Conditions: SARS-CoV-2
Keywords: Rosuvastatin Colchicine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 250
Healthy volunteers: no

Brief summary:
This is a pragmatic randomized open-label study of the safety and efficacy of the combination of colchicine and Rosuvastatin in addition to standard of care (SOC) compared to SOC alone in hospitalized patients with SARS-CoV-2

Detailed description:
This is a prospective 1:1 randomized open-label clinical trial to investigate the safety and efficacy of the combination of Colchicine + Rosuvastatin added to standard of care (SOC) compared to SOC alone in hospitalized subjects with moderate COVID-19.

Subjects will be screened during admission to hospital. Patients with confirmed SARS-CoV-2 infection, and meeting all other inclusion and exclusion criteria, will be randomized to either Colchicine+Rosuvastatin treatment or SOC for the duration of hospitalization. SOC will be guided by the YNHH SARS-CoV-2 Therapeutics Group. In cases where patients require randomization in another trial evaluating an experimental drug, they will continue on study drug. Patients will be assessed daily while hospitalized for clinical, biomarker, safety, and laboratory parameters based on SOC.

Colchicine is an extensively studied oral anti-inflammatory agent with a well-defined safety profile. Colchicine, by inhibiting tubulin polymerization and clathrin-mediated endocytosis has the potential to inhibit SARS-CoV-2 cell entry. In addition, colchicine has a direct anti-inflammatory effect by inhibiting the NLRP3 inflammasome activation which in turn has the potential to reduce the SARS-CoV-2-induced cytokine storm. Statins also have direct anti-inflammatory effects by reducing chemokine release, adhesion molecules, and modulating T cell activity and have the potential to prevent SARS-CoV-2 related endothelial dysfunction and may reduce the morbidity and mortality associated with COVID-19. Rosuvastatin, in particular, appears to have direct antiviral properties by binding and inhibiting the active site of the main protease enzyme (Mpro) of SARS-CoV-2.1

The combination Colchicine + Rosuvastatin may have a synergetic effect to antagonize SARS-CoV-2 infection, modulate the inflammatory response and to reduce morbidity and mortality associated with acute respiratory distress syndrome (ARDS) and myocardial injury in COVID-19 patients.

Both drugs have been in use for decades for gout and pericarditis (colchicine) and hyperlipidemia, coronary disease (CAD) and diabetes (rosuvastatin/Crestor), and have been tested in thousands of patients used individually and in combination with a low and well characterized risk profile. Colchicine and rosuvastatin are currently used as standard of care in COVID-19 patients whether due to pre-existing CAD, gout or pericarditis or acute presentations with acute coronary syndromes or acute gout with no expected added risk in the population being studied.

This study is not intended to support a labeling change or advertising claim for either drug, and the study will be conducted in compliance with the requirements of Yale University's IRB review and a research IND.

Subjects will be screened within 48 hours of hospital admission. Patients with real-time reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infection and meeting all inclusion and exclusion criteria, will be randomized to either Colchicine + Rosuvastatin treatment in addition to SOC or SOC alone for the duration of hospitalization.

Subjects will be randomized in a 1:1 manner to one of two arms:

Active treatment:

In addition to SOC\* subjects randomized to active treatment will receive:

* Rosuvastatin: 40mg daily AND
* Colchicine: 0.6mg twice daily for 3 days then 0.6mg daily Note: Dose adjustment based on medical conditions and drug interactions (see section §7.4.1). Subjects previously on chronic statin therapy will be eligible for enrollment in the trial, and if randomized to active treatment, chronic statin therapy will be discontinued and replaced by rosuvastatin 40 mg for 30 days or hospital discharge and resumed thereafter.

Standard of Care Controls:

Subjects will undergo SOC treatment determined by the primary care team and the YNHH treatment algorithm for hospitalized patients with COVID-19.

\*All standard of care treatments for hospitalized subjects with SARS-CoV-2 are permitted concurrently with the study intervention. This only includes treatments approved by the Yale SOC treatment Committee. Concomitant therapy will be performed according to standard practice, local standards of care and published guidelines. Subjects will not be permitted to participate in other investigational studies. Methods for identifying drug interactions and dose adjustment are listed in section §7.4.1 of the protocol. Drug discontinuation is only permitted with documented adverse reactions (section §7.4.3).

Treatment will continue for a total of 30 days. If the subject is discharged the treatment will stop at that time.

Arms:
arm 1: Patients will take Rosuvastatin 40mg daily and Colchicine 0.6mg twice for 3 days and then 0.6mg daily during hospitalization arm 2: Patients will undergo standard of care treatment during hospitalization determined by the primary care team during hospitalization

Interventions: intervention 1: Standard of Care (SOC) and Colchicine+Rosuvastatin
Intervention descriptions: intervention 1: Patients will take Rosuvastatin 40mg daily and Colchicine 0.6mg twice for 3 days and then 0.6mg daily during hospitalization

Protocol document:
Prot_SAP_000.pdf: 
COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
1 
 
 
 
Colchicine/Statin for the Prevention of COVID-19 
Complications (COLSTAT) Trial 
A pragmatic randomized open-label study of the safety and 
efficacy of the combination of Colchicine and Rosuvastatin in 
addition to standard of care (SOC) compared to SOC alone in 
hospitalized patients with SARS-CoV-2  
 
Clinical Investigational Plan 
Version 2.0  
5 February 2021 
Protocol Number: CIP No. 2.0 
 
 
 
 
Principal Investigator: 
Alexandra Lansky, MD 
Professor of Medicine, Cardiovascular Medicine,  
Yale University School of Medicine/Yale Hew Haven Health 
Director Heart and Vascular Center Clinical Research Program,  
Director Yale Cardiovascular Research Group 
Tel: 203 737 2142 
Email: Alexandra.Lansky@yale.edu 
IND Number: 150567 
IND Holder: Alexandra Lansky, MD 
NCT Number: TBD 
Study Phase 4 
 
NOTICE: The information contained herein is CONFIDENTIAL and PROPRIETARY to the Yale University 
and may not be disclosed to anyone who is not recipient or reviewer of this protocol without express prior 
written consent of the Yale University. 
 
 
 
NCT04472611


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Table of Contents 
1.0 
Document Control ............................................................................................................ 6 
1.1 Version History ................................................................................................................. 6 
1.2 Protocol Approval Page ................................................................................................... 7 
1.3 Investigator Signataure Page ........................................................................................... 8 
2.0 
Protocol Synopsis ............................................................................................................ 9 
3.0 
Study Contacts .............................................................................................................. 16 
4.0 
Introduction .................................................................................................................... 17 
4.1 Background .................................................................................................................... 17 
4.1.1 Drug Combination Safety ........................................................................................ 18 
4.2 Rationale ........................................................................................................................ 18 
4.3 Drug Description ............................................................................................................ 18 
4.4 Regulatory Status........................................................................................................... 19 
5.0 
Study Design ................................................................................................................. 19 
5.1 Study Design Overview .................................................................................................. 19 
5.2 Study Objectives ............................................................................................................ 19 
5.3 Study Endpoints ............................................................................................................. 19 
5.3.1 Primary Endpoints ................................................................................................... 19 
5.3.2 Secondary Endpoints .............................................................................................. 20 
6.0 
Subject Selection and Withdrawal ................................................................................. 21 
6.1 Patient Population .......................................................................................................... 21 
6.2 Eligibility Criteria............................................................................................................. 21 
6.2.1 Inclusion Criteria ...................................................................................................... 21 
6.2.2 Exclusion Criteria ..................................................................................................... 22 
6.3 Subject Screening .......................................................................................................... 22 
6.4 Informed Consent........................................................................................................... 22 
6.5 Subject Enrollment and Randomization ......................................................................... 23 
6.6 Withdrawal and Replacement of Subjects ...................................................................... 23 
6.7 Protocol Deviations ........................................................................................................ 23 
7.0 
Study Procedures .......................................................................................................... 24 
7.1 Study Schedule of Procedures and Assessment ........................................................... 24 
7.2 Screening / Baseline ...................................................................................................... 27 
7.3 Concomitant Therapies .................................................................................................. 27 
7.4 Drug Dosing, Storage and Discontinuation .................................................................... 27 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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7.4.1 Drug Dosing............................................................................................................. 27 
7.4.2 Drug Storage ........................................................................................................... 28 
7.4.3 Drug Discontinuation ............................................................................................... 28 
7.5 In-hospital Follow-up ...................................................................................................... 29 
8.0 
Adverse Events and Serious Adverse Events................................................................ 29 
8.1 Adverse Events (AE) ...................................................................................................... 29 
8.2 Life-threatening Adverse Event or Life-threatening Suspected Adverse Reaction ......... 29 
8.3 Serious Adverse Events (SAE) or Serious Suspected Adverse Reaction ...................... 29 
8.4 Suspected Adverse Reaction ......................................................................................... 30 
8.5 Unexpected Adverse Event or Unexpected Suspected Adverse Reactions ................... 30 
8.6 Documentation ............................................................................................................... 31 
8.6.1 Intensity or Severity ................................................................................................. 31 
8.6.2 Relatedness............................................................................................................. 31 
8.6.3 Outcome .................................................................................................................. 32 
8.6.4 Treatment or Action Taken ...................................................................................... 32 
8.7 Reporting ....................................................................................................................... 32 
8.7.1 General Adverse Event Reporting Procedures ........................................................ 32 
8.7.2 Serious Adverse Events .......................................................................................... 33 
8.7.3 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction .............. 33 
9.0 
Benefit: Risk Analysis .................................................................................................... 35 
9.1 Potential Benefits ........................................................................................................... 35 
9.2 Potential Risks and Discomforts .................................................................................... 36 
9.3 Methods to Minimize Risks ............................................................................................ 36 
10.0 Study Committee ........................................................................................................... 36 
10.1 Executive Committee ................................................................................................... 36 
10.2 Clinical Events Committee ........................................................................................... 36 
10.3 Data Safety Monitoring Board ...................................................................................... 36 
10.3.1 Considerations for Stopping Rules ........................................................................ 37 
11.0 Statistical Considerations and Analysis Plan ................................................................. 37 
11.1 Hypotheses .................................................................................................................. 37 
11.1.1 Primary Efficacy Endpoint ..................................................................................... 38 
11.1.2 Powered Secondary Endpoint ............................................................................... 38 
11.2 Analysis Population ...................................................................................................... 39 
11.2.1 Intention to Treat (ITT) Analysis Population .......................................................... 39 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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11.2.2 As Treated (AT) Analysis Population ..................................................................... 39 
11.2.3 M As Treated (mAT) Analysis Population .............................................................. 39 
11.3 Sample Size Calculation and Assumptions .................................................................. 39 
11.3.1 Primary Endpoint Analysis ..................................................................................... 39 
11.3.2 Powered Secondary Endpoint Analysis ................................................................. 40 
11.3.3 Rationale for Assumptions ..................................................................................... 40 
11.4 Method of Analysis and Reporting ............................................................................... 41 
11.4.1 General Approach ................................................................................................. 41 
11.4.2 Baseline Characteristics ........................................................................................ 41 
11.4.3 Primary Endpoint Analysis ..................................................................................... 41 
11.4.4 Secondary Powered Endpoint ............................................................................... 41 
11.4.5 Secondary Endpoints ............................................................................................ 42 
11.4.6 Secondary Imaging Endpoint................................................................................. 42 
11.4.7 Subgroup Analyses ............................................................................................... 42 
11.5 Measure to Minimize Bias ............................................................................................ 43 
11.5.1 Randomization ....................................................................................................... 43 
11.5.2 Blinding .................................................................................................................. 43 
11.5.3 Independent Assessments .................................................................................... 43 
11.5.4 Publication Policy .................................................................................................. 43 
12.0 Data Collection and Monitoring ...................................................................................... 43 
12.1 Data Collection and Monitoring .................................................................................... 43 
12.2 Source Documentation ................................................................................................. 43 
12.3 Auditing ........................................................................................................................ 44 
13.0 Ethical and Regulatory Considerations .......................................................................... 44 
13.1 Applicable Regulations ................................................................................................. 44 
13.2 Institutional Review Board ............................................................................................ 44 
13.3 Insurance ..................................................................................................................... 44 
13.4 Regulatory Approval ..................................................................................................... 44 
13.5 Trial Registration .......................................................................................................... 45 
13.6 Records and Reports ................................................................................................... 45 
13.7 Protocol Amendments .................................................................................................. 45 
13.8 Informed Consent ......................................................................................................... 45 
13.9 Termination of the Study .............................................................................................. 46 
13.10 Patient Privacy ........................................................................................................... 46 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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14.0 References .................................................................................................................... 47 
15.0 Appendices .................................................................................................................... 51 
15.1 Appendix A: Definitions ................................................................................................ 51 
15.2 Appendix B: List of Abbreviation .................................................................................. 70 
 
 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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1.0 Document Control 
 
1.1 Version History 
Version 
Description  
1.0 
23 June 2020 
Initial Release 
2.0 
8 February 2021 
- 
Changed 
Primary 
Endpoint 
to 
include 
thromboembolic 
complications. 
- 
Allowed for use of SpO2 when PaO2 not available to calculate 
SOFA score for secondary endpoints 
- 
Changed inclusion criteria to allow for enrollment within 72 hours of 
admission. 
- 
Changed exclusion criteria to allow for enrollment of non ICU 
patients requiring BiPAP/CPAP or HFNC (WHO ordinal scale 5) 
- 
Changed exclusion criteria to allow for enrollment of patients on 
chronic oral corticosteroid therapy 
- 
Changed exclusion criteria to allow for patients with WBC ≥ 2,500 
to be enrolled 
- 
Updated trial timeline 
- 
Clarified recommended lab work 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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1.2 Protocol Approval Page 
Study title: 
Colchicine/Statin for the Prevention of COVID-19 Complications 
(COLSTAT) Trial 
A pragmatic randomized open-label study of the safety and efficacy of 
the combination of colchicine and rosuvastatin in addition of standard 
of care (SOC) compared to SOC alone in hospitalized patients with 
SARS-CoV-2  
  
Protocol version: 
2.0 
Protocol date: 
8 February 2021 
 
 
 
Alexandra Lansky, MD  
Principal Investigator 
Yale Cardiovascular Research Group 
 
 
Date 
Michael Cleman, MD 
Co-Investigator 
Yale School of Medicine 
 
Date 
Charles Dela Cruz, MD 
Co-Investigator 
Yale School of Medicine  
 
Date 
Gil Lancaster, MD 
Sub-Investigator 
Bridgeport Hospital 
 
 
Date 
Chris Howes, MD 
Sub-Investigator 
Greenwich Hospital 
 
 
Date 
Brian Cambi, MD 
Sub-Investigator 
Lawrence & Memorial Hospital 
 
Date 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
8 
 
1.3 Investigator Signature Page 
Study title: 
Colchicine/Statin for the Prevention of COVID-19 Complications 
(COLSTAT) Trial 
A pragmatic randomized open-label study of the safety and efficacy of 
the combination of colchicine and rosuvastatin compared to standard 
of care (SOC) in hospitalized patients with SARS-CoV-2    
Protocol version: 
2.0  
Protocol date: 
8 February 2021 
Investigator’s Responsibility 
Prior to participation in the Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) 
Trial, as the site principal investigator, I understand that I must obtain written approval from my 
Institutional Review Board.  This approval must include my name and a copy must be provided to the 
Yale University (or designee), along with the approved Patient Information and Consent Form prior to the 
first enrollment at my study site.   
As the site Principal Investigator, I must also: 
1. Conduct the study in accordance with the study protocol, the signed Clinical Investigation 
Agreement, applicable laws, any conditions of approval imposed by the Yale Institutional Review 
Board, local regulations where applicable, International Conference on Harmonization (ICH) Good 
Clinical Practice guidelines, and the Declaration of Helsinki, and ensure that all study personnel are 
appropriately trained prior to any study activities. 
2. Ensure that the study is not commenced until all approvals have been obtained. 
3. Ensure that written informed consent is obtained from each subject prior to any data collection, 
using the most recent Institutional Review Board approved Patient Information and Consent Form. 
4. Provide all required data and reports and agree to source document verification of study data with 
patient’s medical records by Yale University (or designee) and any regulatory authorities. 
5. Allow Yale University personnel or its designees, as well as regulatory representatives, to inspect 
and copy any documents pertaining to this clinical investigation according to national data protection 
laws.  
Investigator Signature  
I have read and understand the contents of the Colchicine/Statin for the Prevention of COVID-19 
Complications (COLSTAT) Trial protocol and agree to abide by the requirements set forth in this 
document.  
 
