15 
6.4.5 
Sensitivity Analysis ................................................................................................................ 16 
6.4.5.1 
Effect of Baseline Characteristics ................................................................................. 16 
6.4.5.2 
Effect of Missing Data ................................................................................................... 16 
6.4.5.3 
Incidence excluding event-free subjects who died prior to study completion ............ 16 
6.4.5.4 
Analyses on compliant subjects ................................................................................... 16 
6.5 
Safety Analysis ........................................................................................................................... 17 
6.5.1 
Treatment Exposure .............................................................................................................. 17 
6.5.2 
Adverse Events and Serious Adverse Events ......................................................................... 17 
7 
Summary Tables, Figures and Listings ................................................................................................ 18 


 
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Protocol number: MHIPS-2020-001 
 
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Page 7 of 21 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BMI 
Body Mass Index 
CABG 
Coronary Artery Bypass Graft 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MHICC 
Montreal Health Innovations Coordinating Center 
MI 
Myocardial Infarction 
PCI 
Percutaneous Coronary Intervention 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
 
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-2020-001.  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 01-APR-2020 and on the annotated case report form (CRF) version 3.2. In 
case of differences in terms of descriptions or explanations between the SAP and the protocol, the SAP 
will supersede the protocol. Any deviation to this SAP would be reported in the statistical report. 
 
2 
STUDY DESCRIPTION 
 
2.1 
Study Design 
 
This is a randomized, double-blind, placebo-controlled, multi-center study. Following signature of the 
informed consent form, approximately 6000 subjects meeting all inclusion and no exclusion criteria will 
be randomized to receive either colchicine or placebo (1:1 allocation ratio) for 30 days (0.5 mg twice 
daily for the first 3 days and then once daily for the last 27 days). Follow-up phone or video assessments 
will occur at 15 and 30 days following randomization for evaluation of the occurrence of any trial 
endpoints or other adverse events. 
 
Details of the study can be found in the last version of the protocol dated 01-APR-2020. 
 
2.2 
Study Objectives 
 
The primary objective of this study is to determine whether short-term treatment with colchicine 
reduces the rate of death and lung complications related to COVID-19. The secondary objective is to 


 
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determine the safety of treatment with colchicine in this subject population. The exploratory objective is 
to evaluate links between soluble and genetic biomarkers, viral load and treatment effects. 
 
3 
DATASETS ANALYZED 
 
Subjects who were not eligible for randomization but who have been erroneously randomized into the 
study will be excluded from all datasets analyzed if they did not take study product.  
 
3.1 
Intent-To-Treat (ITT) Population  
 
The ITT population will consist in randomized subjects (a randomization number is recorded on 
electronic case report form (eCRF) Form “Randomization”) for whom the study medication was 
delivered (the IP (investigational product) delivery date is not reported “Not Applicable” on eCRF Form 
“Study Drug”). Subjects whose condition declined between randomization and delivery of the study 
medication could be excluded from the ITT population. A listing of these subjects will be reviewed by the 
principal investigator and the clinical team, who will confirm their inclusion or exclusion from the ITT 
population prior to unblinding. Subjects randomized by error or subjects suspected to have eligibility 
issues will also be reviewed by the principal investigator, who will confirm inclusion or exclusion from 
the ITT population prior to unblinding. In the ITT population, subjects are allocated to treatment groups 
as per the randomization assignment. 
 
3.2 
Safety Population 
 
All subjects who took at least one dose of study medication will be included in the safety analysis 
population. A randomized subject will be excluded from the safety population if the date of first dose of 
study medication on eCRF Form “Study Drug” and the date of last dose of study medication on eCRF 
Form “Study Completion” is ‘Not Applicable’. Subjects will be assigned according to the true treatment 
received for analysis purposes. 
 
4 
EFFICACY ENDPOINTS 
 
4.1 
Primary Efficacy Endpoint 
 
The primary endpoint is the composite of death or the need for hospitalization due to COVID-19 
infection in the first 30 days after randomization. Death and hospitalization due to COVID-19 will be 
identified from the eCRF Form “Adverse Event” and derived as outcome of AE= Death Related to 
Adverse Event or AE term= Hospitalization due to covid19 complication. 
 
4.2 
Secondary Efficacy Endpoints 
 
The secondary endpoints are the components of the composite primary endpoint (death and 
hospitalization due to COVID-19), the need for mechanical ventilation in the first 30 days after 
randomization and the time from randomization to end of COVID-19 symptoms in the first 30 days after 
randomization in subjects with symptoms at randomization. The need for mechanical ventilation will be 
identified from the eCRF Form “Adverse Event”. The event (being symptom-free) and the date of last 
known symptoms will be identified from the eCRF Form “Subject Status EOS” or “Subject Status D15”. 


 
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4.3 
Exploratory Efficacy Endpoints 
 
Exploratory endpoints include associations between biomarkers, cytokines and viral load (stored 
samples) and treatment effects. 
 
In consenting subjects, optional nasal swab will be collected at Visit 2 for the assessment of biomarkers, 
possibly including but not limited to markers of inflammation, and viral load. Therefore, the exploratory 
endpoints might not be available in all subjects. These data, as well as the cytokines, will come from 
external databases. 
 
5 
SAFETY PARAMETERS 
 
Drug safety will be assessed by an evaluation of types, frequencies, severities and duration of any 
reported AEs. Subjects will be monitored for signs and symptoms of drug toxicity.  
 
5.1 
Adverse Events 
 
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.  
 
The only AEs to be recorded on the eCRF, in addition to serious adverse events (SAE), 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 regarding AEs will be collected from the first dose of study medication (at Visit 2) through 
and including the last visit. Information collected will include the onset, end date (if applicable), 
intensity, relationship to study drug, and the management. Information regarding SAEs that occur within 
30 days following the last study visit, and reported to the investigational site, will be collected. 
 
In case the intensity of an AE is missing, it will be considered as ‘Severe’. 
 
A treatment-emergent AE is an AE which started after the date of the first dose of study medication or 
on the date of the first dose of study medication but not prior to the delivery of IP (as reported on eCRF 
Form “Adverse Event”; if the AE started on the same date as the IP delivery date (on eCRF Form “Study 
Drug”)). In case the date of first dose of study medication is unknown, the AE will be assumed to be 
treatment-emergent if it did not start prior to the IP delivery. In case the day the event started is 
unknown, the event will be assumed to be treatment-emergent if it started on the same month and year 
as the date of first dose of study medication (or IP delivery date if the date of first dose is missing) but 
did not start prior delivery of IP; otherwise the partial AE start date will be compared to the date of first 
dose of study medication (or IP delivery date if it is missing) and the AE will be classified accordingly. 
 
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. They will be identified from the eCRF Form “Adverse Event” as 
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5.2 
Serious Adverse Events 
 
SAEs 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.  
 
6 
STATISTICAL METHODOLOGY 
 
6.1 
Determination of Sample Size 
 
A sample size of approximately 6000 randomized subjects with 3000 subjects in each treatment group 
will be required to detect a 25% risk reduction with colchicine with a power of 80% given a primary 
endpoint event rate of 7% in the placebo group and a two-sided test at the 0.05 significance level.  
 
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 (see section 6.2.1). However, since this will have a negligible 
impact on power, the sample size calculation was calculated using a significance level of 0.05. 
 
6.2 
Statistical Considerations 
 
Data summaries will be presented using descriptive statistics: N, mean, standard deviation, median, 
Q1, Q3, minimum and maximum will be presented for continuous variables while count and 
proportion will be presented for categorical variables. 
 