__________________________ 
 
 
__________________________ 
 
Investigator Name (print) 
 
 
 
Investigative Site (print) 
 
__________________________ 
 
 
___________________________ 
                       
Investigator Signature                                          
Date 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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2.0 Protocol Synopsis 
Title: 
Colchicine/Statin for the Prevention of COVID-19 Complications 
(COLSTAT) Trial 
Investigational 
Drug 
Colchicine is an extensively studied oral anti-inflammatory agent with a well-
defined safety profile. Colchicine, by inhibiting tubulin polymerization and 
clathrin-mediated endocytosis has the potential to inhibit SARS-CoV-2 cell 
entry. In addition, colchicine has a direct anti-inflammatory effect by inhibiting 
the NLRP3 inflammasome activation which in turn has the potential to reduce 
the SARS-CoV-2-induced cytokine storm. Statins also have direct anti-
inflammatory effects by reducing chemokine release, adhesion molecules, 
and modulating T cell activity and have the potential to prevent SARS-CoV-2 
related endothelial dysfunction and may reduce the morbidity and mortality 
associated with COVID-19. Rosuvastatin, in particular, appears to have direct 
antiviral properties by binding and inhibiting the active site of the main 
protease enzyme (Mpro) of SARS-CoV-2. 
The combination Colchicine + Rosuvastatin may have a synergetic effect 
to antagonize SARS-CoV-2 infection, modulate the inflammatory response 
and to reduce morbidity and mortality associated with acute respiratory 
distress syndrome (ARDS) and myocardial injury in COVID-19 patients.  
Both drugs have been in use for decades for gout and pericarditis (colchicine) 
and 
hyperlipidemia, 
coronary 
disease 
(CAD) 
and 
diabetes 
(rosuvastatin/Crestor), and have been tested in thousands of patients used 
individually and in combination with a low and well characterized risk profile. 
Colchicine and rosuvastatin are currently used as standard of care in COVID-
19 patients whether due to pre-existing CAD, gout or pericarditis or acute 
presentations with acute coronary syndromes or acute gout with no expected 
added risk in the population being studied.  
This study is not intended to support a labeling change or advertising claim 
for either drug, and the study will be conducted in compliance with the 
requirements of Yale University’s IRB review and a research IND. 
Objective 
To investigate the safety and efficacy of the combination of Colchicine + 
Rosuvastatin added to standard of care (SOC) compared to SOC alone in 
hospitalized subjects with moderate COVID-19. 
Study Type 
This is a prospective 1:1 randomized open-label clinical trial  
Study Design 
Subjects will be screened within 48 hours of hospital admission. Patients with 
real-time reverse transcription polymerase chain reaction (RT-PCR) 
confirmed SARS-CoV-2 infection and meeting all inclusion and exclusion 
criteria, will be randomized to either Colchicine + Rosuvastatin treatment in 
addition to SOC or SOC alone for the duration of hospitalization. 
Subjects will be randomized in a 1:1 manner to one of two arms: 
Active treatment: 
In addition to SOC* subjects randomized to active treatment will receive: 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
10 
 
• 
Rosuvastatin: 40mg daily AND 
• 
Colchicine: 0.6mg twice daily for 3 days then 0.6mg daily 
Note: Dose adjustment based on medical conditions and drug 
interactions (see section §7.4.1).  Subjects previously on chronic statin 
therapy will be eligible for enrollment in the trial, and if randomized to 
active treatment, chronic statin therapy will be discontinued and replaced 
by rosuvastatin 40 mg for 30 days or hospital discharge and resumed 
thereafter. 
Standard of Care Controls:  
Subjects will undergo SOC treatment determined by the primary care team 
and the YNHH treatment algorithm for hospitalized patients with COVID-19.  
*All standard of care treatments for hospitalized subjects with SARS-CoV-2 
are permitted concurrently with the study intervention. This only includes 
treatments approved by the Yale SOC treatment Committee. Concomitant 
therapy will be performed according to standard practice, local standards of 
care and published guidelines. Subjects will not be permitted to participate in 
other investigational studies. Methods for identifying drug interactions and 
dose adjustment are listed in section §7.4.1 of the protocol. Drug 
discontinuation is only permitted with documented adverse reactions (section 
§7.4.3). 
Duration of 
Treatment 
Treatment will continue for a total of 30 days.  If the subject is discharged the 
treatment will stop at that time. 
Treatment 
Discontinuation 
Criteria 
Study drug may be discontinued in a subject after review of all available data 
with the medical monitor and discussion with the investigator if any of the 
following occur: 
• 
Any SAE or > Grade 3 AE is suspected to be related to treatment 
• 
Any elevation of ALT>5xULN confirmed by repeat testing 
• 
Any elevation of CK >5xULN confirmed by repeat testing 
• 
Severe myalgias suspected related to statin therapy 
• 
Subjects who develop renal or hepatic impairment and require a 
protease inhibitor or strong CYP3A4 inhibitor should discontinue 
colchicine 
• 
Subjects who develop new blood dyscrasia including leukopenia, 
granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia 
should discontinue colchicine 
Sites and 
Geography 
United States: Yale New Haven Health System includes Yale New Haven 
Hospital, St Raphael Campus, Bridgeport Hospital, Greenwich Hospital, and 
Lawrence and Memorial Hospital in Connecticut 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
11 
 
Primary Efficacy 
Endpoint 
 
 
 
 
 
 
 
 
 
30 day composite of the following: 
 
1) Progression of COVID-19 disease as defined by the World 
Health Organization (WHO) Ordinal Scale for Clinical 
Improvement Scores 5-8 (or 6-8 if patient at score of 5 at time of 
randomization)*. 
2) Arterial or Venous thromboembolic complications confirmed by 
imaging (including DVT/PE, MI, and ischemic stroke). 
 
*WHO ordinal scale: 
• 
Score 5: Hospitalized requiring non-invasive ventilation or high-
flow oxygen/high-flow nasal cannula 
• 
Score 6: Hospitalized requiring intubation and mechanical 
ventilation 
• 
Score 7: Hospitalized requiring ventilation and additional organ 
support (vasopressors, renal replacement therapy, ECMO) 
• 
Score 8: Death 
 
Primary Safety 
Endpoint 
Proportion of subjects with treatment emergent adverse events (TEAE) 
defined as undesirable events not present prior to medical treatment, or an 
already present event that worsens either in intensity or frequency following 
the treatment. 
Powered 
Secondary 
Efficacy 
Endpoint 
Secondary Powered Efficacy Endpoint assessed at 30 days defined as 
a composite of 
a. Respiratory failure requiring invasive mechanical ventilation,  
b. Any Myocardial injury (troponin URL> 99th percentile or a >2-fold 
increase if troponin is abnormal at baseline, or a new >10% 
reduction in LVEF by Echocardiography)  
c. Death 
Secondary 
Endpoints 
Secondary endpoints will be reported by treatment group at 30 and 
60 days: 
Clinical Safety and Efficacy: 
a. Death (all cause and cardiovascular) 
b. Duration of oxygen therapy (days) 
c. Duration of invasive mechanical ventilation (days) 
d. Duration of intensive care treatment (days) 
e. Duration of hospitalization (days) 
f. Any myocardial injury (troponin URL > 99th percentile or a >2-
fold increase if troponin is abnormal at baseline or a new 
>10% reduction in LVEF by Echocardiography), and 
underlying ischemic (Fourth Universal definitions) or 
inflammatory cause 
g. Venous thrombosis or thromboembolic complication confirmed 
by imaging 
h. All stroke (NeuroARC defined) 
i. 
Acute kidney injury (AKIN criteria) 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
12 
 
j. 
Time (in days) to symptomatic improvement: reduction in 
baseline WHO ordinal score by >2 points or achievement of 
scores 1-3 
k. Overall WHO ordinal scale for clinical improvement at 30 and 
60 days 
Other Secondary Biomarker Endpoints: 
a. Sequential Organ Failure Assessment (SOFA) score, defined 
by 6 variables (the respiratory, cardiovascular, hepatic, 
coagulation, renal and neurological systems) scored from 0 
(normal) to 4 (high degree of dysfunction/failure). 
b. Change of the SOFA from baseline.  
c. Peak and change from baseline in routine biomarkers (CRP, 
procalcitonin, D-dimer, PTT/INR, ferritin, troponin/CK-MB, 
BNP, CPK, AST, ALT, ALP, bilirubin, white blood cell count), 
as available. 
d. Peak and change from baseline in cytokine panel (IL-1, IL-2, IL-
6, IL-8, TNF-α, IL-17A, IL-17F, IP-10, CCL5), as available 
 
*If an arterial blood gas (ABG) is not available to calculate the PaO2/FiO2 
ratio for the SOFA assessment the SpO2/FiO2 ratio may be used as an 
alternative per prior literature.2 
 
Secondary Imaging Endpoints (Imaging substudy)  
a. Proportion of subjects with reduction in LVEF defined as a 
decrease of more than 10% in LVEF by clinically driven point of 
care echocardiography measured in hospital 
b. Cardiac MRI in a subset of subjects with adjudicated suspected 
myocarditis assessed at 60 days.  
Patient 
Population 
A total of 466 adult subjects with RT-PCR confirmed SARS-CoV-2 infection 
hospitalized with initially moderate (non ICU) COVID-19 will be recruited 
within 72 hours of admission. 
Subject Follow-
Up 
All subjects will be assessed daily while hospitalized for clinical, biomarker, 
safety, and laboratory parameters based on the YNHH SOC algorithm. 
Baseline biomarker measurements and subsequent frequency will be based 
on each center’s SOC but preferably should occur every 24 hours during 
hospitalization and preferably should include at minimum a basic metabolic 
panel, CBC with differential, LFTs, CRP, procalcitonin, D-dimer, and troponin 
(or CK-MB if not available). Cytokine measurement and other labs/imaging 
will occur according to the SOC of each center. Study treatment will be 
continued for 30 days or until hospital discharge whichever occurs sooner. 
All subjects will be followed clinically in hospital, at 30 days and 60 days from 
trial enrollment. After discharge, the follow-up will be by phone.  
Study 
Committees 
Clinical Events Committee 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
13 
 
An independent Clinical Events Committee (CEC) will adjudicate all primary 
and major secondary clinical events potentially meeting endpoint criteria in 
an ongoing fashion during the trial.  
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be 
responsible for the oversight and safety monitoring of the study. The DSMB 
will advise the Sponsor regarding the continuing safety of the trial subjects 
and those yet to be recruited to the trial, as well as the continuing validity and 
scientific merit of the trial.   
Inclusion 
Criteria 
Subjects must meet ALL of the following criteria to be eligible for inclusion in 
the study: 
1. 
18 years or older and confirmed SARS-CoV-2 infection by RT-PCR 
2. 
Patient is admitted to the floor or step down (non-ICU) within 72 hours of 
hospital admission 
3. 
The patient, or legally authorized representative, has been informed of 
the nature of the study, agrees to its provisions and has provided 
witnessed (by 2 independent members of the health care team) oral 
informed consent, or a photograph of the signed informed consent 
approved by the Institutional Review Board (IRB) 
Exclusion 
Criteria 
 
Subjects will be excluded if ANY of the following criteria apply: 
1. Known pregnancy or nursing mothers 
2. Known allergy to statins or colchicine 
3. Patient is on chronic colchicine  
4. Acute liver disease defined by elevated transaminases (AST/ALT > 3x 
ULN)   
5. Severe chronic kidney disease defined as glomerular filtration rate 
(GFR) < 30mL/min1.73 m2 
6. Severe QTc prolongation (>500ms narrow QRS<120ms and >550ms for 
wide QRS>120) 
7. Presents with severe disease on admission requiring ICU admission 
(WHO ordinal scale of clinical improvement scores 6-8) 
8. Rhabdomyolysis or CPK > 5x ULN 
9. Thrombocytopenia defined as platelet count < 50,000 / mm3 
10. Leukopenia defined as white blood cell count < 2,500/ µl 
11. Severe anemia defined as Hemoglobin value <8 g/100ml 
12. Participation in any other clinical trial of an experimental treatment for 
COVID-19 
Randomization 
Randomization will occur using the incorporated EPIC algorithm 
Blinding  
This is an open-label study. The Clinical Event Committee will be blinded to 
treatment allocation. 
Analysis Plan 
Primary Efficacy Endpoint Analysis:  
The primary efficacy endpoint analysis will be a test of superiority of 
Colchicine + Rosuvastatin in addition to SOC compared to SOC alone 
assessed by the primary outcome of progression to severe COVID-19 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
14 
 
disease (as defined by WHO ordinal scale scores 5-8 or 6-8 if patient at score 
of 5 at time of randomization) and arterial and venous thromboembolic 
complications at 30 days. A total of 466 evaluable subjects (233 per group) 
will provide at least 80% power to test the primary hypothesis assuming a 
44% event rate at 30 days in the control group, a 30% relative reduction in 
events with treatment, a 2-sided α=0.05 and at most 10% loss to follow-up at 
30 days. The primary endpoint will be evaluated in the ITT population (defined 
as all subjects enrolled in the study, by assigned treatment, regardless of the 
treatment actually received). A secondary analysis will be performed in the 
As Treated (AT) population (defined by the treatment actually received, rather 
than the treatment assigned). An additional analysis will be performed in the 
mAT population (defined by the treatment actually received, rather than the 
treatment assigned and excludes all subjects with prior statin therapy). 
Primary Safety Endpoint Analysis: 
Primary safety endpoints will be evaluated in the ITT population using 
appropriate descriptive statistics at discharge, 30 days, and 60 days from 
hospital admission. 
Powered Secondary Efficacy Endpoint Analysis:  
The secondary powered endpoint analysis will be a test of superiority of 
Colchicine + Rosuvastatin in addition to SOC compared to SOC alone 
assessed by the composite outcome of mechanical ventilation, any 
myocardial injury and death measured at 30 days.  The sample size of 466 
subjects (233 per group) will provide 85% power to test the secondary 
hypothesis assuming a 48% composite event rate at 30 days in the control 
group (based on internal data from YNHH), a 30% relative reduction in events 
with treatment, a 2-sided α=0.05 and 5% loss to follow-up at 30 days. The 
secondary endpoint will be evaluated in the ITT population (defined as all 
subjects enrolled in the study, by assigned treatment, regardless of the 
treatment actually received). A secondary analysis will be performed in the 
AT population (defined by the treatment actually received, rather than the 
treatment assigned). An additional analysis will be performed in the mAT 
population (defined by the treatment actually received, rather than the 
treatment assigned and excludes all subjects with prior statin therapy). 
Secondary Endpoint Analysis  
All secondary endpoints will be evaluated in the ITT population using 
appropriate descriptive statistics at 30 and 60 days from hospital admission. 
Statistics for continuous variables will include mean, median, standard 
deviation, minimum, maximum, and sample size for each treatment group. 
Binary variables will be summarized using frequencies, percentages, and 
sample size for each treatment group. Proportions of subjects with various 
scores on ordinal scales (i.e. WHO ordinal scale for clinical improvement) will 
be compared between groups using the Chi-squared test for the ordinal 
logistic regression model (null hypothesis states that the slope coefficients in 
the model are the same across response categories). As a secondary 
analysis, all secondary safety endpoints will be evaluated in the AT 
population. An additional analysis will be performed in the mAT population. 
Secondary Imaging Endpoints 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
15 
 
Secondary imaging endpoint based on cardiac MRI at 60 days will be 
performed in a subset of 50 subjects with documented reduced left 
ventricular ejection fraction and adjudicated suspected myocarditis during 
index hospitalization. No formal hypothesis testing will be performed. 
Statistics for continuous variables will include mean, median, standard 
deviation, minimum, maximum, and sample size for each treatment group. 
Subgroup Analyses 
Subgroup analyses will be performed for all primary and secondary endpoints 
for the following subgroups: 
• 
Subject age (<65 years vs. ≥65 years) 
• 
Subject gender (males vs. females) 
• 
Presence of diabetes 
• 
Presence of hypertension 
• 
Presence of CAD  
• 
Presence of high-risk factors including CAD, HTN, cerebrovascular 
disease, CKD, heart failure. 
• 
Subjects naive to colchicine/statins prior to admission  
• 
Subjects receiving other medications as part of SOC (including 
antiplatelet 
agents, 
ACEi/ARB, 
dexamethasone, 
Remdesivir, 
tocilizumab, interferon-beta, therapeutic anticoagulation, etc.) 
• 
SOFA score tertiles on randomization 
• 
WHO score on randomization 
• 
Country and center of enrollment 
Anticipated 
Timelines 
First subject enrolled:   October 2020 
Last subject enrolled: June  2021 
Final analysis: September 2021 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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3.0 Study Contacts 
 
Sponsor 
Yale University School of Medicine 
Address:789 Howard Ave., Dana Rm 309, New Haven, CT 06510 
Contact:  
Name: Alexandra Lansky 
Position: Professor of Medicine, Cardiovascular Medicine 
Yale University School of Medicine/Yale New Haven Health 
Director Heart and Vascular Center Clinical Research Program 
Director Yale Cardiovascular Research Group 
Tel: 203 737 2142 
email: Alexandra.lansky@yale.edu 
  
  
 
 
 
 
 
 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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4.0 Introduction 
4.1 Background 
Patients admitted to hospital with SARS-CoV-2 have a 30% likelihood of developing acute 
respiratory distress syndrome (ARDS), acute lung injury (ALI), or death, mediated through a 
cytokine release syndrome (CRS), associated with systemic inflammation, hemodynamic 
instability, and multiple organ failure. SARS-CoV-2 infection is caused by binding of the viral 
surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor. Upon 
entering the cells, SARS-CoV viroporins, transmembrane pore-forming viral proteins, may 
induce the activation of the NLRP3 inflammasome and production of pro-inflammatory cytokines, 
thought to contribute to the development of myocardial injury and ARDS/ALI.3-7 Worldwide, 
COVID-19 is associated with higher morbidity and mortality among patients with underlying 
comorbidities. Modifying the host inflammatory response may help reduce COVID-19 
complications as one observational study has demonstrated that treating COVID-19 ARDS 
patients with methylprednisolone significantly reduced mortality.8 
Colchicine is an extensively studied and safe potent oral anti-inflammatory agent that was 
initially extracted from the autumn crocus. Colchicine inhibits tubulin polymerization and 
microtubule formation, which virtually brings to a halt any process that requires intracellular 
trafficking along microtubules, cell mitosis and cell migration.9,10 Colchicine downregulates 
multiple inflammatory pathways and modulates innate immunity.9,11 Importantly, colchicine 
interferes with the activation the NLRP3 inflammasome by disrupting the NLRP3 assembly or 
by inhibiting the polymerization of apoptosis-associated speck-like protein containing a caspase 
recruitment domain.12-14 In addition, colchicine may interfere with SARS-CoV-2 viral 
endocytosis and disrupt the virus exit from the cell by preventing spike protein binding to 
microtubules.15 Colchicine is currently being studied in multiple clinical trials as a stand-alone 
agent for the treatment of COVID-19 in the inpatient and outpatient setting.16  
Colchicine is currently indicated for the treatment of gout, Behcet's syndrome, familial 
Mediterranean fever and pericarditis.17,18 The cardiovascular benefits and safety profile of 
colchicine in the setting of secondary prevention therapy including high intensity statin therapy 
was demonstrated in two randomized controlled trials (RCTs): the Low-Dose Colchicine 
(LoDoCo) trial for patients with stable coronary disease19, as well as in patients with a recent 
myocardial infarction in the COLCOT (Colchicine Cardiovascular Outcomes Trial).20  
Statins are known to increase ACE2 expression in animals and humans21-23, which may reduce 
the incidence of ARDS and improves survival.24-27 In addition, statins have anti-inflammatory 
effects by antagonizing TLR-MYD88 pathways, often upregulated in severe SARS infection and 
by reducing inflammation-mediated endothelial dysfunction via Angpt/Tie2 signaling. 
Rosuvastatin, in particular, may have direct antiviral properties by binding and inhibiting the 
active site of the main protease enzyme (Mpro) of SARS-CoV-2. Consequently, it has been 
postulated that statin therapy may reduce the mortality of  respiratory infections including Middle 
East Respiratory Syndrome (MERS) infection and several observational studies demonstrated 
that hospitalized patients on statin therapy have reduced morbidity and mortality associated with 
pneumonia.28-30 Multiple RCTs have studied the use of moderate to high dose statin therapy in 
septic and/or intubated patients with variable results. 31-36 All studies verified the safety of statin 
usage and a few demonstrated efficacy with regards to various endpoints including mortality or 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
18 
 
incidence of ventilator associated pneumonia31, ICU length of stay32, development of  severe 
sepsis36, and reduction in inflammatory cytokines 37. However only two studies demonstrated 
efficacy with regards to their primary endpoint.31,36 These differences may be because negative 
studies enrolled patients too late in their disease course. In line with this evidence, statins are 
being used in the treatment strategy of many COVID-19 patients (de novo use and continuation 
of chronic therapy).38,39 One retrospective study published in a preprint has also demonstrated 
significant symptomatic benefit of chronic prior statin therapy in elderly patients infected with 
SARS-CoV-2.40 
4.1.1 Drug Combination Safety 
The long-term safety of the concurrent use of colchicine and high intensity statin therapy has 
been well established in two RCTs (>5000 patients total) studying colchicine in patients with 
coronary artery disease with low rates of adverse events – particularly infections, myopathy, and 
rhabdomyolysis (< 1-3% at 3 year follow-up).19,20 Drug labels for both medications caution that 
use of both drugs can synergistically cause myopathy or rhabdomyolysis, especially in patients 
with renal impairment. However, rates of these events remain low in RCTs and observational 
studies and do not  significantly differ from patients receiving only one of the medications; 
myositis resulted in withdrawal of <0.5% of patients in LoDoCo trial, there was no serious 
adverse event of myopathy reported in the COLCOT trial, and in a registry from South Korea 
(2.7% vs. 1.4%; p=0.3) of patients on colchicine and statin therapy vs. colchicine alone 
experienced myopathy while 0.3% vs. 0.5% experienced rhabdomyolosis.19,20,41 There is no 
safety data currently available on concurrent use of both medications in COVID-19 patients. 
4.2 Rationale 
To reduce morbidity and mortality associated with acute respiratory distress syndrome (ARDS) 
and myocardial injury in patients with SARS-CoV-2 we propose to test a combined treatment of 
colchicine and statin in a randomized clinical trial. 
4.3 Drug Description 
Colchicine was approved in the US in 1961 for use in the prophylaxis and treatment of acute 
gout and familial Mediterranean fever, for which long-term administration is recommended. 
Extensive experience of this drug in clinical practice, established oral dosing and drug-drug 
interactions are well documented in the prescribing information. 
Rosuvastatin is approved to reduce the risk of MI, stroke, revascularization, angina and to reduce 
total cholesterol and LDL-C, TG. There is extensive experience with this drug in clinical practice, 
with established oral dosing and drug-drug interactions are well documented in the prescribing 
information. Rosuvastatin is contraindicated in patients with hypersensitivity reactions, active 
liver disease, pregnancy, or nursing. Myopathy is increased with use of strong CYP3A4 inhibitors 
and protease inhibitors and requires dose adjustment (section §7.4.1).  Elevation of liver 
enzymes was reported in 2.3% of cases and resolves with discontinuation. Other reported 
adverse reactions include myalgia, abdominal pain and nausea. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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4.4 Regulatory Status 
Both drugs have been in use for decades for gout and pericarditis (colchicine) and 
hyperlipidemia, coronary disease and diabetes (rosuvastatin), and tested in thousands of 
patients with a low but well characterized risk profile.  
Colchicine and rosuvastatin are currently used as standard of care in COVID-19 patients 
whether due to pre-existing disease or acute presentations with acute coronary syndromes or 
acute gout and we do not expect added risk in the population being studied.  
This study is not intended to support a labeling change for a new indication for use or significant 
safety change or advertising claim for either drug, and the study will be conducted in compliance 
with the requirements of the Yale institutional review board (IRB), the ethics/regulatory bodies 
of international participating centers, and of the Research investigational new drug application 
(IND). 
5.0 Study Design 
The Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) Trial is a 
pragmatic randomized open-label study to evaluate the safety and efficacy of the combination 
of Colchicine + Rosuvastatin in addition to standard of care (SOC) compared to SOC alone in 
hospitalized patients with SARS-CoV-2.  
5.1 Study Design Overview 
Subjects will be screened within 48 hours of hospital admission. A total of 466 subjects with RT-
PCR confirmed SARS-CoV-2 infection meeting all inclusion and no exclusion criteria, will be 
randomized to either Colchicine + Rosuvastatin treatment added to SOC or SOC alone for the 
duration of hospitalization. SOC will be guided by the Yale New Haven Health SARS-CoV-2 
Therapeutics Group. Subjects will be assessed daily while hospitalized for clinical, biomarker, 
safety, and laboratory parameters based on the YNHH SOC algorithm. Study treatment will be 
continued for 30 days or until hospital discharge whichever occurs sooner. The subjects will be 
followed clinically until hospital discharge, at 30 days and 60 days from randomization. After 
discharge follow-up will be by phone (Figure 1). A subset of 50 patients with CEC adjudicated 
suspected myocarditis and new reduced LVEF (>10% reduction) by in hospital 
echocardiography will undergo cardiac MRI at 60 days for assessment   
Figure 1. COLSTAT Trial Design 
 
5.2 Study Objectives 
To investigate the safety and efficacy of the combination of Colchicine + Rosuvastatin added 
to standard of care (SOC) compared to SOC alone in hospitalized subjects with moderate 
COVID-19. 
5.3 Study Endpoints 
5.3.1 Primary Endpoints 
5.3.1.1 Primary Efficacy Endpoint 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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The primary efficacy endpoint will be a 30 day composite of the following:  
1) Progression of COVID-19 disease as defined by the World Health Organization (WHO) Ordinal 
Scale for Clinical Improvement Scores 5-8 (or 6-8 if patient at score of 5 at time of 
randomization)*. 
2) Arterial or Venous thromboembolic complications confirmed by imaging (including DVT/PE, MI, 
and ischemic stroke). 
 
*WHO ordinal Scale: 
• Score 5: Hospitalized requiring non-invasive ventilation or high-flow oxygen/high-
flow nasal cannula 
• Score 6: Hospitalized requiring intubation and mechanical ventilation 
• Score 7: Hospitalized requiring ventilation and additional organ support 
(vasopressors, renal replacement therapy, ECMO) 
• Score 8: Death 
5.3.1.2 Primary Safety Endpoint 
The primary safety endpoint will be the proportion of subjects with treatment emergent adverse 
events (TEAE) defined as undesirable events not present prior to medical treatment, or an 
already present event that worsens either in intensity or frequency following the treatment. 
5.3.2 Secondary Endpoints 
5.3.2.1 Powered Secondary Efficacy Endpoint  
The secondary powered efficacy endpoint will be a composite outcome assessed at 30 days 
including: 
a. Respiratory failure requiring invasive mechanical ventilation,  
b. Any myocardial injury (troponin URL> 99th percentile or ≥2-fold increase if troponin is 
abnormal at baseline or a new >10% reduction in LVEF by Echocardiography)  
c. Death 
5.3.2.2 Secondary Endpoints 
The following secondary endpoints will be reported by treatment group at 30 and 60 days: 
Clinical Safety and Efficacy: 
 
a. Death (all cause and cardiovascular) 
b. Duration of oxygen therapy (days) 
c. Duration of invasive mechanical ventilation (days) 
d. Duration of intensive care treatment (days) 
e. Duration of hospitalization (days) 
f. Any myocardial injury (troponin URL > 99th percentile or a >2-fold increase if troponin is 
abnormal at baseline or a new >10% reduction in LVEF by Echocardiography), and 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
21 
 
underlying ischemic (Fourth Universal definitions) or inflammatory cause 
g. Venous thrombosis or thromboembolic complication confirmed by imaging 
h. All stroke (NeuroARC defined) 
i. Acute kidney injury (AKIN criteria) 
j. Time (in days) to symptomatic improvement: reduction in baseline WHO ordinal score 
by >2 points or achievement of scores 1-3. 
k. Overall WHO ordinal scale for clinical improvement at 30 and 60 days. 
Other Secondary Biomarker Endpoints: 
a. Sequential Organ Failure Assessment (SOFA) score, defined by 6 variables (the 
respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems) 
scored from 0 (normal) to 4 (high degree of dysfunction/failure). 
b. Change of the SOFA from baseline.  
c. Peak and change from baseline in routine biomarkers (CRP, procalcitonin, D-dimer, 
PTT/INR, ferritin, troponin/CK-MB, BNP, CPK, AST, ALT, ALP, bilirubin, white blood 
cell count), as available. 
d. Peak and change from baseline in cytokine panel (IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17A, 
IL-17F, IP-10, CCL5), as available 
 
*If an arterial blood gas (ABG) is not available to calculate the PaO2/FiO2 ratio for the SOFA 
assessment the SpO2/FiO2 ratio may be used as an alternative per prior literature.2 
 
Secondary Imaging Endpoints (Imaging substudy)  
a. Proportion of subjects with reduction in LVEF defined as a decrease of more than 10% 
in LVEF by a clinically driven point of care echocardiography measured in hospital 
b. Cardiac MRI in a subset of subjects with adjudicated suspected myocarditis assessed 
at 60 days.  
6.0 Subject Selection and Withdrawal 
6.1 Patient Population 
A total of 466 adult subjects with RT-PCR confirmed SARS-CoV-2 infection hospitalized with 
moderate (non ICU) COVID-19 will be recruited within 48 hours of admission.  
6.2 Eligibility Criteria 
6.2.1 Inclusion Criteria 
Subjects must meet ALL of the following criteria to be eligible for inclusion in the study: 
1. 18 years or older and confirmed SARS-CoV-2 infection by RT-PCR 
2. Patient is admitted to the floor or step down (non-ICU) within 72 hours of hospital 
admission 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
22 
 
3. The patient, or legally authorized representative, has been informed of the nature of 
the study, agrees to its provisions and has provided witnessed (by 2 independent 
members of the health care team) oral informed consent, or a photograph of the 
signed informed consent approved by the appropriate Institutional Review Board 
(IRB) 
6.2.2 Exclusion Criteria 
Subjects will be excluded if ANY of the following criteria apply: 
1. Known pregnancy or nursing mothers 
2. Known allergy to statins or colchicine 
3. Patient is on chronic colchicine  
4. Acute liver disease defined by elevated transaminases (AST/ALT > 3x ULN)   
5. Severe chronic kidney disease defined as glomerular filtration rate (GFR) < 
30mL/min1.73 m2 
6. Severe QTc prolongation (>500ms narrow QRS<120ms and >550ms for wide 
QRS>120) 
7. Presents with severe disease on admission requiring ICU admission (WHO ordinal 
scale of clinical improvement scores 6-8) 
8. Rhabdomyolysis or CPK > 5x ULN 
9. Thrombocytopenia defined as platelet count < 50,000 / mm3 
10.  Leukopenia defined as white blood cell count < 2,500/ µl 
11.  Severe anemia defined as Hemoglobin value <8 g/100ml 
12. Participation in any other clinical trial of an experimental treatment for COVID-19 
6.3 Subject Screening 
All COVID-19 positive patients older than 18 years of age identified through EPIC will be 
screened for enrollment. All potential subjects will be screened by study coordinators in 
consultation with the treating clinicians for eligibility in the COLSTAT trial. After confirmation of 
clinical diagnosis of SARS-CoV-2, the research coordinator will review all inclusion and 
exclusion criteria.  
6.4 Informed Consent 
Subjects will be recruited from the Yale New Haven Hospital (YNHH) and health system. 
Subjects confirmed SARS-CoV-2 positive older than 18 years of age will be offered participation 
in the study using a verbal consent witnessed by 2 health care professionals to limit unnecessary 
handling of forms, or a photograph of the signed informed consent approved by the Institutional 
Review Board (IRB). Video consenting will be implemented whenever possible to limit direct 
patient exposure. The informed consent and HIPAA authorization will be obtained prior to patient 
participation in this trial. The overall protocol (including objectives, procedures and duration), 
potential risks and benefits, voluntary nature and ability to withdraw will be discussed and 
reviewed with each patient and/or their legally authorized representative. The patient and/or their 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
23 
 
legally authorized representative will be given a copy of the IRB-approved ICF to review and will 
have all questions answered before being asked to provide verbal consent witnessed by 2 health 
care providers. Verification of comprehension of the consent will be obtained by asking the 
subject to describe in their words the purpose and risks of the study. The patient and/or their 
legally authorized representative will be instructed that his or her care will not be affected by his 
or her decision to participate, or not. If the patient and/or their legally authorized representative 
voluntarily agrees to participate in the trial, he or she will be asked to provide a verbal consent 
witnessed by 2 healthcare providers (coordinator and physician or nurse) and consent will be 
documented in EPIC by the research coordinator, health care provider or principal investigator.  
Study subjects and/or their legally authorized representatives will be considered to have capacity 
to provide informed consent if they provide comprehensible and sensible answers to the 
following questions: 
(1) Tell me what will happen if you agree to partake in this study? 
(2) Can you leave this study once it begins? 
(3) What should you do if you want to stop being in this study? 
6.5 Subject Enrollment and Randomization 
Subjects meeting eligibility criteria and providing informed consent will be randomized to 
Colchicine 0.6mg twice daily for 3 days followed by 0.6mg daily + Rosuvastatin 40mg daily in 
addition to SOC or SOC only using electronic block randomization programed within EPIC. 
Investigational treatment will continue until hospital discharge. 
Randomized patients will undergo management based on standard of care treatment 
determined by the primary care team and the YNHH treatment algorithm for hospitalized patients 
with COVID-19. Baseline screening will include History & Physical (H&P), chest X-ray (CXR), 
and baseline ECG. SOFA score including Glasgow coma score will be preferably be recorded 
every 24 hours as able. Baseline biomarker measurements and subsequent frequency will be 
based on each center’s SOC but preferably should occur every 24 hours during hospitalization 
and should preferably include at minimum a basic metabolic panel, CBC with differential, LFTs, 
CRP, procalcitonin, D-dimer, and troponin (or CK-MB if not available). Cytokine measurement 
and other labs/imaging will occur according to the SOC of each center. 
6.6 Withdrawal and Replacement of Subjects 
Subjects can withdraw from the study at any time; the reason(s) for withdrawal (if given) will be 
documented. All data available at the time of withdrawal (if any) will be used for analysis. There 
will be no further follow-up (per this study protocol) on subjects who have withdrawn. Subjects 
who withdraw from the study will not be replaced. The withdrawal of a subject can be initiated 
by the Investigator if he/she determines it is in the best interest of the patient. 
6.7 Protocol Deviations 
All deviations from the requirements of this Clinical Investigation Plan will be considered protocol 
deviations.  
A major protocol deviation is a protocol deviation that may affect the scientific soundness of the 
protocol or the rights, safety, or welfare of the patients. Major protocol deviations require urgent 
reporting to the Study Monitor and the Institutional Review Board.  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
24 
 
Patient-level deviations are those that occur in direct association with a specific study patient. 
These include, but are not limited to, deviations from informed consent procedures, 
inclusion/exclusion criteria, protocol-specified procedures and assessments, and drug handling 
and usage. 
Site-level deviations are those that occur at the study center but are not directly related to a 
study specific patient. All efforts shall be made to avoid any protocol deviation. 
7.0 Study Procedures 
7.1 Study Schedule of Procedures and Assessment 
Randomized subjects will undergo management based on standard of care. Baseline screening 
will include History & Physical (H&P), chest X-ray (CXR), and baseline ECG as clinically 
indicated. SOFA score including Glasgow coma score will be recorded  preferably every 24 
hours as able. Baseline biomarker measurements and subsequent frequency will be based on 
each center’s SOC but preferably should occur every 24 hours during hospitalization and 
preferably  should include at minimum a basic metabolic panel, CBC with differential, LFTs, 
CRP, procalcitonin, D-dimer, and troponin (or CK-MB if not available). Cytokine measurement 
and other labs/imaging will occur according to the SOC of each center. 
 
 
Table 1. Study Schedule of Procedures and Assessments 
Visit Identifier 
. 
Screening Day 
1 
Daily 
Assessments 
End of 
Treatment 
(Discharge) 
30 day  
follow-up 
(by 
phone) 
60 day  
follow-up 
(by 
phone) 
Follow-up 
(30 days 
post-
discharge) 
Cardiac 
MRI 
subgroup 
Visit Window 
 
 
  
  
 
 
 
 
 
 
Informed consent 
X 
 
  
  
 
 
 
 
 
 
Randomization 
 
X 
  
  
 
 
 
 
 
 
Medical history 
X 
 
  
  
 
 
 
 
 
 
Physical 
examination 
X 
X X X X X X X 
X 
 
 
 
Height/Weight* 
X 
 
  
  
 
 
 
 
 
 
ECG** 
X 
 
  
  
 
 
 
 
 
 
Chest X ray** 
X 
 
  
  
 
 
 
 
 
 
Vital signs (pulse, 
blood pressure, 
respiratory rate, 
SpO2 by pulse 
oximetry, 
temperature) 
X 
X X X X X X X 
X 
 
 
 
Laboratory1 
 
 
  
  
 
 
 
 
 
 
Hematology 
X 
X X X X X X X 
X 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
25 
 
Visit Identifier 
. 
Screening Day 
1 
Daily 
Assessments 
End of 
Treatment 
(Discharge) 
30 day  
follow-up 
(by 
phone) 
60 day  
follow-up 
(by 
phone) 
Follow-up 
(30 days 
post-
discharge) 
Cardiac 
MRI 
subgroup 
Visit Window 
 
 
  
  
 
 
 
 
 
 
Blood chemistry 
X 
X X X X X X X 
X 
 
 
 
Inflammation 
panel2 
X 
X X X X X X X 
X 
 
 
 
Coagulation3 
X 
X X X X X X X 
X 
 
 
 
Cardiac panel4 
X 
X X X X X X X 
X 
 
 
 
Liver function 
test 
X 
X X X X X X X 
X 
 
 
 
Arterial blood 
gas* 
 
 
  
  
 
 
 
 
 
 
Record if 
admitted to 
intensive care 
unit (ICU) 
 
X X X X X X X 
X 
 
 
 
Assessments 
 
 
X X X X X X 
X 
 
 
 
Efficacy: 
X 
X X X X X X X 
X 
 
 
 
FiO2 
X 
X X X X X X X 
X 
 
 
 
WHO Ordinal scale 
of clinical 
improvement 
X 
X X X X X X X 
X 
 
 
 
SOFA score *** 
X 
X X X X X X X 
X 
 
 
 
Assessment of 
level of 
consciousness 
X 
X X X X X X X 
X 
 
 
 
Cytokine panel5 
 
X 
 X  X  X 
X 
 
 
 
Test for SARS-
CoV26 
X 
 
  
  
 
 
 
 
 
 
Concomitant 
treatment(s) 
 
X X X X X X X 
X 
X 
 
 
Hand-held Echo** 
 
X X X X X X X 
 
 
 
 
Serious and 
nonserious adverse 
event monitoring 
X 
X X X X X X X 
X 
X 
X 
 
Hospital 
Readmission 
 
 
  
  
 
 
 
X 
X 
 
Cardiac MRI 
 
 
  
 
 
 
 
 
 
 
X 
*As clinically indicated  
** Diagnostics including ECG, Chest X-ray, and echo should occur according to each centers SOC as 
clinically indicated. It is preferably but not required if every patient has baseline ECG and Chest X-ray. 
If a patient is suspected of having myocarditis due to rise an cardiac enzymes or clinical signs it is 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
26 
 
recommended but not required that they receive a point of care echo if within center’s SOC. Further 
imaging is not mandated and should only occur as clinically indicated.  
*** The SOFA score requires LFTs, creatinine, and an ABG. It should be recorded for every patient 
when appropriate labs are available within a 24 hour period. If and ABG is not available to assess 
PaO2/FiO2 it is okay to substitute using SpO2/FiO2 ratio per prior literature. See definitions in Section 
15.1. 
 