Basic assumptions of the proposed analyses will be verified prior to the analyses. Since efficacy 
endpoints death, hospitalization due to COVID-19 infection and need for mechanical ventilation are 
defined in the 30 days following randomization, the delay between an event of interest and 
randomization will be calculated as date of the event (date of death, admission date or mechanical 
ventilation start date) – date of randomization (in days), and any event for which the delay is > 30 days 
will be excluded from the efficacy analysis. In case the date of the event is incomplete (the exact day 
could be unknown, but the month and year should be known as they are required fields), the following 
rule will be applied: Missing event date will be replaced by the maximum between the partially 
incomplete date where the missing day is replaced by 01 and the randomization date. The secondary 
endpoint “Time from randomization to end of COVID-19 symptoms” is also defined in the 30 days 
following randomization. For this analysis, the “event” is to be symptom-free and the “event date” is the 
date of last known symptoms. The delay between the end of symptoms and randomization will be 
calculated as (date of last known symptoms – date of randomization). If the delay is ˃ 30 days, the 
subject will be censored on day 31 (i.e. analyzed as being not symptom-free on day 31; day 1 being the 
day of randomization for this analysis). Missing event date will be replaced by the minimum between 
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replaced by the last day of the month (or last day of the year) and the date of the visit at which the 
event was reported (EOS visit if the subject is symptom-free at EOS or Day 15 visit if the subject did not 
report being symptom-free or not symptom-free at EOS). 
 
Because the main focus of this study is on the primary endpoint, no adjustment to control the overall 
type I error rate for multiple comparison across the methods used to analyze the primary endpoint and 
the secondary endpoints is planned. The primary analysis will be conducted at a significance level close 
to 0.05 (to account for the interim analysis). For the other efficacy analyses, point estimates with 95% 
confidence intervals will be presented.  
 
Missing data will be imputed in a sensitivity analyses on the primary endpoint described in section 
6.4.5.2. 
 
Interim analyses for efficacy and for futility are planned during the study. They are described in section 
6.2.1.  
 
Statistical analyses will be performed using SAS Version 9.4 or higher. 
 
6.2.1 
Interim Analysis  
 
A fully independent Data and Safety Monitoring Board (DSMB) was established and will review 
unblinded efficacy and safety data. 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 method of interim efficacy and futility analyses and the rules for early study termination 
are detailed in the DSMB charter, approved by all board members, and are described in this section.  
 
Three formal interim efficacy analyses on the primary endpoint will be done after approximately 25%, 
50% and 75% of the predicted number of primary events (approximately 368 events). That is, three 
formal interim analyses on the primary endpoint will be done using the Lan-DeMets procedure with the 
O’Brien-Fleming alpha spending function to determine the significance level (expecting interim analyses 
to be conducted at the 0.000015, 0.0030 and 0.0183 significant levels respectively, and final analysis to 
be conducted at the 0.0440 significant level). The exact significance levels that will be used might be 
slightly different as they will be computed according to the exact number of events/subjects included at 
the time of the interim analyses. Of note, the plan is to conduct three interim analyses and the number 
and timing of these interim analyses are not to be changed according to observed treatment effect. The 
circumstances under which the number and timing of the interim analyses could be modified include 
higher/slower than expected enrollment rate or external information. 
 
Futility will be considered by the DSMB in a fashion similar to that for efficacy. Based on the interim 
analyses, futility will be assessed by computing the conditional power and judged at the 15% level.  
 
The results of the interim statistical analyses and the assessment of futility will be considered as 
guidance by the DSMB which will be considered along with the results for the secondary efficacy 
outcomes, the safety profile of the treatments, recruitment and the current medical and public health 
environment. It should be emphasized that the DSMB will consider all available information before 


 
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recommending stopping or extending the trial for safety, efficacy or futility. The decision is not to be 
taken on statistical considerations alone but also considering for public good in the epidemic. 
 
The interim analyses will be performed by the MHICC unblinded study biostatistician not otherwise 
involved in the study. More details about the interim analyses can be found in the DSMB charter dated 
17-APR-2020.  
 
6.3 
Study Subjects 
 
6.3.1 
Subject Disposition 
 
Number of subjects randomized, number of subjects who did not take any study medication, number of 
subjects completing the study and reasons for study discontinuation will be summarized by randomized 
treatment group, for all randomized subjects as well as for the ITT population. This table will also be 
presented broken down by Country for all randomized subjects and for the ITT population. 
 
A listing of subject disposition will be presented and will include subject ID, date of positive diagnosis for 
COVID-19, date of informed consent, date of randomization, IP delivery date, randomization group, age 
at randomization, sex, date of first dose of study medication, date of last dose of study medication, date 
of completion/discontinuation and subject’s status at study completion. 
 
Subject disposition will also be presented with a flow chart reporting the following information: subjects 
randomized, subjects for whom the study medication was delivered, subjects who took at least one dose 
of study medication, subjects completing the study and reasons for study discontinuation. 
 