We will collect serum samples for biobanking. Samples will be obtained at Day 1 prior to treatment 
administration and then every 72 hours thereafter until discharge (see Figure 1. COLSTAT Trial Design). 
All biomarker measurements and subsequent imaging/tests will occur based on SOC at respective center 
and decision of primary team when clinically indicated. However, preferably should occur every 24 hours 
during hospitalization and preferably should include at minimum a basic metabolic panel, CBC with 
differential, LFTs, CRP, procalcitonin, D-dimer, and troponin (or CK-MB if not available). Cytokine 
measurement and other labs/imaging will occur according to the SOC of each center. 
1Routine labs should occur per center’s SOC, preferably should occur at least every 24 hours and 
preferably should include at minimum a basic metabolic panel, CBC with differential, LFTs, CRP, 
procalcitonin, D-dimer, and troponin (or CK-MB if not available). BNP, ferritin, LDH, PTT/INR are 
useful parameters that may also be measured based on SOC and clinical indication when 
appropriate. 
2 Inflammatory panel per center’s SOC: preferably CRP and procalcitonin should be measured every 24 
hours. If Cytokines are measured in hospital per SOC it would be preferably to measure IL-1, IL-6, and 
TNF-α at minimum, preferably on day 1, day 3, day 7/discharge, and if patient is transferred to the MICU.  
IL-2, IL-8, IL-17A, IL-17F, IP-10, CCL5, ferritin, and LDH may also be useful and may be measured based 
on center’s SOC when clinically indicated. 
3 Coagulation panel per center’s SOC:  Preferably D-dimer should be measured every 24-48 hours at 
minimum. Fibrinogen, PT/PTT may also be measured based on center’s SOC 
4 Cardiac panel per center’s SOC: Preferably quantitative troponin (or CK-MB when troponin not 
available) should be measured every 24-48 hoors at minimum.  BNP and LDH may also be measured 
based on center’s SOC 
5 Cytokine panel per center’s SOC: IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17A, IL-17F, IP-10, CCL5 may be 
measured if part of center’s SOC. If Cytokines are measured in hospital per SOC it would be preferably 
to measure IL-1, IL-6, and TNF-α at minimum, preferably on day 1, day 3, day 7/discharge, and if 
patient is transferred to the MICU. 
6 Test for SARS-CoV2 by real time reverse transcription polymerase chain reaction RT-PCR. Mandated 
to occur before enrollment. Retesting to occur based on center’s SOC 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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7.2 Screening / Baseline 
Subjects will be recruited from the Yale New Haven Hospital (YNHH) and health system. 
Subjects will be screened within 48 hours of admission for SARS-CoV-2. Informed consent will 
be obtained after confirmation of COVID-19 positivity by RT-PCR and eligibility criteria. Subjects 
will not be compensated.  
Screening for enrollment in the study will include subject information and all standard of care 
(SOC) in the evaluation of patients with SARS-CoV-2.  Subjects will be excluded for known 
pregnancy, known hypersensitivity to statins or colchicine, if they are on chronic colchicine or 
oral corticosteroid treatment, liver failure, severe kidney disease (glomerular filtration rate (GFR) 
< 30mL/min), prolonged QTc, requiring intubation on admission. 
7.3 Concomitant Therapies 
Selection and dosing of concomitant therapies, all standard of care treatments for hospitalized 
patients with SARS-CoV-2 are permitted during the period of treatment with the study 
intervention. This only includes treatments approved by the Yale SOC treatment Committee. 
Concomitant therapy will be performed according to standard practice, local standards of care 
and published guidelines. Subjects will not be permitted to participate in other investigational 
studies. 
All medications administered will be recorded in the patient’s medical record. 
7.4 Drug Dosing, Storage and Discontinuation 
7.4.1 Drug Dosing 
In addition to standard of care patients randomized to active treatment will receive: 
• Rosuvastatin: 40mg daily AND 
• Colchicine: 0.6mg twice daily for 3 days then 0.6mg daily 
Note: Subjects previously on chronic statin therapy will be eligible for enrollment in the trial, and if 
randomized to active treatment, chronic statin therapy will be discontinued and replaced by rosuvastatin 
40 mg for 30 days or hospital discharge and resumed thereafter. 
7.4.1.1 Drug Interactions and Dosing Adjustment 
 
Note: for subjects taking drugs with interaction with colchicine the dose will be reduced according 
to the following: 
• Co-administration with Strong CYP3A4 Inhibitors (includes Atazanvir): 
0.3mg once a day X3 days then 0.3mg every other day 
• Co-administration 
with 
Moderate 
CYP3A4 
Inhibitors 
(includes 
Erythromycin, Diltiazem, Verapamil, Fosamprenavir): 0.3mg twice a day X3 
days then 0.3mg every day 
• Co-administered with Protease Inhibitors (atazanavir, Darunavir, Indinavir, 
Ritonavir, saquinavir, Tipranavir, Nelfinavir) 0.3mg once a day X3 days 
then 0.3mg every other day 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Drug interactions will be screened throughout hospitalization and active treatment and will be 
programmed in EPIC to notify the treatment team and research coordinator. All standard of care 
treatments for hospitalized patients with SARS-COV-19 are permitted during the period of 
treatment with study intervention. Dose adjustments for drug interactions are listed above. Drug 
discontinuation is only permitted with documented adverse reactions. The standard of care 
treatment will be determined by the primary care team and the YNHH treatment algorithm for 
hospitalized patients with COVID-19. 
7.4.1.2 Dose Modification and Renal Impairment 
• 
Patients who develop mild or moderate renal impairment (estimated GFR >30 mL/Min) will 
be monitored for adverse effects.  Dose reduction of colchicine may be necessary. 
• 
Patients with severe renal impairment (estimated GFR < 30mL/Min)  
o Recommended colchicine dose is 0.3mg twice a day X3 days then 
0.3mg every day and should be monitored closely for adverse 
effects of colchicine 
o Recommended rosuvastatin dose is 10 mg daily 
7.4.1.3 Dose Modification and Hepatic Impairment 
• 
Patients with or who develop mild or severe hepatic impairment should be monitored 
closely for adverse effects of colchicine and rosuvastatin 
• 
Patients with severe hepatic impairment,  
o recommended dose is 0.3mg twice a day X3 days then 0.3mg every 
day and should be monitored closely for adverse effects of 
colchicine 
o Recommend discontinuation of rosuvastatin 
7.4.2 Drug Storage 
Commercially available tablets will be stored at and dispensed by the YNHH pharmacy. The 
tablets or suspension can be given by mouth or via nasogastric tube.  The pharmacy may convert 
the active ingredient into a suspension form. 
7.4.3 Drug Discontinuation 
Study drug may be discontinued in a subject after review of all available data with the medical 
monitor and discussion with the investigator if any of the following occur: 
• Any SAE or > Grade 3 AE is suspected to be related to treatment 
• Any elevation of ALT>5xULN confirmed by repeat testing 
• Any elevation of CK >5xULN confirmed by repeat testing 
• Severe myalgias suspected related to statin therapy 
• Subjects who develop renal or hepatic impairment and require a protease inhibitor or 
strong CYP3A4 inhibitor should discontinue colchicine 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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• Subjects who develop new blood dyscrasia including leukopenia, granulocytopenia, 
thrombocytopenia, pancytopenia, aplastic anemia should discontinue colchicine 
7.5 In-hospital Follow-up 
Randomized subjects will be assessed daily while hospitalized for clinical, cardiac and 
inflammatory biomarkers, safety, and laboratory parameters based on SOC. 
8.0 Adverse Events and Serious Adverse Events 
Adverse events will be reviewed by the DSMB. Both treatment drugs are approved and 
commonly prescribed. The trial is open labeled and driven by standard of care.  We will therefore 
monitor discontinuations of treatment and the underlying reasons to monitor adverse events 
attributable to treatment. 
8.1 Adverse Events (AE) 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An adverse event could present as an 
abnormal laboratory finding, abnormal imaging finding or an abnormal clinical finding or 
symptom. 
8.2 Life-threatening Adverse Event or Life-threatening Suspected 
Adverse Reaction 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
8.3 Serious Adverse Events (SAE) or Serious Suspected Adverse 
Reaction 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• Death,  
• A life-threatening adverse event,  
• Inpatient hospitalization or prolongation of existing hospitalization,  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions,  
• A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  
8.4 Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. For the purposes of IND safety reporting, “reasonable possibility” means there is evidence 
to suggest a causal relationship between the drug and the adverse event. Suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug.   
For rosuvastatin, these may include (2%) 
• Myalgia 
• Abdominal pain 
• Nausea 
• Headache 
For cochicine, these may include (up to 20%): 
• Abdominal pain 
• Nausea 
• Diarrhea 
• Vomiting 
• Rash 
• Elevated AST/ALT 
• Myopathy 
 
8.5 Unexpected Adverse Event or Unexpected Suspected Adverse 
Reactions 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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8.6 Documentation 
Adverse events must be listed on the patient’s medical record. All AEs will be characterized by 
the following criteria:  
• Intensity or Severity 
• Relatedness 
• Outcome 
• Treatment or Action Taken 
8.6.1 Intensity or Severity 
The following grades of the intensity of an adverse event will be used, according to Common 
Terminology Criteria for Adverse Events (CTCAE) v5.042:  
Grade 1  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE. 
ADL=Activities of Daily Living; *Instrumental ADL refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. **Self care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
8.6.2 Relatedness 
The investigator will use the following definitions to assess the relationship to the treatment: 
Not related 
 
The cause of the AE is known, and the event is not related to any 
aspect of study participation. 
Unlikely to be 
related 
There is little or no temporal relationship to the study drug and/or a 
more likely alternative etiology exists. 
Possibly related 
There is a reasonable possibility that the event may have been caused 
by study participation.  
The AE has a timely relationship to the study procedure(s); however, 
follows no known pattern of response, and an alternative cause 
seems more likely or there is significant uncertainty about the cause of 
the event.  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Probably related 
It is likely that the event was caused by study participation. 
The AE has a timely relationship to the study treatment and follows a 
known pattern of response; a potential alternative cause, however, 
may explain the event. 
Related 
A related event has a strong temporal relationship and an alternative 
cause is unlikely. 
If the relationship between any adverse event and the use of the investigational drug is 
considered to be possibly or probably related, that event will be classified as an ADE or SAE 
8.6.3 Outcome 
The clinical outcome of the AE or SAE will be characterized as follows: 
Death 
The SAE CRF must be completed for this outcome 
Recovered without sequelae 
The patient returned to baseline status 
Ongoing 
Patient did not recover and symptoms continue 
Recovered with sequelae 
The patient has recovered but with clinical sequelae from the event 
Unknown 
The patient outcome is unknown 
8.6.4 Treatment or Action Taken 
The treatment or action taken after the occurrence of an AE or SAE will be reported as: 
Interventional Treatment 
Surgical, percutaneous or other procedure 
Medical Treatment 
Medication dose reduction/interruption or discontinuation, or 
medication initiated for event 
None 
No action is taken 
8.7 Reporting 
8.7.1 General Adverse Event Reporting Procedures 
The principal investigator will report the following types of events to the IRB: a) adverse events 
that are serious or life-threatening AND unanticipated (or anticipated but occurring with a greater 
frequency than expected) AND possibly, probably or definitely related to the drug; and b) other 
unanticipated problems involving risks to subjects or others. These adverse events or 
unanticipated problems involving risks to subjects or others will be reported to the IRB in 
accordance with IRB Policy 710. 
8.7.1.1 Safety Reports Submitted to FDA 
For studies conducted under an IND, there are two types of Safety Reports submitted to FDA: 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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• 7-Calendar-Day FDA Telephone or Fax Report: The sponsor-investigator will 
directly notify the FDA, within 7 calendar days after initial receipt of the information, 
of any adverse event that is fatal or life-threatening, unexpected, and considered 
at least possibly related to the investigational product.  
• 15-Calendar-Day FDA Written Report:  The sponsor-investigator will directly notify 
the FDA within 15 calendar days after initial receipt of the information, of any 
serious adverse event (other than those that are fatal or life-threatening) that is 
unexpected and considered at least possibly related to the investigational product. 
Serious Adverse Events which do not meet the criteria for expedited reporting will be reported 
to the FDA in the IND Annual Report. 
8.7.2 Serious Adverse Events 
The Principal Investigator will notify the Yale IRB within 3 working days of first learning of any 
SAE using the EDC CRF. If necessary, the Investigator may be requested to provide copies of 
de-identified source documentation (e.g., physician/nurse notes or summaries) regarding the 
event. If required, SAEs will be reported by YALE to the applicable authority. 
8.7.3 Unexpected Adverse Event or Unexpected Suspected Adverse 
Reaction 
The Principal Investigator will notify the Yale IRB within 3 working days of first learning of any 
unexpected adverse event or unexpected suspected adverse reaction using the EDC CRF. If 
necessary, the Investigator may be requested to provide copies of de-identified source 
documentation (e.g., physician/nurse notes or summaries) regarding the event. If required, 
unexpected adverse event or unexpected suspected adverse reaction will be reported by YALE 
to the applicable authority. 
8.7.3.1 Expected Adverse Events 
The following adverse events have been identified as actual or potential complications 
associated with colchicine and rosuvastatin therapy. 
Risks reported with colchicine: 
• 
Rhabdomyolysis 
• 
Neuromuscular toxicity 
• 
Renal and hepatic toxicity 
• 
Disseminated intravascular coagulation 
• 
Diarrhea 
• 
Pharyngolaryngeal pain 
• 
Nausea 
• 
Abdominal pain 
• 
vomiting 
• 
fatigue 
• 
Headache 
• 
Leukopenia 
• 
Granulocytopenia 
• 
Thrombocytopenia 
• 
Pancytopenia 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
34 
 
• 
Myopathy 
• 
Elevated CPK     
Risks reported with rosuvastatin: 
• 
Myalgia 
• 
Abdominal pain 
• 
Nausea 
• 
Headache 
• 
Rhabdomyolysis 
• 
Liver enzymes abnormalities 
• 
Constipation 
 
Frequencies of common side effects by dose of each of these drugs are shown in Table 2 and 
3 below: 
 
Table 2: Colchicine: Number (%) of Patients with at Least One Drug-Related Treatment-
Emergent Adverse Event with an Incidence of >2% of Patients in Any Treatment Group 
 
 
 
 
 
 
 
 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
35 
 
 
 
 
 
Table 3: Rosuvastatin: Adverse Reactions* Reported by ≥ 2% of Patients Treated with 
CRESTOR and > Placebo in the METEOR Trial (% of Patients) 
9.0 Benefit: Risk Analysis 
9.1 Potential Benefits 
We estimate from data collected by the Yale New Haven Health System (including 1,412 COVID-
19 patients) that hospitalized patients with SARS-COV-19 have a 48% risk of requiring 
mechanical ventilation, myocardial injury or death.  Based on prior literature we estimate a 30% 
benefit from the use of Colchicine + Rosuvastatin started early during admission. If proven 
beneficial, the enrolled subjects will have a direct benefit in reducing complication rate and other 
subsequent patients hospitalized with SARS-COV-19 will also benefit from a proven treatment 
of this morbid and sometimes fatal disease. 
Because the drug combination Colchicine + Rosuvastatin is low risk and cheap, this treatment 
can be implemented early with significant impact on clinical outcomes. 
The trial is expected to make a substantial contribution to medical science and clinical decision-
making that could benefit future patients with SARS-CoV-2. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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9.2 Potential Risks and Discomforts 
Both Colchicine and Rosuvastatin have been extensively studied in thousands of patients 
used individually and in combination with a low and well characterized risk profile. Colchicine 
and rosuvastatin are currently used as standard of care in COVID-19 patients whether due to 
pre-existing CAD, gout or pericarditis or acute presentations with acute coronary syndromes or 
acute gout with no expected added risk in the population being studied. Because both drugs are 
used in combination in COVID-19 positive patients the potential risk is deemed low/moderate, 
however has not been evaluated previously. 
9.3 Methods to Minimize Risks 
Patients will be evaluated at least once daily depending on level of acuity. Daily laboratory 
monitoring including CBC, CMP are all included in the standard of care.  In addition, CPK will be 
monitored with symptoms of muscle pain.  Patients at risk for drug complications are excluded 
from the study (sever liver disease and severe kidney disease). 
10.0 Study Committee 
10.1 Executive Committee 
The executive committee will be comprised of the principal investigator, co-investigators and 
sub-investigators.  They will convene on a monthly basis to review enrolment and compliance 
with the protocol and provide guidance for the conduct of the trial. 
10.2 Clinical Events Committee 
An independent Clinical Events Committee (CEC), or Independent Physician Adjudicator, will be 
responsible for systematic review and adjudication of all primary and secondary safety events 
as identified in this protocol to ensure uniform classification of events according to pre-specified 
definitions as well as relationship to the drug(s) or combination of drugs versus underlying 
disease. Clinical experts will be selected based upon their expertise with cardiovascular disease, 
infectious disease, renal disease and or neurological disease therapeutic areas as well as their 
expertise and familiarity with the growing body of knowledge regarding SARS-CoV-2. 
  
In order to enhance objectivity and reduce the potential for bias, the CEC members shall be 
independent of direct treatment of subjects enrolled under this research protocol. The 
methodology for performing these responsibilities shall be developed and outlined in the CEC 
Charter. Operational provisions shall be established to minimize potential bias.  
10.3 Data Safety Monitoring Board 
An independent data safety monitoring board will oversee the safe and ethical conduct of the 
trial. The DSMB will have the authority to discontinue the trial on the basis of safety concerns. 
Given the current unknown effect of multiple treatment effects, emerging treatment interventions 
and the evolving knowledge of the course and impact of SARS-CoV-2 on public and individual 
subject health and safety, the DSMB may comment or advise the Sponsor on potential signs of 
futility. 
Adverse events will be reviewed by the DSMB. Both treatment drugs are approved and 
commonly prescribed. The trial is open labeled and driven by standard of care.   


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
37 
 
DSMB will therefore monitor discontinuations of treatment and the underlying reasons to monitor 
adverse events attributable to treatment. 
10.3.1 Considerations for Stopping Rules 
The DSMB may consider making a recommendation for a temporary hold on enrollment and 
further randomization should any of the following be observed:  
• A two-fold increase in event rates for key events of special interest is seen in the treatment 
arm versus the control arm, or a two-fold increase in serious adverse events overall is 
seen in the treatment arm versus the control arm.  
Key events of special interest for the purpose of DSMB evaluation include: 
• Elevations in hepatic transaminases 
• Myopathies 
• Myalgia 
• Asthenia 
• Rhabdomyolysis 
• Impaired renal function as evidenced by change in either serum creatinine or creatinine 
clearance 
• Gastrointestinal adverse events including nausea, vomiting or diarrhea 
• Death 
• Thrombosis or thromboembolic events 
The DSMC shall conduct a full investigation of potential contributing causes prior to making any 
recommendation for enrollment to resume, a change to protocol, or termination of further 
enrollment or randomization.  
The DMC reserves the right to make a recommendation for temporary suspension of enrollment 
until circumstances are investigated should the number of deaths reported to the committee in 
an expedited fashion appear higher in the treatment arm than the number reported in the control 
arm or if >5 unanticipated suspected adverse reactions are reported via expedited event 
reporting. 
11.0 Statistical Considerations and Analysis Plan 
11.1 Hypotheses 
The COLSTAT Trial will test the following hypotheses:  
Primary Hypothesis: Among hospitalized SARS-CoV-2 confirmed subjects treated with 
standard therapy, the addition of Colchicine + Rosuvastatin is superior to standard of 
care in reducing the composite outcome of progression to severe COVID-19 disease (as 
defined by WHO ordinal scale scores 5-8 or 6-8 if at score of 5 on admission) and arterial 
and venous thromboembolic complications at 30 days.  
Secondary Powered Endpoint: Among hospitalized SARS-CoV-2 confirmed subjects 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
38 
 
treated with standard therapy, the addition of Colchicine + Rosuvastatin is superior to 
standard of care in reducing the composite outcome of respiratory failure requiring 
mechanical ventilation, myocardial injury or death at 30 days.  
Secondary Hypothesis: Among hospitalized SARS-CoV-2 confirmed subjects treated 
with standard therapy, the addition of Colchicine + Rosuvastatin reduces length of stay, 
need and duration of ICU care, myocardial injury, respiratory failure and duration, 
multiorgan failure or death, acute kidney injury, use of Extracorporeal Membrane 
Oxygenation (ECMO) and cytokine, inflammatory and cardiac biomarkers compared to 
standard of care measured at hospital discharge. 
To determine the treatment effect in subgroup analysis (test of interaction) and predictors 
of the secondary powered endpoint of mechanical ventilation, myocardial injury or death 
among candidate variables including baseline risk factors, cytokines, inflammatory and 
cardiac biomarkers. We hypothesize that Colchicine + Rosuvastatin will have a 
consistent treatment effect across all subgroups.  
Among subjects who develop myocardial injury during hospitalization, Colchicine + 
Rosuvastatin compared to standard of care will improve cardiac function and recovery 
based on 30-day post discharge cardiac Magnetic Resonance Imaging (MRI). 
11.1.1 Primary Efficacy Endpoint  
The primary efficacy endpoint hypothesis is a test of superiority of Colchicine + Rosuvastatin 
in addition of SOC compared to SOC alone assessed by the primary composite outcome of 
progression to severe COVID-19 disease (as defined by WHO ordinal scale scores 5-8) at 30 
days. Specifically, the superiority hypotheses are 
H0: P1 – P2 =0 vs. H1: P1-P2 ≠ 0 
Where: 
P1 = the true rate of primary endpoint at 30 days in the Colchicine + Rosuvastatin 
in addition to SOC arm  
P2 = the true rate of primary endpoint at 30 days in the SOC only arm 
The null hypothesis will be tested at a two-sided 0.05 level of significance and using the two-
sample proportion test. Superiority will be demonstrated if the true primary outcome of 
progression to severe COVID-19 disease are not equal using the two-proportion tests. 
11.1.2 Powered Secondary Endpoint  
The powered secondary efficacy endpoint analysis will be a test of superiority of Colchicine + 
Rosuvastatin in addition to SOC compared to SOC alone assessed by the composite outcome 
of mechanical ventilation, myocardial injury and death measured at 30 days. Specifically, the 
superiority hypotheses are: 
H0: P1 – P2 =0 vs. H1: P1-P2 ≠ 0 
Where: 
P1 = the true rate of composite outcome of mechanical ventilation, myocardial 
injury and death in the Colchicine + Rosuvastatin in addition to SOC arm  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
39 
 
P2 = the true rate of composite outcome of mechanical ventilation, myocardial 
injury and death in the SOC only arm 
The null hypothesis will be tested at a two-sided 0.05 level of significance and using the two- 
sample proportion likelihood test. Superiority will be demonstrated if the true composite primary 
outcome of mechanical ventilation, myocardial injury and death rates are not equal using the 
two-proportion tests. 
11.2 Analysis Population 
11.2.1 Intention to Treat (ITT) Analysis Population 
The Intention to Treat (ITT) analysis population is defined as all subjects enrolled in the study, 
by assigned treatment, regardless of the treatment actually received. 
The ITT population will be the primary analysis population for all primary and secondary 
endpoints  
11.2.2 As Treated (AT) Analysis Population 
The As Treated (AT) analysis population is defined by the treatment actually received, rather 
than the treatment assigned.  
The AT population is the secondary analysis population for all primary and secondary endpoints. 
11.2.3  M As Treated (mAT) Analysis Population 
The mAT analysis population is defined by the treatment actually received, rather than the 
treatment assigned and excludes all subjects with prior statin therapy.     
The mAT population is an additional analysis population for all primary and secondary endpoints. 
11.3 Sample Size Calculation and Assumptions 
11.3.1 Primary Endpoint Analysis 
The primary efficacy endpoint hypothesis is a test of superiority of Colchicine + Rosuvastatin 
in addition of SOC compared to SOC alone assessed by the primary outcome of progression to 
severe COVID-19 disease (as defined by WHO ordinal scale scores 5-8 or 6-8 if patient at score 
of 5 at time of randomization) and arterial and venous thromboembolic complications at 30 days. 
The primary endpoint will be evaluated in the ITT population. A secondary analysis will be 
performed in the AT population. 
The following assumptions were made: 
 Expected rate of the primary outcome of progression to severe COVID-19 disease (as 
defined by WHO ordinal scale scores 5-8) in the SOC alone arm at 30 days= 44.2% 
 Assumes the true rates of primary outcome are not equal between two groups using the 
two sample proportion tests. 
 2-sided α=0.05 
 Assumes 30% relative reduction in events with Colchicine + Rosuvastatin treatment  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
40 
 
A total of 466 subjects (233 per group) will provide at least 80% power to test the primary 
hypothesis assuming a 44.2% event rate at 30 days in the control group, a 30% relative reduction 
in events with treatment, a 2-sided α=0.05 and at 10% loss to follow-up at 30 days.  
11.3.2 Powered Secondary Endpoint Analysis 
The secondary powered efficacy endpoint analysis will be a test of superiority of Colchicine + 
Rosuvastatin in addition to SOC compared to SOC alone assessed by the composite outcome 
of mechanical ventilation, myocardial injury and death measured at 30 days. The secondary 
endpoint will be evaluated in the ITT population. A secondary analysis will be performed in the 
AT population. 
The sample size of 466 subjects (233 per group) will provide 85% power to test the secondary 
hypothesis assuming a 48% composite event rate at 30 days in the control group, a 30% relative 
reduction in events with treatment, a 2-sided α=0.05 and 5% loss to follow-up at 30 days.  
11.3.3 Rationale for Assumptions 
11.3.3.1 Expected Control Event Rate for Primary Endpoint 
11.3.3.2 The primary endpoint event rate at 30 days was estimated using data 
from more recent COVID-19 studies given that improvements in SOC have 
reduced event rates. Per the RCT comparing dexamethasone use to placebo in 
COVID-19 patients from the RECOVERY trial the event rate of mechanical 
ventilation and death in patients not requiring mechanical ventilation at time of 
randomization 
in 
dexamethasone 
arm 
was 
25.6%.43 
The 
rates 
of 
CPAP/BiPAP/HFNC use in COVID-19 patients are not well reported but in the 
Remdesivir trial at 15 days 10.7% of patients were requiring their use.44 The true 
30-day event rate will be higher given some patients will progress later and some 
patients would have improved by this time point. This is balanced by 
improvements in SOC since this trial. Per a recent meta-analysis the rate of PE 
and DVT in non-ICU COVID-19 patients is 10.5% and 7.4%, respectively with 
about 42% of patients with PE having an identified DVT.45 This makes the 
composite event rate of DVT/PE approximately 14.8%. The true incidence will 
likely be slightly higher given that some patients in trial will eventually be admitted 
to ICU and rates of DVT/PE are significantly higher in this population. Finally, the 
incidence of acute MI and/or ischemic stroke appears to be approximately 1% 
based on a recent registry.46 In total the sum of these event rates is 52.1%. 
Assuming a conservative 15% overlap in events the assumed event rate of 
44.2% in the SOC arm is reasonable. Expected Control Event Rate for 
Secondary Powered Endpoint 
The secondary powered endpoint (composite of death, myocardial injury, and invasive 
mechanical ventilation) event rate was estimated from data from 1,412 COVID-19 patients 
discharged from the Yale New Haven Health System, the system in which this trial will be 
undertaken. In the system the event rates for the three individual endpoints in the composite are 
death (17%), myocardial injury (48%), and invasive mechanical ventilation (33%). Although rates 
are not currently available for the composite of these three, a conservative event rate of 48% 
was assumed based on the highest individual event rate. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
41 
 
11.4 Method of Analysis and Reporting 
11.4.1 General Approach 
Superiority testing for the primary efficacy endpoint (Proportion of subjects that progress to 
severe COVID-19 disease by 30 days, as defined by the World Health Organization (WHO) 
Ordinal Scale for Clinical Improvement Scores 5-8) and powered secondary efficacy endpoint 
(Composite outcome of mechanical ventilation, myocardial injury and death measured at 
discharge) will be 2-sided and perfomed at 0.05 significance level. Proportions of subjects with 
various scores on ordinal scales (i.e. WHO ordinal scale for clinical improvement) will be 
compared between groups using the Chi-squared test for the ordinal logistic regression model.  
Analysis of all additional secondary endpoint results will be summarized using descriptive 
statistics. For binary variables, descriptive statistics will include counts, percentages, and sample 
size for each treatment group; p-values may be presented for hypothesis-generating purposes. 
For continuous variables, descriptive statistics include mean, median, standard deviation, 
quartiles, minimum, maximum, and sample size for each treatment group. Binary variables will 
be summarized using frequencies, percentages, and sample size for each treatment group. For 
time-to-event data, Kaplan-Meier estimates at the indicated time points will be displayed 
graphically.  
Analysis will be conducted using SAS (version 9.3 or greater), unless otherwise noted. Please 
refer to the formal Statistical Analysis Plan (SAP) for additional details. 
11.4.2 Baseline Characteristics 
The following data will be summarized using descriptive statistics and presented by treatment 
group for the ITT and PP populations:  
• Baseline demographics  
• Baseline comorbidities, risk factors, medical history, and medication usage 
• Baseline SOFA score 
11.4.3 Primary Endpoint Analysis 
The primary efficacy endpoint analysis will be a test of superiority of Colchicine + Rosuvastatin 
in addition to SOC compared to SOC alone assessed by the primary outcome of progression to 
severe COVID-19 disease (as defined by WHO ordinal scale scores 5-8 or 6-8 if patient at score 
of 5 at time of randomization) and arterial and venous thromboembolic complications at 30 days. 
The primary endpoint will be evaluated in the ITT population. A secondary analysis will be 
performed in the AT population. An additional analysis will be performed in the mAT population.  
11.4.4 Secondary Powered Endpoint 
The secondary powered endpoint analysis will be a test of superiority of Colchicine + 
Rosuvastatin in addition to SOC compared to SOC alone assessed by the composite outcome 
of mechanical ventilation, myocardial injury and death measured at 30 days. The secondary 
endpoint will be evaluated in the ITT population. A secondary analysis will be performed in the 
AT population. An additional analysis will be performed in mAT population. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
42 
 
11.4.5 Secondary Endpoints 
All secondary endpoints will be evaluated in the ITT population using appropriate descriptive 
statistics at 30 and 60 day timepoints. Statistics for continuous variables will include mean, 
median, standard deviation, minimum, maximum, and sample size for each treatment group. 
Binary variables will be summarized using frequencies, percentages, and sample size for each 
treatment group. Proportions of subjects with various scores on ordinal scales (i.e. WHO ordinal 
scale for clinical improvement) will be compared between groups using the Chi-squared test for 
the ordinal logistic regression model (null hypothesis states that the slope coefficients in the 
model are the same across response categories). An additional analysis will be performed in 
mAT population. 
11.4.6 Secondary Imaging Endpoint 
Secondary imaging endpoint will be performed in a subset of 50 subjects with documented 
myocarditis at 30 days after discharge by MRI. No formal hypothesis testing will be performed. 
Statistics for continuous variables will include mean, median, standard deviation, minimum, 
maximum, and sample size for each treatment group. 
11.4.7 Subgroup Analyses 
Subgroup analyses will be performed for all primary and secondary endpoints for the following 
subgroups: 
• Subject age (<65 years vs. ≥65 years) 
• Subject gender (males vs. females) 
• Presence of diabetes 
• Presence of hypertension 
• Presence of CAD  
• Presence of high-risk factors including CAD, HTN, cerebrovascular disease, CKD, heart 
failure. 
• Subjects naive to colchicine/statins prior to admission  
• Subjects receiving other medications as part of SOC or other experimental trial (including 
antiplatelet agents, ACEi/ARB, Remdesivir, tocilizumab, interferon-beta, and/or 
methylprednisolone) 
• SOFA score tertiles on randomization 
• WHO score on randomization  
• Center of enrollment 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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11.5 Measure to Minimize Bias 
11.5.1 Randomization 
All COVID 19 + patients identified at YNHH and health system through EPIC will be screened 
for enrollment and randomized to SOC or SOC in addition to Rosuvastatin and Colchicine using 
an EPIC based randomization tool. 
11.5.2 Blinding 
The COLSTAT trail is an open-label trial. The Clinical Event Committee will be blinded to 
treatment allocation. 
11.5.3 Independent Assessments 
An independent DSMB will oversee the safe and ethical conduct of the trial. The DSMB will have 
the authority to discontinue the trial on the basis of safety concerns. 
11.5.4 Publication Policy 
The Yale University and the Principal Investigators are committed to the publication and 
widespread dissemination of the results of the study in the scientific community. 
12.0 Data Collection and Monitoring  
12.1 Data Collection and Monitoring 
Block randomization will be performed through the electronic medical records (EPIC) and will be 
linked to and order set for colchicine and rosuvastatin. All data testing, blood samples, and point 
of care echocardiography are within the current standard of care algorithm and no additional 
data collection beyond standard of care is required.  Data will be exported using a Joint Data 
Analytics Team (JDAT) export from EPIC enabling a system wide implementation of the trial.  
Data will be monitored for completeness and accuracy. 
12.2 Source Documentation 
Auditors, monitors, the Yale University IRB, and other regulatory authorities may have access 
to the medical records related to this study. Original or certified copies of all relevant clinical 
findings, observations, and other activities throughout the clinical investigation must be recorded 
and maintained in the medical file of each enrolled patient (no source documentation will be 
recorded directly on the CRF). At a minimum, the following must be included in each patient’s 
file: 
• Sufficient medical history and current physical condition, including any medication(s) the 
patient is taking at the time of the procedure to assess the patient’s eligibility; 
• The medical file should reveal the patient’s participation in this study, including 
documentation of informed consent; 
• Dated results of required laboratory tests; 
• Any adverse event(s), the resultant action or treatment, and outcome, if applicable; and 
• In the case of withdrawal of patient consent, the reason and patient status at time of 
withdrawal. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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The Principal Investigator will permit study-related monitoring, audits, IRB review, and other 
applicable regulatory authority inspections by allowing direct access to the source data. 
In case of electronic source data, periodic access will be allowed for full safety review. The 
review will be specific to study subjects and the records that would contain potential safety data. 
Dated printouts are acceptable for preliminary review of safety information. Print-outs should 
include all available data related to the identified patient(s). 
12.3 Auditing 
As a quality assurance measure, investigational sites may be audited during the trial or following 
trial completion. The purpose of an audit is to provide an independent evaluation of trial conduct 
and protocol and GCP compliance, separate from routine monitoring and quality control 
functions. The audit may be conducted by the Yale University personnel (or designee), or 
another regulatory body.  
The Principal Investigator shall permit the Yale University and regulatory bodies direct access 
to source data and all other relevant documents.  
13.0 Ethical and Regulatory Considerations 
13.1 Applicable Regulations 
This trial will be conducted in compliance with this protocol, the Yale University’s standard 
operating procedures and/or guidelines, FDA regulation, ICH GCP guidelines and, the 
Declaration of Helsinki.  
13.2 Institutional Review Board 
This trial will be conducted in accordance with Yale Institutional Review Boards. Any 
amendments to the protocol, as well as possible associated information and consent form 
changes, will be submitted to the IRB and written approval obtained prior to implementation.  
Substantive changes will be submitted to the Yale IRB prior to implementation, and local 
regulatory authorities, as applicable, will be notified of any changes not requiring approval 
according to applicable guidelines. 
13.3 Insurance 
The Yale University will maintain clinical trial insurance coverage for the duration of the study in 
accordance with applicable local laws and regulations. Details of insurance, indemnity, 
compensation, and reimbursement shall be addressed in a separate agreement approved by 
the interested parties. 
13.4 Regulatory Approval 
The Yale University is responsible for notifying the study to any relevant authorities (as 
applicable) according to regulatory requirements. Investigators may not commence enrollment 
of subjects until they have met any local IRB and hospital management requirements and have 
received confirmation from the Yale University that the appropriate regulatory approvals have 
been obtained. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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13.5 Trial Registration 
This trial meets the definition of an “applicable clinical trial” according to Section 801 of the Food 
and Drug Administration Amendments Act. The Yale University affirms that it will serve as the 
Responsible Party and fulfill all requirements regarding trial registration, the provision of clinical 
trial information, and results reporting through the ClinicalTrials.gov registry data bank.  
Clinical trial information will be submitted no more than 21 days after the first subject is enrolled 
in the trial, and results information will be submitted no later than 1 year after completion of the 
trial. 
13.6 Records and Reports 
The Yale University and Principal Investigator will maintain records related to this study for 7 
years (or longer according to local requirements) after the end of this study.  
Records will include: 
• All essential correspondence related to the clinical trial 
• Signed Investigator Agreement 
• Curriculum vitae  
• Adverse event information 
• Complaint documentation 
• All data forms prepared and signed by the Investigators and all received source 
documentation and core laboratory reports 
• Clinical Investigation Plan (CIP) and any amendments 
• Site monitoring reports 
• Financial disclosure information 
The Yale University and Principal Investigator are each responsible for the preparation, review, 
and submission of all required reports in accordance with local laws and regulations, the 
requirements of the FDA and other regulatory authorities as applicable, and the requirements of 
the Yale IRB.  
13.7 Protocol Amendments 
Any protocol amendments will be approved by the Yale University, the Principal Investigators, 
the IRB and any necessary regulatory body before it can be implemented. Substantive changes 
will be submitted to regulatory authorities as applicable for approval prior to implementation, and 
regulatory authorities as applicable will be notified of any changes not requiring approval in 
accordance with relevant guidelines. 
13.8 Informed Consent 
Informed consent will be obtained and documented as described §6.4 prior to the performance 
of any study-specific procedures or assessments in accordance with applicable laws and 
regulations, and local IRB requirements. 
Subjects will not be compensated. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
46 
 
13.9 Termination of the Study 
The Yale University reserves the right to terminate the study but intends only to exercise this 
right for valid scientific or administrative reasons and reasons related to protection of patients. 
Possible reasons for early trial termination include: 
• Unanticipated Adverse Effects present an unreasonable risk to patients 
• Recommendation from the DSMB 
Data will be reviewed based on JDAT exports at the same intervals defined for the DSMB.  If a 
determination to discontinue the trial is recommended by the DSMB, the IRB will be notified 
within 5 days.  Study investigators in the health system will be notified and the randomization 
through EPIC disabled. 
The Yale University will also inform the FDA when required. In the case of early termination of 
trial enrollment, follow-up visits will continue for all enrolled subjects. 
13.10 Patient Privacy 
The Yale University affirms and upholds the principle of patient confidentiality. Throughout this 
study, all data provided will only be identified by a study-specific subject identification number. 
“Protected Health Information” will be maintained in compliance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA) and applicable local regulations. 
The Principal Investigator agrees that representatives of the Yale University, its designee(s), 
and regulatory authorities may inspect included patients’ records to verify trial data, provide the 
data are treated as confidential and that the subject’s privacy is maintained. 
 