Delays since first symptoms of COVID-19 will be summarized by treatment group, for the ITT population. 
The number of days between the date of first symptom of COVID-19 and the following dates will be 
presented in this table: date of positive diagnosis for COVID-19, date of informed consent and date of 
first dose of study medication. In addition, the number of days between the date of positive diagnosis of 
COVID-19 and the date of randomization will be presented, as well as how the diagnosis of COVID-19 
was established. 
 
Visit type (how was the visit conducted) for the 15 days visit and EOS visit will also be summarized by 
treatment group, for the ITT population. 
 
Subject status (Are you symptom-free?, Since your last visit have you been diagnosed with pneumonia?, 
If Yes, required hospitalization?) at day 15 and at EOS will be summarized by treatment group and 
overall for the ITT population. In addition, if the date of first symptoms associated to potential COVID-19 
infection and the date of last known symptoms are available and complete, the number of days with 
symptoms will be calculated as (Date of last known symptoms - Date of first symptoms associated to 
potential COVID-19 infection + 1).  
 
6.3.2 
Protocol Deviations  
 


 
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Protocol deviations will be summarized overall and by treatment group for the ITT population. A listing 
will also be provided and will include subject ID, date of informed consent, date of randomization, 
randomization group and description and date of deviation.  
 
6.3.3 
Datasets Analyzed 
 
The number of subjects in the ITT population and the number of subjects in the Safety population will be 
summarized overall and by treatment group. 
 
A listing of datasets analyzed will be presented and will include subject ID, randomization group, actual 
treatment received, ITT population (Yes/No), reason for exclusion from the ITT population, Safety 
population (Yes/No) and reason for exclusion from the Safety population. 
 
6.3.4 
Demographic and Baseline Characteristics 
 
Demographic data will be summarized by treatment group and overall for the ITT population. Baseline 
characteristics (medical and surgical history and physical data) will also be summarized by treatment 
group and overall for the ITT population. 
 
In case the date of birth is incomplete, the following imputation will be done: 
 
the partial date will be replaced by the fifteenth day of the month if month and year are known; 
 
the partial date will be replaced by the first day of July if only the year is known. 
 
6.3.5 
Prior and Concomitant Medications 
 
Prior and concomitant medications will be coded with respect to indication and generic name using the 
WHO drug dictionary (version MAR2018).   
 
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. 
 
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) 
 
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 
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 
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 prior and concomitant medications will also be presented for the subjects of the ITT 
population by therapeutic class and preferred term, overall and for each treatment arm. 
 
6.4 
Efficacy Analysis 
 
All efficacy analyses will be conducted on the ITT population. 
 
6.4.1 
Primary Analysis 
 
For each treatment group, the incidence of the primary endpoint, the composite of death or 
hospitalization due to COVID-19 infection in the first 30 days after randomization, will be calculated as 
the number of subjects who either died or were hospitalized due to COVID-19 infection in the first 30 
days after randomization, divided by the number of subjects randomized to that treatment group. The 
incidence in each treatment group will then be compared using a chi-square test. Because of the interim 
analyses, this test might be conducted at a slightly lower significance level than 0.05 (ex. 0.0440). The 
final significance level will be confirmed prior to database lock and unblinding. The odds ratio will also 
be provided with the confidence interval calculated at the appropriate level. In addition to the incidence 
of the endpoint, the delay between the occurrence of the event (the first event if more than one event 
per subject) and randomization will be summarized. 
 
6.4.2 
Secondary Analysis 
 
The secondary endpoints death, hospitalization due to COVID-19 infection and need for mechanical 
ventilation in the first 30 days after randomization, will be analyzed using chi-square tests, similarly to 
what is described for the primary endpoint. Odds ratios with 95% confidence intervals will be presented. 
The delay between the occurrence of the event of interest (the first event if more than one event per 
subject) and randomization will also be summarized. The incidence per treatment group will be 
calculated as the number of subjects who experienced the event of interest in the first 30 days after 
randomization divided by the number of subjects randomized to that treatment group. For 
hospitalization due to COVID-19 infection and need for mechanical ventilation (endpoints not including 
mortality), this means that subjects who will die without being hospitalized or needing mechanical 
ventilation will be included in the denominator. However, for each of these two endpoints, a sensitivity 
analysis will be conducted excluding the event-free subjects who died prior to study completion. This 
analysis is described in section 6.4.5.3. 
 