 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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14.0 References 
1. 
Ayman F, Ping W, Mahmoud A, Hesham S. Identification of FDA Approved Drugs 
Targeting COVID-19 Virus by Structure-Based Drug Repositioning. 2020. 
2. 
Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of 
Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the 
Sequential Organ Failure Assessment score. Crit Care Med. 2009;37(4):1317-1321. 
3. 
Grailer JJ, Canning BA, Kalbitz M, et al. Critical role for the NLRP3 inflammasome during 
acute lung injury. Journal of immunology (Baltimore, Md. : 1950). 2014;192(12):5974-
5983. 
4. 
Jones HD, Crother TR, Gonzalez-Villalobos RA, et al. The NLRP3 inflammasome is 
required for the development of hypoxemia in LPS/mechanical ventilation acute lung 
injury. American journal of respiratory cell and molecular biology. 2014;50(2):270-280. 
5. 
Castano-Rodriguez C, Honrubia JM, Gutierrez-Alvarez J, et al. Role of Severe Acute 
Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and 
Pathogenesis. mBio. 2018;9(3):e02325-02317. 
6. 
Nieto-Torres JL, Verdia-Baguena C, Jimenez-Guardeno JM, et al. Severe acute 
respiratory syndrome coronavirus E protein transports calcium ions and activates the 
NLRP3 inflammasome. Virology. 2015;485:330-339. 
7. 
Siu KL, Yuen KS, Castano-Rodriguez C, et al. Severe acute respiratory syndrome 
coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-
dependent ubiquitination of ASC. FASEB journal : official publication of the Federation of 
American Societies for Experimental Biology. 2019;33(8):8865-8877. 
8. 
Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 
coronavirus disease 2019: retrospective study. BMJ (Clinical research ed.). 
2020;368:m1091. 
9. 
Deftereos S, Giannopoulos G, Papoutsidakis N, et al. Colchicine and the heart: pushing 
the envelope. Journal of the American College of Cardiology. 2013;62(20):1817-1825. 
10. 
Ravelli RB, Gigant B, Curmi PA, et al. Insight into tubulin regulation from a complex with 
colchicine and a stathmin-like domain. Nature. 2004;428(6979):198-202. 
11. 
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. Journal of the American Society of Nephrology : JASN. 1996;7(4):594-
601. 
12. 
Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and 
therapeutic uses. Seminars in arthritis and rheumatism. 2015;45(3):341-350. 
13. 
Pope RM, Tschopp J. The role of interleukin-1 and the inflammasome in gout: implications 
for therapy. Arthritis and rheumatism. 2007;56(10):3183-3188. 
14. 
Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nature 
reviews. Cardiology. 2018;15(4):203-214. 
15. 
Rudiger AT, Mayrhofer P, Ma-Lauer Y, et al. Tubulins interact with porcine and human S 
proteins of the genus Alphacoronavirus and support successful assembly and release of 
infectious viral particles. Virology. 2016;497:185-197. 
16. 
Deftereos S, Giannopoulos G, Vrachatis DA, et al. Colchicine as a potent anti-
inflammatory treatment in COVID-19: can we teach an old dog new tricks? Eur Heart J 
Cardiovasc Pharmacother. 2020:pvaa033. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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17. 
Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R. Pharmacological 
and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or 
analogues: an update. Current drug targets. Inflammation and allergy. 2005;4(1):117-
124. 
18. 
Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for 
acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 
2005;112(13):2012-2016. 
19. 
Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for 
secondary prevention of cardiovascular disease. Journal of the American College of 
Cardiology. 2013;61(4):404-410. 
20. 
Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after 
Myocardial Infarction. N Engl J Med. 2019;381(26):2497-2505. 
21. 
Fedson DS. Treating the host response to emerging virus diseases: lessons learned from 
sepsis, pneumonia, influenza and Ebola. Ann Transl Med. 2016;4(21):421. 
22. 
Li YH, Wang QX, Zhou JW, et al. Effects of rosuvastatin on expression of angiotensin-
converting enzyme 2 after vascular balloon injury in rats. J Geriatr Cardiol. 
2013;10(2):151-158. 
23. 
Tikoo K, Patel G, Kumar S, et al. Tissue specific up regulation of ACE2 in rabbit model of 
atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem 
Pharmacol. 2015;93(3):343-351. 
24. 
Gu H, Xie Z, Li T, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by 
respiratory syncytial virus. Sci Rep. 2016;6:19840. 
25. 
Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian 
influenza A H5N1 infections. Nat Commun. 2014;5:3594. 
26. 
Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute 
lung failure. Nature. 2005;436(7047):112-116. 
27. 
Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) 
in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879. 
28. 
Douglas I, Evans S, Smeeth L. Effect of statin treatment on short term mortality after 
pneumonia episode: cohort study. BMJ (Clinical research ed.). 2011;342:d1642. 
29. 
Mortensen EM, Pugh MJ, Copeland LA, et al. Impact of statins and angiotensin-
converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia. Eur 
Respir J. 2008;31(3):611-617. 
30. 
Chopra V, Rogers MA, Buist M, et al. Is statin use associated with reduced mortality after 
pneumonia? A systematic review and meta-analysis. Am J Med. 2012;125(11):1111-
1123. 
31. 
Makris D, Manoulakas E, Komnos A, et al. Effect of pravastatin on the frequency of 
ventilator-associated pneumonia and on intensive care unit mortality: open-label, 
randomized study. Crit Care Med. 2011;39(11):2440-2446. 
32. 
Kruger P, Bailey M, Bellomo R, et al. A multicenter randomized trial of atorvastatin therapy 
in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 
2013;187(7):743-750. 
33. 
Papazian L, Roch A, Charles PE, et al. Effect of statin therapy on mortality in patients 
with 
ventilator-associated 
pneumonia: 
a 
randomized 
clinical 
trial. 
JAMA. 
2013;310(16):1692-1700. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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34. 
National Heart L, Blood Institute ACTN, Truwit JD, et al. Rosuvastatin for sepsis-
associated acute respiratory distress syndrome. N Engl J Med. 2014;370(23):2191-2200. 
35. 
McAuley DF, Laffey JG, O'Kane CM, et al. Simvastatin in the acute respiratory distress 
syndrome. N Engl J Med. 2014;371(18):1695-1703. 
36. 
Patel JM, Snaith C, Thickett DR, et al. Randomized double-blind placebo-controlled trial 
of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS 
Trial). Crit Care. 2012;16(6):R231. 
37. 
Novack V, Eisinger M, Frenkel A, et al. The effects of statin therapy on inflammatory 
cytokines in patients with bacterial infections: a randomized double-blind placebo 
controlled clinical trial. Intensive Care Med. 2009;35(7):1255-1260. 
38. 
Dashti-Khavidaki S, Khalili H. Considerations for Statin Therapy in Patients with COVID-
19. Pharmacotherapy. 2020;40(5):484-486. 
39. 
Rationale 
for 
Consideration 
of 
Statins 
for 
COVID-19 
Patients. 
2020; 
https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/covid-
19_domID_statin.pdf. Accessed 6/11/2020. 
40. 
De Spiegeleer A, Bronselaer A, Teo JT, et al. The effects of ARBs, ACEIs and statins on 
clinical outcomes of COVID-19 infection among nursing home residents. medRxiv. 
2020:2020.2005.2011.20096347. 
41. 
Kwon OC, Hong S, Ghang B, Kim YG, Lee CK, Yoo B. Risk of Colchicine-Associated 
Myopathy in Gout: Influence of Concomitant Use of Statin. Am J Med. 2017;130(5):583-
587. 
42. 
NIH. NIH/NCI/CTEP: Common Terminology Criteria for Adverse Events (CTCAE) v5.0:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_5x7.pdf. 2017. 
43. 
Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New 
England Journal of Medicine. 2020. 
44. 
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — 
Final Report. New England Journal of Medicine. 2020;383(19):1813-1826. 
45. 
Suh YJ, Hong H, Ohana M, et al. Pulmonary Embolism and Deep Vein Thrombosis in 
COVID-19: A Systematic Review and Meta-Analysis. Radiology. 2020;298(2):E70-E80. 
46. 
Modin D, Claggett B, Sindet-Pedersen C, et al. Acute COVID-19 and the Incidence of 
Ischemic Stroke and Acute Myocardial Infarction. Circulation. 2020;142(21):2080-2082. 
47. 
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — 
Preliminary Report. New England Journal of Medicine. 2020. 
48. 
Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions 
for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 
consensus document. Journal of the American College of Cardiology. 2012;60(15):1438-
1454. 
49. 
Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing 
with lower extremity ischemia: revised version. J Vasc Surg. 1997;26(3):517-538. 
50. 
Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular 
clinical trials: a consensus report from the Bleeding Academic Research Consortium. 
Circulation. 2011;123(23):2736-2747. 
51. 
Applegate RJ, Yaqub M, Hermiller JB, et al. Long-term (three-year) safety and efficacy of 
everolimus-eluting stents compared to paclitaxel-eluting stents (from the SPIRIT III Trial). 
Am J Cardiol. 2011;107(6):833-840. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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52. 
Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction 
(2018). Journal of the American College of Cardiology. 2018;72(18):2231-2264. 
53. 
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. 
European heart journal. 2012;33(20):2551-2567. 
54. 
Bozkurt B, Colvin M, Cook J, et al. Current Diagnostic and Treatment Strategies for 
Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart 
Association. Circulation. 2016;134(23):e579-e646. 
55. 
McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin 
Safety Assessment Task F. Final conclusions and recommendations of the National Lipid 
Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97(8A):89C-94C. 
56. 
Toh CH, Hoots WK, ISTH SSCoDICot. The scoring system of the Scientific and 
Standardisation Committee on Disseminated Intravascular Coagulation of the 
International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb 
Haemost. 2007;5(3):604-606. 
57. 
Lansky AJ, Messe SR, Brickman AM, et al. Proposed Standardized Neurological 
Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium 
Initiative. Journal of the American College of Cardiology. 2017;69(6):679-691. 
58. 
Tzikas A, Holmes DR, Jr., Gafoor S, et al. Percutaneous left atrial appendage occlusion: 
the Munich consensus document on definitions, endpoints and data collection 
requirements for clinical studies. EuroIntervention. 2016;12(1):103-111. 
59. 
WHO R&D Blueprint Novel Coronavirus COVID-19 Therapeutic Trial Synopsis. 2020; 
file:///C:/Users/tayya/Downloads/covid-19-therapeutic-trial-synopsis%20(1).pdf. 
Accessed June 11 2020. 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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15.0 Appendices 
15.1 Appendix A: Definitions 
Acute Kidney Injury (AKI) 
[AKIN classification] 
Change in serum creatinine (up to 7 days) compared with baseline48:  
• 
Stage 1: 
o Increase in serum creatinine to 150–199% (1.5–1.99 
× increase compared with baseline) OR increase of 
≥0.3 mg/dL (≥26.4 mmol/L) OR  
o Urine output <0.5 ml/kg per hour for >6 but <12 hours 
• 
Stage 2: 
o Increase in serum creatinine to 200–299% (2.0–2.99 
× increase compared with baseline) OR 
o Urine output <0.5 ml/kg per hour for >12 but <24 
hours 
• 
Stage 3:  
o Increase in serum creatinine to ≥300% (>3 × increase 
compared with baseline) OR serum creatinine of ≥4.0 
mg/dL (≥354 mmol/L) with an acute increase of at 
least 0.5 mg/dL (44 mmol/L) OR 
o Urine output <0.3 ml/kg per hour for ≥24 hours OR 
o Anuria for >12 hours  
o  [Patients receiving renal replacement therapy are 
considered to meet Stage 3 criteria irrespective of 
other criteria] 
Acute Limb Ischemia 
A rapid or sudden decrease in limb perfusion plus either 1) a new 
pulse deficit, rest pain, pallor, paresthesia, or paralysis; or 2) 
confirmation of arterial obstruction by limb hemodynamics (ankle or 
toe pressure), imaging, intraoperative findings, or pathological 
evaluation. Events will be classified per the Rutherford 
Classification49 
 
Adverse Events 
 
According to 21CFR312.32: 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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An adverse event could present as an abnormal laboratory finding, 
abnormal imaging finding or an abnormal clinical finding or symptom. 
 
Life-threatening adverse event or life-threatening suspected 
adverse reaction 
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. 
It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused 
death. 
Serious adverse event or serious suspected adverse reaction  
An adverse event or suspected adverse reaction is considered 
“serious” if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes:  
• 
Death,  
• 
A life-threatening adverse event,  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization,  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions,  
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse. 
Suspected adverse reaction  
Any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the adverse 
event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any 
adverse event caused by a drug.  
Unexpected adverse event or unexpected suspected adverse 
reaction.  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended.  
“Unexpected,” as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under 
investigation.  
As Treated (AT) Population 
As Treated (AT) analysis population is defined by the treatment 
actually received, rather than the treatment assigned. 
The mAT analysis population is defined by the treatment actually 
received, rather than the treatment assigned and excludes all 
subjects with prior statin therapy. 
Bleeding 
Defined according to the following BARC definitions50: 
• 
Type 0: no bleeding 
• 
Type 1: bleeding that is not actionable and does not cause 
the patient to seek unscheduled performance of studies, 
hospitalization, or treatment by a healthcare professional; 
may include episodes leading to self-discontinuation of 
medical therapy by the patient without consulting a 
healthcare professional 
• 
Type 2: any overt, actionable sign of hemorrhage (e.g., 
more bleeding than would be expected for a clinical 
circumstance, including bleeding found by imaging alone) 
that does not fit the criteria for type 3, 4, or 5 but does meet 
at least one of the following criteria: (1) requiring 
nonsurgical, medical intervention by a healthcare 
professional, (2) leading to hospitalization or increased level 
of care, or (3) prompting evaluation 
• 
Type 3 
Type 3a 
Over bleeding plus hemoglobin drop of 3 to <5 g/dL* 
(provided hemoglobin drop is related to bleed) 
Any transfusion with over bleeding 
Type 3b 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
54 
 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided 
hemoglobin drop is related to bleed) 
Cardiac tamponade 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
Bleeding requiring intravenous vasoactive agents 
Type 3c 
Intracranial hemorrhage (does not include microbleeds or 
hemorrhagic transformation, does include intraspinal) 
Subcategories confirmed by autopsy or imaging or lumbar 
puncture 
Intraocular bleed comprising vision 
• 
Type 4: CABG-related bleeding 
Perioperative intracranial bleeding within 48 h 
Reoperation after closure of sternotomy for the purpose of 
controlling bleeding 
Transfusion of ≥5 U whole blood or packed red blood cells within 
a 48-h period (NOTE: cell saver products are not counted) 
Chest tube output ≥2L within a 24-h period 
• 
Type 5: fatal bleeding 
Type 5a 
Probable fatal bleeding; no autopsy or imaging confirmation 
but clinically suspicious 
Type 5b 
Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation 
NOTES:  
Platelet transfusions should be recorded and reported but are not 
included in these definitions until further information is obtained 
about the relationship to outcomes. If a CABG-related bleed is not 
adjudicated as at least a type 3 severity event, it will be classified as 
not a bleeding event. If a bleeding event occurs with a clear temporal 
relationship to CABG (i.e., within a 48-h time frame) but does not 
meet type 4 severity criteria, it will be classified as not a bleeding 
event.  
* Corrected for transfusion (1 U packed red blood cells or 1 U whole 
blood = 1 g/dL hemoglobin) 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
55 
 
Childs-Pugh Class 
Points 
+1 
+2 
+3 
Encephalopathy* None 
Grade 1-2 
(or precipitant-
induced) 
Grade 3-4 
(or chronic) 
Ascites 
None 
Mild/Moderate 
(diuretic-
responsive) 
Severe 
(diuretic-
refractory) 
Bilirubin (mg/dL) < 2 
2-3 
> 3 
Albumin (g/dL) 
> 3.5 
2.8-3.5 
< 2.8 
PT (sec 
prolonged) 
or INR 
< 4 
< 1.7 
4-6 
1.7-2.3 
> 6 
> 2.3 
Child-Pugh Class: 
A = 5-6 points 
B = 7-9 points 
C = 10-15 points 
*Encephalopathy Grade 
Grade 0: normal consciousness, personality, neurological 
examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired 
handwriting, 5 cps waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, 
slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive 
reflexes, rigidity, slower waves 
Grade 4: unrousable coma, no personality/behavior, decerebrate, 
slow 2-3 cps delta activity 
Death 
Classified as cardiac, vascular, or noncardiovascular according to 
the following ARC definitions.51 All deaths are considered cardiac 
unless an unequivocal noncardiac cause can be established. 
Specifically, any unexpected death even in patients with coexisting 
potentially fatal noncardiac disease (e.g., cancer, infection) should 
be classified as cardiac. 
• 
Cardiac death: Any death due to proximate cardiac cause 
(e.g., MI, low-output failure, fatal arrhythmia), unwitnessed 
death and death of unknown cause, and all procedure-


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
56 
 
related deaths, including those related to concomitant 
treatment, will be classified as cardiac death.  
• 
Vascular death: Death caused by noncoronary vascular 
causes, such as cerebrovascular disease, pulmonary 
embolism, ruptured aortic aneurysm, dissecting aneurysm, 
or other vascular diseases.  
• 
Non-cardiovascular death: Any death not covered by the 
above definitions, such as death caused by infection, 
malignancy, sepsis, pulmonary causes, accident, suicide, or 
trauma.   
 
 
Glasgow Coma Scale 
The Glasgow coma scale is a score between 3-15 assessed as 
the sum of three categories: 
 
• 
Eye Response 
1. No eye opening 
2. Eye opening to pain 
3. Eye opening to verbal command 
4. Eyes open spontaneously  
• 
Motor Response 
1. No motor response 
2. Extension response to pain 
3. Flexion response to pain 
4. Withdraws from pain 
5. Localizes to pain 
6. Obeys commands 
• 
Verbal Response 
1. No verbal response 
2. Incomprehensible sounds 
3. Inappropriate words 
4. Confused 
5. Oriented 
High Flow Nasal 
Cannula/High Flow Oxygen 
Delivery of warmed and humidified oxygen at high flows through 
nasal cannula typically at rates of 5-60L/min 
Intention to Treat (ITT) 
Population 
All subjects enrolled in the study, analyzed by assigned treatment, 
regardless of the treatment actually received. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Invasive Mechanical 
Ventilation 
Assisted ventilation with endotracheal tube or tracheostomy tube 
Mortality 
See “death”  
Myocardial infarction (MI) 
The primary protocol definition of myocardial infarction is the Fourth 
Universal Definition52 provided in the Table below, which will be 
adjudicated and classified by an independent CEC. When 
quantitative troponin is not available CK-MB will be used in its place 
In addition, the CEC will also adjudicate PCI-related MI according to 
several alternate thresholds of cTn (3, 10, 35, and 70 × 99th 
percentile URL), and all MI types (except Type 3) will be tabulated 
according to multiples of the 99th percentile URL of cTn as 
recommended by Thygesen et al.53  
Definition of Myocardial Infarction52,53 
Criteria for myocardial injury 
The term myocardial injury should be used when there is evidence of elevated cardiac troponin values 
(cTn) with at least one value above the 99th percentile upper reference limit (URL). The myocardial 
injury is considered acute if there is a rise and/or fall of cTn values. 
Criteria for acute myocardial infarction (types 1, 2, and 3 MI) 
The term acute myocardial infarction should be used when there is acute myocardial injury with clinical 
evidence of acute myocardial ischaemia and with detection of a rise and/or fall of cTn values with at 
least one value above the 99th percentile URL and at least one of the following: 
• 
Symptoms of myocardial ischaemia;  
• 
New ischaemic ECG changes;  
• 
Development of pathological Q waves;  
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischaemic aetiology;  
• 
Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs).  
Post-mortem demonstration of acute athero-thrombosis in the artery supplying the infarcted 
myocardium meets criteria for type 1 MI.  
Evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute 
athero-thrombosis meets criteria for type 2 MI.  
Cardiac death in patients with symptoms suggestive of myocardial ischaemia and presumed new 
ischaemic ECG changes before cTn values become available or abnormal meets criteria for type 
3 MI. 
Criteria for coronary procedure-related myocardial infarction (types 4 and 5) 
Percutaneous coronary intervention (PCI) related MI is termed type 4a MI.  
Coronary artery bypass grafting (CABG) related MI is termed type 5 MI.  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Coronary procedure-related MI ≤ 48 hours after the index procedure is arbitrarily defined by an 
elevation of cTn values > 5 times for type 4a MI and > 10 times for type 5 MI of the 99th percentile 
URL in patients with normal baseline values. Patients with elevated pre-procedural cTn values, in 
whom the pre-procedural cTn level are stable (≤ 20% variation) or falling, must meet the criteria for a 
> 5 or > 10 fold increase and manifest a change from the baseline value of > 20%. In addition with at 
least one of the following:  
• 
New ischaemic ECG changes (this criterion is related to type 4a MI only);  
• 
Development of new pathological Q waves;  
• 
Imaging evidence of loss of viable myocardium that is presumed to be new and in a pattern 
consistent with an ischaemic aetiology;  
• 
Angiographic findings consistent with a procedural flow-limiting complication such as coronary 
dissection, occlusion of a major epicardial artery or graft, side-branch occlusion-thrombus, 
disruption of collateral flow or distal embolization.  
Isolated development of new pathological Q waves meets the type 4a MI or type 5 MI criteria with 
either revascularization procedure if cTn values are elevated and rising but less than the pre-specified 
thresholds for PCI and CABG.  
Other types of 4 MI include type 4b MI stent thrombosis and type 4c MI restenosis that both meet type 
1 MI criteria.  
Post-mortem demonstration of a procedure-related thrombus meets the type 4a MI criteria or type 4b 
MI criteria if associated with a stent. 
Criteria for prior or silent/unrecognized myocardial infarction 
Any one of the following criteria meets the diagnosis for prior or silent/ unrecognized MI:  
• 
Abnormal Q waves with or without symptoms in the absence of nonischaemic causes.  
• 
Imaging evidence of loss of viable myocardium in a pattern consistent with ischaemic 
aetiology.  
• 
Patho-anatomical findings of a prior MI. 
Clinical criteria 
Clinical criteria for MI 
The clinical definition of MI denotes the presence of acute myocardial injury detected by abnormal 
cardiac biomarkers in the setting of evidence of acute myocardial ischaemia. 
Clinical criteria for myocardial injury 
Detection of an elevated cTn value above the 99th percentile URL is defined as myocardial injury. The 
injury is considered acute if there is a rise and/or fall of cTn values. 
Criteria for type 1 MI 
Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL and 
with at least one of the following: Symptoms of acute myocardial ischaemia; New ischaemic ECG 
changes; Development of pathological Q waves; Imaging evidence of new loss of viable myocardium 
or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology; 
Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy.a 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Criteria for type 2 MI 
Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL, and 
evidence of an imbalance between myocardial oxygen supply and demand unrelated to coronary 
thrombosis, requiring at least one of the following:  
• 
Symptoms of acute myocardial ischaemia;  
• 
New ischaemic ECG changes;  
• 
Development of pathological Q waves;  
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischaemic aetiology. 
Criteria for type 3 MI 
Patients who suffer cardiac death, with symptoms suggestive of myocardial ischaemia accompanied 
by presumed new ischaemic ECG changes or ventricular fibrillation, but die before blood samples for 
biomarkers can be obtained, or before increases in cardiac biomarkers can be identified, or MI is 
detected by autopsy examination. 
Criteria for cardiac procedural myocardial injury 
Cardiac procedural myocardial injury is arbitrarily defined by increases of cTn values (> 99th percentile 
URL) in patients with normal baseline values (≤ 99th percentile URL) or a rise of cTn values > 20% of 
the baseline value when it is above the 99th percentile URL but it is stable or falling 
Criteria for PCI-related MI ≤48 h after the index procedure (type 4a MI) 
Coronary intervention-related MI is arbitrarily defined by an elevation of cTn values more than five 
times the 99th percentile URL in patients with normal baseline values. In patients with elevated pre-
procedure cTn in whom the cTn level are stable (≤ 20% variation) or falling, the postprocedure cTn 
must rise by >20%. However, the absolute post-procedural value must still be at least five times the 
99th percentile URL. In addition, one of the following elements is required:  
• 
New ischaemic ECG changes;  
• 
Development of new pathological Q waves;b  
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischaemic aetiology;  
• 
Angiographic findings consistent with a procedural flow-limiting complication such as coronary 
dissection, occlusion of a major epicardial artery or a side branch occlusion/thrombus, 
disruption of collateral flow, or distal embolization.c 
Criteria for CABG-related MI ≤ 48 h after the index procedure (type 5 MI) 
CABG-related MI is arbitrarily defined as elevation of cTn values > 10 times the 99th percentile URL 
in patients with normal baseline cTn values. In patients with elevated pre-procedure cTn in whom cTn 
levels are stable (≤ 20% variation) or falling, the post-procedure cTn must rise by > 20%. However, the 
absolute postprocedural value still must be > 10 times the 99th percentile URL. In addition, one of the 
following elements is required:  
• 
Development of new pathological Q waves;d  
• 
Angiographic documented new graft occlusion or new native coronary artery occlusion;  


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischaemic etiology.  
Criteria for prior or silent/unrecognized MI 
Any one of the following criteria meets the diagnosis for prior or silent/unrecognized MI:  
• 
Pathological Q waves, with or without symptoms, in the absence of nonischaemic causes;  
• 
Imaging evidence of loss of viable myocardium in a pattern consistent with ischaemic 
aetiology;  
• 
Pathological findings of a prior MI. 
Electrocardiographic manifestations suggestive of acute myocardial ischaemia (in the 
absence of left ventricular hypertrophy and bundle branch block) 
ST-elevation 
New ST-elevation at the J-point in two contiguous leads with the cutpoint: ≥ 1 mm in all leads other 
than leads V2–V3 where the following cut-points apply: ≥ 2mm in men ≥ 40 years; ≥ 2.5 mm in men < 
40 years, or ≥ 1.5 mm in women regardless of age.e 
ST-depression and T wave changes 
New horizontal or downsloping ST-depression ≥ 0.5 mm in two contiguous leads and/or T inversion > 
1 mm in two contiguous leads with prominent R wave or R/S ratio > 1. 
Electrocardiographic changes associated with prior myocardial infarction (in the absence of 
left ventricular hypertrophy and left bundle branch block) 
Any Q wave in leads V2–V3 > 0.02 s or QS complex in leads V2–V3.  
Q wave ≥ 0.03 s and ≥ 1 mm deep or QS complex in leads I, II, aVL, aVF or V4–V6 in any two leads of 
a contiguous lead grouping (I, aVL; V1–V6; II, III, aVF).f  
R wave > 0.04 s in V1–V2 and R/S > 1 with a concordant positive T wave in absence of conduction 
defect. 
*If cTn is not available, CKMB (measured by mass assay) is an acceptable alternative. The CKMB 
threshold for the diagnosis of PCI-related MI is >5 × 99th percentile URL in patients with normal 
baseline values. 
CABG = coronary artery bypass grafting; cTn = cardiac troponin; ECG = electrocardiogram; MI = 
myocardial infarction; PCI = percutaneous coronary intervention; URL = upper reference limit. 
aPost-mortem demonstration of an atherothrombus in the artery supplying the infarcted myocardium, 
or a macroscopically large circumscribed area of necrosis with or without intramyocardial 
haemorrhage, meets the type 1 MI criteria regardless of cTn values. 
bIsolated development of new pathological Q waves meets the type 4a MI criteria if cTn values are 
elevated and rising but more than five times the 99th percentile URL.  
cPost-mortem demonstration of a procedure-related thrombus in the culprit artery, or a macroscopically 
large circumscribed area of necrosis with or without intra-myocardial haemorrhage meets the type 4a 
MI criteria. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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dIsolated development of new pathological Q waves meets the type 5 MI criteria if cTn values are 
elevated and rising but < 10 times the 99th percentile URL. 
eWhen the magnitudes of J-point elevation in leads V2 and V3 are registered from a prior 
electrocardiogram, new J-point elevation ≥ 1 mm (as compared with the earlier electrocardiogram) 
should be considered an ischaemic response. 
fThe same criteria are used for supplemental leads V7–V9. s = seconds  
 
 
Myocarditis 
Based on the scientific statement from the American Heart 
Association54:   
Clinical presentations* 
Acute chest pain, pericarditic, or pseudoischemic 
New onset (days up to 3 mo) or worsening of dyspnea at rest or 
exercise, and/or fatigue, with or without signs of left- and/or right- 
sided heart failure 
Subacute/chronic (>3 mo) or worsening of dyspnea at rest or 
exercise, and or fatigue with or without left- and/or right-sided 
heart failure 
Palpitation and/or unexplained arrhythmia symptoms and/or 
syncope and/or aborted sudden cardiac death 
Unexplained cardiogenic shock  
Diagnostic criteria 
I. ECG/Holter/stress test features 
New abnormal 12-lead ECG and/or Holter stress testing, any 
of the following: first- to third-degree atrioventricular block or 
bundle-branch block; ST/T-wave changes; sinus arrest; 
ventricular tachycardia or fibrillation and asystole; atrial 
fibrillation; reduced R-wave height; intraventricular conduction 
delay (widened QRS complex); abnormal Q waves; low-
voltage, 
frequent 
premature 
beats; 
supraventricular 
tachycardia 
II. Myocardiocytolysis markers  
Elevated TnT/TnI 
III. Functional and structural abnormalities on cardiac imaging 
(echocardiogram/angiography/CMR) 
New, otherwise unexplained LV and/or RV structure and 
function 
abnormality 
(including 
incidental 
finding 
in 
apparently asymptomatic subjects): regional wall motion or 
global systolic or diastolic function abnormality, with or 
without ventricular dilatation, with or without increased wall 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
62 
 
thickness, with or without pericardial effusion, with or without 
endocavitary thrombi 
IV. Tissue characterization by CMR 
Edema and/or LGE of classic myocarditic pattern (see Role of 
Cardiac MRI in Suspected Myocarditis) 
Clinically suspected myocarditis if ≥1 clinical presentation and ≥1 
diagnostic criteria from different categories in the absence of (1) 
angiographically detectable coronary artery disease (coronary 
stenosis ≥50%) or (2) known preexisting cardiovascular disease or 
extracardiac causes that could explain the syndrome (eg, valve 
disease, congenital heart disease, hyperthyroidism). Suspicion is 
higher with higher number of fulfilled criteria. CMR indicates cardiac 
magnetic resonance; LGE, late gadolinium enhancement; LV, left 
ventricular; RV, right ventricular; TnI, troponin I; and TnT, troponin T. 
*If the patient is asymptomatic, ≥2 diagnostic criteria should be met.   
Myopathy55 
- 
Complaints of myalgia (muscle pain or soreness), weakness, 
and/or cramps, plus  
- 
Elevation in serum CK >10× the ULN 
- 
A patient may describe intolerable muscle symptoms but not 
be found to have a CK level >10 times the ULN. This patient 
may be considered to be experiencing myopathy for the 
purposes of further evaluation. 
Noninvasive Ventilation 
Assisted ventilation using mouth, nasal, and/or face mask such as 
bilevel positive airway pressure (BiPAP) or continuous positive airway 
pressure [CPAP]. Does not include nasal cannula or high flow oxygen 
Overt Disseminated 
Intravascular Coagulation 
(DIC)56 
Variable 
 
Points 
Platelet count, cells x 
109/L 
≥100 
+0 
50 to <100 
+1 
<50 
+2 
Elevated levels of a 
fibrin-related marker* 
(e.g. D-dimer, fibrin 
degradation 
products) 
No increase 
+0 
Moderate increase 
+2 
Severe increase 
+3 
Prolonged PT, 
seconds 
<3 
+0 
3 to <6 
+1 
≥6 
+2 
Fibrinogen level, g/L 
≥1 
+0 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
63 
 
<1 
+1 
* Use lab-specific cutoff values 
 
Score: 
< 5: Not suggestive of overt DIC, may be non-overt DIC; repeat 
within next 1-2 days and manage clinically as appropriate 
> 5: Compatible with overt DIC; treat for DIC as appropriate and 
repeat scoring daily 
 
 
Pulmonary Embolism (PE) 
Pulmonary embolism is a mechanical obstruction of one or more 
branches of the pulmonary vasculature, usually from a clot. 
These must be diagnosed by objective image such as computed 
tomography angiography and will be stratified based on following 
criteria: 
- 
Massive or high-risk: the PE is causing hemodynamic 
instability. 
- 
Submassive or intermediate risk: the PE is causing cardiac 
dysfunction with right ventricular strain (echocardiographic 
findings may include right ventricular hypokinesis or dilation, 
tricuspid regurgitation, and/or paradoxic septal movement), 
frequently with elevations in troponin and/or brain natriuretic 
peptide (BNP). 
- 
Low risk: absence of any signs of massive or submassive PE. 
QTc prolongation (Per 
YNHH COVID-19 protocol) 
QTc > 470 ms and narrow QRS (<120 ms) OR QTc > 500 ms and 
wide QRS (>120 ms) 
 
OR if already abnormal on enrollment an increase by 50ms 
 
Rhabdomyolysis55 
- 
CK >10,000 IU/L, or 
- 
CK >10× the ULN plus an elevation in serum creatinine or 
medical intervention with IV hydration therapy (the CK level 
may be <10 times the ULN depending on the temporal 
relation between the event and the drawing of the laboratory 
sample) 
 
 
Sequential Organ Failure 
Assessment (SOFA) score 
Score based on organ dysfunction that predicts ICU mortality. Scored 
in six categories with scores of 0-24 possible: 
PaO2/FiO2 
≥400 
0 
300-399 
+1 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
64 
 
200-299 
+2 
100-199 and 
mechanically 
ventilated 
+3 
<100 and 
mechanically 
ventilated 
+4 
 
Ok to replace use SpO2/FiO2 ratio when ABG not available 
using the following criteria2: 
 
SOFA Respiratory score PaO2/FiO2 SpO2/FiO2 
1 
<400 
<512 
2 
<300 
<357 
3 
<200 
<214 
4 
<100 
<89 
 
Platelets x 1000 
≥150 
0 
100-149 
+1 
50-99 
+2 
20-49 
+3 
<20 
+4 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Glasgow Coma Scale 
15 
0 
13–14 
+1 
10–12 
+2 
6–9 
+3 
<6 
+4 
 