The secondary endpoint time from randomization to end of COVID-19 symptoms will be compared 
between the two treatment groups using a log rank test and Kaplan-Meier failure curves will be 
presented. Only subjects for whom the date of first symptoms associated to potential COVID-19 
infection is before or on the same day as the date of randomization will be considered in this analysis 
and subjects for whom the date of last known symptoms is before the date of randomization will be 
excluded. If the date of first symptoms associated to potential COVID-19 infection is incomplete and the 
day and month of the partial date is before or is the same as the day and month of randomization, the 
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following randomization) will be calculated as (date of last known symptoms – date of randomization 
+1), where a missing date of last know symptoms is imputed as described in Section 6.2 (Statistical 
consideration). Subjects who are not symptom-free (‘Are you symptom-free’ = No) at EOS will be 
censored and time to censoring will be computed as the minimum between 31 and (date of EOS phone 
contact – date of randomization +1 day). For subjects who did not do the EOS phone contact, who did 
not answer “Are you symptom-free?” by Yes or No at EOS or for whom the time to event/censoring 
cannot be derived, the 15 days phone contact data will be used in place of the EOS data in the above 
definitions. 
 
6.4.3 
Exploratory Analysis 
 
For each biomarker, exploratory analysis will consist in logistic regression models with the primary 
endpoint and secondary endpoints death, hospitalization due to COVID-19 infection and need for 
mechanical ventilation in the first 30 days after randomization (yes/no) as dependant variables and 
treatment group, biomarker and the treatment group x biomarker interaction as independent variables. 
This interaction term will indicate whether the treatment effect is affected by the level of the biomarker. 
The odds ratio will be provided with the 95% confidence interval for treatment group comparison given 
that the biomarker is taking the value of the 1st quartile, median and 3rd quartile of its distribution.  
 
Similar analysis will be conducted with the viral load measure in place of the biomarker in the models. 
For the analysis with the viral load measure, the odds ratio for a one unit increase, with a 95% 
confidence interval, will also be provided for each treatment group. 
 
Similar analysis will also be conducted on the primary endpoint, with each of the cytokine in place of the 
biomarker. 
 
6.4.4 
Subgroup Analysis 
 
Subgroup analyses will be performed for the primary endpoint, looking at the homogeneity of the 
treatment effect across the following factors: age at randomization (≥ 70 years or < 70 years), sex, race 
(black or not black), body mass index (BMI) at screening (≥ 30 kg/m2 or < 30 kg/m2), smoking status at 
screening, history of diabetes, history of hypertension, history of respiratory disease, history of coronary 
disease or heart failure (prior myocardial infarction (MI), prior percutaneous coronary intervention (PCI), 
prior coronary artery bypass graft (CABG) or prior heart failure), use of agent acting on the renin-
angiotensin-aldosterone system at randomization and how was the COVID-19 diagnosis established. The 
subgroup analyses will be conducted using logistic regression models including the treatment group, the 
subgroup factor and the treatment x subgroup factor interaction. This interaction will be tested at the 
0.10 significance level and will determine whether the treatment effect is impacted by the presence of 
the factor. Treatment effects will also be estimated and presented with 95% confidence interval within 
subgroups. 
 
Similar subgroup analyses for the primary endpoint will be performed with the genetic variant 
rs149354567 (genotype: G G, G GA or GA GA) and the genetic variant rs10811106 (genotype: C C, C T or 
T T) as subgroup factors. For these two analyses, however, the interaction will be tested at the 0.05 
significance level. The genetic parameters will come from an external database. 
 


 
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6.4.5 
Sensitivity Analysis 
 
6.4.5.1 
Effect of Baseline Characteristics 
 
As a sensitivity analysis for the primary endpoint, a multivariable logistic regression model will be used 
with occurrence of the primary endpoint (yes/no) as the dependent variable and, as potential 
independent variables, the treatment group (forced in the model) as well as the following important 
baseline characteristics: age at randomization, sex, BMI at screening, smoking status at screening, 
history of diabetes, history of hypertension, history of respiratory disease, prior MI, prior coronary 
revascularization (prior PCI or prior CABG) and prior heart failure. The results from univariable logistic 
models with only the baseline characteristic as the independent variable will be carefully reviewed and 
baseline characteristics that will 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 will be candidate for 
inclusion in a stepwise multivariable logistic regression model in which the treatment group will be 
forced. Adjusted odds ratios along with 95% confidence intervals will be provided.  
 
6.4.5.2 
Effect of Missing Data 
 
Because of the short follow-up (30 days) and the nature of the primary endpoint (death or 
hospitalization), no missing primary endpoint data is expected. In other words, for all randomized 
subjects, it is expected that the information on death or hospitalization during the follow-up will be 
retrieved. However, should there be any subjects for whom no death or hospitalization due to COVID-19 
infection is reported in the eCRF (event-free subjects) and who discontinued the study prior to day 30 or 
for whom no information is available at the EOS phone call (visit not done or Were any new adverse 
events experienced? = Unknown), a sensitivity analysis will be conducted in which these subjects will be 
assumed to have experienced a primary event in the 30 days following randomization. The primary 
analysis described in section 6.4.1 will be repeated with these imputed events. 
 
6.4.5.3 
Incidence excluding event-free subjects who died prior to study completion 
 
As sensitivity analysis for hospitalization due to COVID-19 infection and need for mechanical ventilation 
(endpoints not including mortality), the secondary analysis of section 6.4.2 will be repeated with the 
incidence per treatment group calculated as the number of subjects who experienced the event of 
interest in the first 30 days after randomization divided by the number of subjects randomized to that 
group and who either had the event of interest or were event-free and did not discontinue the study 
due to death. 
 
6.4.5.4 
Analyses on compliant subjects 
 
As sensitivity analyses for the primary endpoint, the primary analysis will be repeated on subjects for 
whom the treatment duration is at least 50% of the planned duration (planned duration: 30 days) and 
on subjects for whom the treatment duration is at least 75% of the planned duration; treatment 
duration being used as a measure of compliance. Treatment duration will be calculated as (date of last 
dose of study medication – date of first dose of study medication +1). In case the date of last dose is 
missing, the study completion date will be used instead. In case the date of first dose is missing, the date 


 
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of delivery of IP will be used instead. If the date of delivery of IP is also missing, it will be replaced by the 
date of randomization. 
 
Subjects with a treatment duration ≥ 15 days will be included in the first analysis (duration is at least 
50%) and subjects with a treatment duration ≥ 23 days will be included in the second analysis (duration 
is at least 75%). 
 
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. 
 
6.5.1 
Treatment Exposure 
 
Exposure to study medication at Day 15 and at EOS (did subject take the IP every day since the last visit 
(yes/no/not applicable) and number of days the study medication has been missed since last visit) will 
be summarized by treatment group, for the safety population. Number of days in the study (calculated 
as (Date of study completion/discontinuation – Date of randomization +1)), treatment duration 
(calculation described above in section 6.4.5.4) and number of pills taken (calculated as (35- number of 
pills left in the bottle (as entered on eCRF Form “Compliance”)) will also be presented with descriptive 
statistics.  
 
6.5.2 
Adverse Events and Serious Adverse Events 
 
AEs will be coded by system organ class and preferred term according to the MedDRA dictionary 
(version 22.1). 
 
Treatment-emergent AEs (TEAE) will be summarized. Number and proportion of subjects experiencing a 
treatment-emergent AE will be presented by system organ class, preferred term and intensity for each 
treatment arm. 
 
The total number of TEAEs reported, the number and proportion of subjects experiencing at least one 
TEAE, at least one severe TEAE, at least one TEAE related to the study treatment, and at least one TEAE 
leading to drug withdrawal will also be presented. 
 
Because in this study adverse events are either categorized as SAE, gastrointestinal AE, AE related to 
study drug as per investigator judgment or laboratory abnormality, the presentation described above 
will be done for each category of AE. 
 
All SAEs will also be listed. The listing will include subject ID, randomization group, age at randomization, 
sex, date of first dose of study medication, name and preferred term of AE, SOC term, start and end date 
(if applicable), type of SAE, treatment/procedure performed for the event, intensity, relationship to 
study drug, action taken and outcome. 
  
A separate listing for deaths will be also provided. This listing will include subject ID, randomization 
group, age at randomization, sex, date of first dose of study medication, date of death as well as the 
cause of death and the AE term leading to death. 


 
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7 
SUMMARY TABLES, FIGURES AND LISTINGS 
 
1 Study subject 
1.1 Subject disposition 
Table 1.1.1 
Subject disposition 
Table 1.1.1b 
Subject disposition, ITT population 
Table 1.1.2 
Subject disposition by country the subject is treated in 
Table 1.1.2b 
Subject disposition by country the subject is treated in, ITT population 
Table 1.1.3 
Delays since first symptoms of COVID-19 and positive diagnosis, ITT 
population 
Table 1.1.4 
Visit information, ITT population 
Table 1.1.5 
Summary of subject status at day 15, ITT population 
Table 1.1.6 
Summary of subject status at EOS, ITT population 
Table 1.1.7 
Protocol deviations, ITT population 
Table 1.1.8 
Datasets analyzed 
 
 
1.2 Demographic and baseline characteristics 
Table 1.2.1 
Summary of demographics, ITT population 
Table 1.2.2 
Summary of medical and surgical history, ITT population 
Table 1.2.3 
Summary of physical data, ITT population 
 
 
1.3 Prior and concomitant medication 
Table 1.3.1 
Summary of medication at randomization, ITT population 
Table 1.3.2 
Summary of prior and concomitant medication, ITT population 
 
2 Efficacy analysis 
2.1 Primary analysis 
Table 2.1.1 
Summary of and statistical analysis for composite of death or hospitalization 
due to COVID-19 infection, ITT population 
 
 
2.2 Secondary analysis 
Table 2.2.1 
Summary of and statistical analysis for death, ITT population 
Table 2.2.2 
Summary of and statistical analysis for hospitalization due to COVID-19 
infection, ITT population 
Table 2.2.3 
Summary of and statistical analysis for need for mechanical ventilation, ITT 
population 
Table 2.2.4 
Summary of and statistical analysis for time from randomization to end of 
COVID-19 symptoms, ITT population 
 
 
2.3 Exploratory analysis 
Table 2.3.1 
Summary of and statistical analysis for impact of biomarker 1 on composite of 
death or hospitalization due to COVID-19 infection, ITT population 
Table 2.3.2 
Summary of and statistical analysis for impact of biomarker 1 on death, ITT 
population 
Table 2.3.3 
Summary of and statistical analysis for impact of biomarker 1 on 


 
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hospitalization due to COVID-19 infection, ITT population 
Table 2.3.4 
Summary of and statistical analysis for impact of biomarker 1 on need for 
mechanical ventilation, ITT population 
Each biomarker and viral load parameter will be presented in separate tables similarly as tables 2.3.1, 
2.3.2, 2.3.3 and 2.3.4.Each cytokine will be presented in separate tables similarly as table 2.3.1. 
 
2.4 Subgroup analysis 
Table 2.4.1 
Composite of death or hospitalization due to COVID-19 infection broken down 
by age at randomization (≥ 70 years or < 70 years), ITT population 
Table 2.4.2 
Composite of death or hospitalization due to COVID-19 infection broken down 
by sex, ITT population 
Table 2.4.3 
Composite of death or hospitalization due to COVID-19 infection broken down 
by race (black or not black), ITT population 
Table 2.4.4 
Composite of death or hospitalization due to COVID-19 infection broken down 
by BMI at screening (≥ 30 kg/m2 or < 30 kg/m2), ITT population 
Table 2.4.5 
Composite of death or hospitalization due to COVID-19 infection broken down 
by smoking status at screening, ITT population 
Table 2.4.6 
Composite of death or hospitalization due to COVID-19 infection broken down 
by history of diabetes, ITT population 
Table 2.4.7 
Composite of death or hospitalization due to COVID-19 infection broken down 
by history of hypertension, ITT population 
Table 2.4.8 
Composite of death or hospitalization due to COVID-19 infection broken down 
by history of respiratory disease, ITT population 
Table 2.4.9 
Composite of death or hospitalization due to COVID-19 infection broken down 
by history of coronary disease or heart failure, ITT population 
Table 2.4.10 
Composite of death or hospitalization due to COVID-19 infection broken down 
by use of agent acting on the renin-angiotensin-aldosterone system at 
randomization, ITT population 
Table 2.4.11 
Composite of death or hospitalization due to COVID-19 infection broken down 
by how was the COVID-19 diagnosis established, ITT population 
Table 2.4.12 
Composite of death or hospitalization due to COVID-19 infection broken down 
by genotypes for genetic variant rs149354567, ITT population 
Table 2.4.13 
Composite of death or hospitalization due to COVID-19 infection broken down 
by genotypes for genetic variant rs10811106, ITT population 
 
2.5 Sensitivity analysis 
Table 2.5.1 
Summary of and stepwise multivariable logistic regression model for 
composite of death or hospitalization due to COVID-19 infection, ITT 
population 
Table 2.5.2 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: age at randomization , 
ITT population 
Table 2.5.3 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: sex, ITT population 
Table 2.5.4 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: BMI at screening, ITT 


 
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population 
Table 2.5.5 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: smoking status at 
screening, ITT population 
Table 2.5.6 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: history of diabetes, ITT 
population 
Table 2.5.7 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: history of hypertension, 
ITT population 
Table 2.5.8 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: history of respiratory 
disease, ITT population 
Table 2.5.9 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: prior MI, ITT population 
Table 2.5.10 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: prior coronary 
revascularization, ITT population 
Table 2.5.11 
Summary of and univariable logistic regression model for composite of death 
or hospitalization due to COVID-19 infection ,variable: prior heart failure, ITT 
population 
Table 2.5.12 
Summary of and statistical analysis for composite of death or hospitalization 
due to COVID-19 infection, with missing data imputation, ITT population 
Table 2.5.13 
Summary of and statistical analysis for hospitalization due to COVID-19 
infection, excluding event-free deceased subjects, ITT population 
Table 2.5.14 
Summary of and statistical analysis for the need for mechanical ventilation, 
excluding event-free deceased subjects, ITT population 
Table 2.5.15 
Summary of and statistical analysis for composite of death or hospitalization 
due to COVID-19 infection, on subjects with a treatment duration ≥ 15 days, 
ITT population 
Table 2.5.16 
Summary of and statistical analysis for composite of death or hospitalization 
due to COVID-19 infection, on subjects with a treatment duration ≥ 23 days, 
ITT population 
 
3 Safety analysis 
3.1 Treatment exposure 
Table 3.1.1 
Summary of exposure to study medication, safety population 
 
 
3.2 Adverse events and serious adverse events 
Table.3.2.1 
Overall summary of treatment emergent SAEs (TESAE), safety population 
Table 3.2.2 
Summary of treatment emergent SAEs (TESAE) by preferred term, system 
organ class and intensity, safety population 
Table 3.2.3 
Overall summary of gastrointestinal treatment emergent AEs (TEAE), safety 
population 
Table 3.2.4 
Summary of gastrointestinal treatment emergent AE (TEAE)s by preferred 
term, system organ class and intensity, safety population 


 
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Table 3.2.5 
Overall summary of treatment emergent AEs (TEAE) related to study drug, 
safety population 
Table 3.2.6 
Summary of treatment emergent AEs (TEAE) related to study drug by 
preferred term, system organ class and intensity, safety population 
Table 3.2.7 
Overall summary of treatment emergent laboratory abnormalities, safety 
population 
Table 3.2.8 
Summary of treatment emergent laboratory abnormalities by preferred term, 
system organ class and intensity, safety population 
 
Figures 
Figure 1 
Subject Disposition (flow chart) 
Figure 2 
Kaplan-Meier failure curves for time from randomization to end of COVID-19 
symptoms, ITT population 
 
Listings 
Listing 1 
Subject Disposition 
Listing 2 
Protocol Deviations 
Listing 3 
Datasets analyzed 
Listing 4 
SAEs 
Listing 5 
Deaths