Bilirubin (mg/dL) 
<1.2 (<20) 
0 
1.2–1.9 (20-
32) 
+1 
2.0–5.9 (33-
101) 
+2 
6.0–11.9 
(102-204) 
+3 
≥12.0 (>204) 
+4 
 
Mean arterial pressure OR administration of vasoactive agents 
required (listed doses are in units of mcg/kg/min) 
No hypotension 
0 
MAP <70 mmHg 
+1 
DOPamine ≤5 or 
DOBUTamine (any dose) 
+2 
DOPamine >5, EPINEPHrine 
≤0.1, or norEPINEPHrine 
≤0.1 
+3 
DOPamine >15, EPINEPHrine 
>0.1, or norEPINEPHrine 
>0.1 
+4 
 
Creatinine (mg/dL) 
<1.2 (<110) 
0 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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1.2–1.9 (110-170) 
+1 
2.0–3.4 (171-299) 
+2 
3.5–4.9 (300-440) or UOP 
<500 mL/day) 
+3 
≥5.0 (>440) or UOP <200 
mL/day 
+4 
 
 
Severe QTc Prolongation 
(Per 
YNHH 
COVID-19 
protocol) 
QTc > 500 ms with narrow QRS (<120 ms) OR QTc > 550 ms with 
wide QRS (>120 ms) 
 
 
Stroke 48 
Diagnostic criteria: 
Acute episode of a focal or global neurological deficit with at least one 
of the following: change in the level of consciousness, hemiplegia, 
hemiparesis, numbness, or sensory loss affecting one side of the 
body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other 
neurological signs or symptoms consistent with stroke 
Stroke: duration of a focal or global neurological deficit ≥24 h; OR <24 
h if available neuroimaging documents a new haemorrhage or infarct; 
OR the neurological deficit results in death 
TIA: duration of a focal or global neurological deficit <24 h, any 
variable neuroimaging does not demonstrate a new haemorrhage or 
infarct 
No other readily identifiable non-stroke cause for the clinical 
presentation (e.g. brain tumor, trauma, infection, hypoglycemia, 
peripheral lesion, pharmacological influences), to be determined by or 
in conjunction with the designated neurologist 
Confirmation of the diagnosis by at least one of the following 
Neurologist or neurosurgical specialist 
Neuroimaging procedure (CT scan or brain MRI), but stroke may be 
diagnosed on clinical grounds alone 
Stroke classification 
Ischemic: an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of the central nervous system tissue 
Hemorrhagic: an acute episode of focal or global cerebral or spinal 
dysfunction 
caused 
by 
intraparenchymal, 
intraventricular, 
or 
subarachnoid hemorrhage 
A stroke may be classified as undetermined if there is insufficient 
information to allow categorization as ischemic or hemorrhagic. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
67 
 
 
According to the NeuroARC definition57: 
Overt CNS Injury: Acutely symptomatic brain or spinal cord injury 
(NeuroARC Type 1) including: 
Type 1.a Ischemic stroke 
Sudden onset of neurological signs or symptoms fitting a focal or 
multifocal vascular territory within the brain, spinal cord, or retina, 
that: 
1) Persist for ≥24 h or until death, with pathology or 
neuroimaging evidence that demonstrates either: 
a) CNS infarction in the corresponding vascular territory 
(with or without hemorrhage); or 
b) Absence of other apparent causes (including 
hemorrhage), even if no evidence of acute ischemia in 
the corresponding vascular territory is detected 
or 
2) Symptoms lasting <24 h, with pathology or neuroimaging 
confirmation of CNS infarction in the corresponding vascular 
territory. Note: When CNS infarction location does not match 
the transient symptoms, the event would be classified as 
covert CNS infarction (Type 2a) and a TIA (Type 3a), but not 
as an ischemic stroke.  
Signs and symptoms consistent with stroke typically include an 
acute onset of 1 of the following: focal weakness and/or numbness; 
impaired language production or comprehension; homonymous 
hemianopia or quadrantanopsia; diplopia; altitudinal monocular 
blindness; hemispatial neglect; dysarthria; vertigo; or ataxia. 
Subtype 1.a.H Ischemic stroke with hemorrhagic conversion 
Ischemic stroke includes hemorrhagic conversions. These 
should be subclassified as Class A or B when ischemic stroke is 
the primary mechanism and pathology or neuroimaging 
confirms a hemorrhagic conversion. 
Class A (Petechial hemorrhage): Petechiae or confluent 
petechiae within the infarction or its margins, but without a 
space-occupying effect 
Class B (Confluent hemorrhage): Confluent hemorrhage or 
hematoma originating from within the infarcted area with 
space-occupying effect  
Type 1.b Symptomatic intracerebral hemorrhage 
Rapidly developing neurological signs or symptoms (focal or global) 
caused by an intraparenchymal, intraventricular, spinal cord, or 
retinal collection of blood, not caused by trauma 
Type 1.c Symptomatic subarachnoid hemorrhage 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
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Rapidly developing neurological signs or symptoms (focal or global) 
and/or headache caused by bleeding into the subarachnoid space, 
not caused by trauma 
Type 1.d Stroke, not otherwise specified 
An episode of acute focal neurological signs or symptoms and/or 
headache presumed to be caused by CNS ischemia or CNS 
hemorrhage, persisting ≥24 h or until death, but without sufficient 
evidence to be classified as either (i.e., no neuroimaging performed) 
Type 1.e Symptomatic hypoxic-ischemic injury 
Nonfocal (global) neurological signs or symptoms due to diffuse brain, 
spinal cord, or retinal cell death (confirmed by pathology or 
neuroimaging) 
in 
a nonvascular 
distribution, 
attributable 
to 
hypotension and/or hypoxia 
 
Covert CNS Injury: Acutely symptomatic brain or spinal cord injury 
detected by neuroimaging (NeuroARC Type 2) including: 
Brain, spinal cord, or retinal cell death attributable to focal or multifocal 
ischemia, on the basis of neuroimaging or pathological evidence of 
CNS infarction, without a history of acute neurological symptoms 
consistent with the lesion location 
Subtype 2.a.H Covert CNS infarction with hemorrhagic conversion 
Covert CNS infarction includes hemorrhagic conversions. These 
should be subclassified as Class A or B when CNS infarction is the 
primary mechanism and neuroimaging or pathology confirms a 
hemorrhagic conversion. 
Class A (Petechial hemorrhage): Petechiae or confluent petechiae 
within the infarction or its margins, but without a space-occupying 
effect 
Class B (Confluent hemorrhage): Confluent hemorrhage or 
hematoma originating from within the infarcted area with space-
occupying effect  
Type 2.b Covert CNS hemorrhage 
Neuroimaging or pathological evidence of CNS hemorrhage within the 
brain parenchyma, subarachnoid space, ventricular system, spinal 
cord, or retina on neuroimaging that is not caused by trauma, without 
a history of acute neurological symptoms consistent with the bleeding 
location 
Systemic 
Thromboembolism 
Acute vascular insufficiency or occlusion of the extremities or any non-
CNS organ associated with clinical, imaging, surgical/autopsy 
evidence of arterial occlusion in the absence of other likely 
mechanism (e.g. trauma, atherosclerosis, or instrumentation).58 When 
there is presence of prior peripheral artery disease, angiographic or 
surgical or autopsy evidence is required to show abrupt arterial 
occlusion. 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
69 
 
Thromboembolism may be arterial or venous in nature and involves 
the obstruction, partial or total occlusion, of a part of the circulatory 
system and may detected by a variety of imaging modalities including 
angiography, venography, computed tomography, radiography and 
other or may be detected on autopsy. 
 
Thrombosis 
 
Local coagulation or clotting of the blood in a part of the circulatory 
system. Thrombosis in the central nervous system or brain 
parenchyma should be evaluated for the occurrence of an ischemic 
stroke. 
 
Venous Thrombosis 
Venous thrombosis is defined as a blood clot forming in venous 
system, most often in the deep veins of the leg, groin or arm (i.e. deep 
vein thrombosis). 
 
For purposes of this trial this must be diagnosed with objective 
imaging such as ultrasound, computed tomography, or angiography 
 
 
WHO 
Ordinal 
Scale 
for 
Clinical Improvement59 
 
 
 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
70 
 
15.2 Appendix B: List of Abbreviation 
 
Abbreviation 
Definition 
ADL 
AE  
Activities of Daily Living 
Adverse Event 
ACEi 
Angiotensin Converting Enzyme inhibitor 
ACE2 
Angiotensin Converting Enzyme 2 
ACS 
Acute Coronary Syndromes 
AKI 
Acute Kidney Injury 
ALI 
Acute Lung Injury 
ARB 
Angiotensin II Receptor Blocker 
ARC 
Academic Research Consortium 
ARDS 
Acute Respiratory Distress Syndrome 
AT 
As Treated 
BARC 
Bleeding Academic Research Consortium 
BiPAP 
Bilevel Positive Airway Pressure 
BNP 
Brain Natriuretic Peptide 
CAD 
Coronary Artery Disease 
CBC 
Complete Blood Count 
CCL5 
C-C Chemokine Ligand 5 
CCS 
Canadian Cardiovascular Society (grading scale of angina pectoris) 
CEC 
Clinical Events Committee 
CI 
Confidence Interval 
CIP 
Clinical Investigation Plan 
CK  
Creatine Kinase 
CKMB 
Creatine Kinase MB isoform 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
71 
 
CMP 
Complete Metabolic Panel 
COLCOT 
Colchicine Cardiovascular Outcomes Trial 
COVID-19 
Coronavirus Disease of 2019 
CP 
Conditional Power 
CPAP 
Continuous Positive Airway Pressure 
CPK 
Creatine Phospokinase 
CRF  
Case Report Form 
CRP 
C-reactive Protein 
CTCAE 
cTn 
Common Terminology Criteria for Adverse Events 
Cardiac Troponin 
CXR 
Chest X-Ray 
DIC 
Disseminated Intravascular Coagulation 
DSMB 
Data Safety Monitoring Board 
DSMC 
Data Safety Monitoring Committee 
ECG  
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture (system) 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
U.S. Food and Drug Administration 
FiO2 
Fraction of inspired Oxygen 
GCP  
Good Clinical Practices 
GFR 
Glomerular Filtration Rate 
HFNC 
High Flow Nasal Cannula 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
H&P 
History and Physical 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
72 
 
HR 
Hazard Ratio 
hsCRP 
High Sensitivity C-Reactive Protein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IFG 
Interferon Gamma 
IL 
Interleukin  
IL-2R 
Interleukin 2 Receptor 
IP-10 
Inducible Protein 10 
IRB  
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT  
Intention To Treat 
IV  
Intravenous 
IVIG 
Intravenous Immunoglobulin 
JDAT 
Joint Data Analytics Team 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LoDoCo 
Low-Dose Colchicine trial 
LVEF 
Left Ventricular Ejection Fraction 
MERS 
Middle East Respiratory Syndrome 
MI  
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
NSTEMI 
Non-ST-Segment Elevation Myocardial Infarction 
PaO2 
Partial Pressure of Oxygen 
PCI  
Percutaneous Coronary Intervention 


COLSTAT TRIAL [CIP-TBD (v1.0)]                                                                                             YALE UNIVERSITY                     
 
 
 
73 
 
PE 
Pulmonary Embolism 
PP  
Per Protocol 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RCT 
Randomized Controlled Trial 
RT-PCR 
Real-Time Reverse Transcription Polymerase Chain Reaction 
SAE  
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SD 
Standard Deviation 
SOC 
Standard of Care 
SOFA Score 
Sequential Organ Failure Assessment Score 
SpO2 
Oxygen Saturation 
STEMI 
ST-Segment Elevation Myocardial Infarction 
TBD 
To Be Determined 
TEAE 
Treatment Emergent Adverse Events 
TG 
Triglyceride 
TNF-α 
Tumor Necrosis Factor Alpha 
ULN 
Upper Limit Normal 
URL  
Upper Reference Limit 
VARC-2 
Valve Academic Research Consortium-2 
WHO 
World Health Organization 
 
 

ICF_001.pdf: 
APPROVED BY THE YALE UNIVERSITY IRB 4/6/2021
Page 1 of 9
ICF-03 (0.2) date: February 23, 2021
YALE UNIVERSITY SCHOOL OF MEDICINE
Yale-New Haven Hospital & Saint Raphael Campus
Yale New Haven Health Network- Greenwich Hospital
Yale New Haven Health Network-Bridgeport Hospital
Yale New Haven Health Network-Lawrence & Memorial Hospital
CONSENT FOR PARTICIPATION IN A RESEARCH STUDY
Study Title: Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) 
Trial 
Principal Investigator: Alexandra Lansky, MD
Funding Source: American Diabetes Association, Inc.
Invitation to Participate and Description of Project
You are being invited to participate in a research study designed to look at the safety and 
effectiveness of the combination of colchicine+rosuvastatin added to standard of care compared 
to usual standard of care in patients admitted to the hospital with coronavirus infection. The 
purpose of the study is to find out whether colchicine+rosuvastatin can prevent progressing to 
severe complications from COVID-19. You have been asked to participate because you are 
admitted to the hospital with coronavirus infection. A total of 466 patients will be asked to take 
part in this study at Yale New Haven Hospital and Yale New Haven Health System. 
In order to decide whether or not you wish to be a part of this research study, you should know 
enough about its risks and benefits to make an informed decision. This consent form gives you 
detailed information about the research study, which a member of the research team will discuss 
with you. This discussion should go over all aspects of this research: its purpose, the procedures 
that will be performed, any risks of the procedures, possible benefits, and possible alternative 
treatments. Once you understand the study, you will be asked if you wish to participate; if so, you 
will be asked to sign this form. If you choose to participate in the study, your 
colchicine+rosuvastatin treatment will last until you leave the hospital and your participation will 
last for a total of 60 days.
Background
Infection with coronavirus can lead to difficulty breathing and the need for admission to the 
hospital for oxygen treatment. Once admitted to the hospital most patients with coronavirus 
infection will recover, but approximately 44% will develop severe breathing difficulty that will 
require ventilation with oxygen, a breathing machine or ventilator, kidney or blood pressure 
support or death. The complications of coronavirus infection are caused by a surge in the release 
of ones own inflammatory cells in response to the infection. Therefore, modifying the 
inflammatory response may help reduce coronavirus complications. The purpose of this study is 
to study whether the combination of colchicine+rosuvastatin, two commonly used drugs, both with 
anti-inflammatory effects and long track records of use can reduce complications of coronavirus 
infection.
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ICF-03 (0.2) date: February 23, 2021
Colchicine is an inexpensive, extensively studied and safe anti-inflammatory medication taken 
by mouth that has been used to treat gout for decades. Colchicine has several anti-inflammatory 
effects and may also prevent uptake of the virus into cells and may limit the virus’ ability to enter 
human cells.  Recently the benefits of Colchicine were demonstrated for patients with heart 
disease in 2 large clinical studies. 
Rosuvastatin, is a Statin, which has also been extensively studied and is commonly prescribed for 
the treatment of high cholesterol. It also has known anti-inflammatory effects and increases ACE2 
expression which may reduce severe breathing difficulties and improve survival and reduce 
damage of the lining of blood vessels which is thought to cause the clotting problems linked with 
coronavirus infection. Rosuvastatin may have direct antiviral properties by preventing the virus 
from binding and entering human cells. 
Both drugs are FDA approved.
If your doctor determines that you may be eligible for the study, your doctor may ask if you would 
like to take part in the study. You will be asked to sign this consent form before being able to 
participate in the study. 
If you agree to participate in the study, you will be randomly selected (“randomized”) to one of 2 
study groups for the duration of your hospitalization. Randomization is like flipping a coin (based 
on chance) with a 50:50 chance of being selected for one group or the other.
1. Standard treatment with the addition of Colchicine+Rosuvastatin
2. Standard treatment alone
Follow-up Procedures after Hospital Discharge
After you leave the hospital, there will be 2 phone calls at 1 and 2 months to see how you are 
feeling. After hospital discharge and if you have had damage to your heart from the infection, we 
will ask you to have a follow-up cardiac Magnetic Resonance Imaging (MRI) to study your heart. 
Cardiac MRI is a non-invasive test that uses a magnet and radio wave pulses to create detailed 
images of the heart. Some people feel nervous (claustrophobic) while in the space that houses the 
MRI magnet. You may be given medication to help you relax. If you have had certain medical 
devices implanted (metal devices, surgical “clips”, a pacemaker, implantable cardiac defibrillator 
or insulin pump) you may not be able to have an MRI test. It is important that you inform your 
study doctor of any implanted medical devices or past surgical procedures.
Risks and Inconveniences 
As with any medical treatment, the combination of colchicine+rosuvastatin carries known 
potential risks, as well as risks that may be unknown. Your study doctor will explain the risks. 
The following have been identified as possible complications of the study treatment:
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Page 3 of 9
ICF-03 (0.2) date: February 23, 2021
•
Rhabdomyolysis- condition of damaged skeletal muscle that causes release 
of myoglobin- protein that stores oxygen in muscles- into bloodstream and 
can cause kidney failure in extreme cases
•
Neuromuscular toxicity
•
Diarrhea- loose stools
•
Pharyngolaryngeal pain- pharynx is membrane behind nose and mouth; 
larynx is known as the “voice box” located in your throat
•
Nausea
•
Abdominal pain
•
Vomiting
•
Fatigue
•
Headache
•
Leukopenia- low white blood cell count
•
Granulocytopenia- less than the normal number of granular leukocytes in 
the blood. Can result in frequent number of bacterial infections of skin and 
throat
•
Thrombocytopenia- causes low level of platelets, the cells that help your 
blood clot
•
Pancytopenia- condition in which the body has too few red blood cells, 
white blood cells, and platelets. Can lead to excess bleeding and increased 
risk for infections
•
Myopathy- disease of the muscle in which the muscle fibers do not 
function properly 
•
Elevated CPK-CPK stands for Creatine Phosphokinase. This is a substance 
that is found in the human body in places like the heart muscle and skeletal 
muscles. The CPK blood test is used to determine if any damage has 
occurred to these muscles or to other locations of the body where CPK is 
found. The CPK blood test is often used to evaluate if a person has suffered 
from a heart attack
•
Myalgia- muscle pain
•
Liver enzymes abnormalities
•
Constipation
Potential Risks/Discomforts Associated with Non-Experimental Study Procedures
Magnetic Resonance Imaging Procedure
Magnetic resonance (MR) is a technique that uses magnets and radio waves, not x-rays, to take 
pictures and measure chemicals of various parts of the body. The United States Food and Drug 
Administration (FDA) have set guidelines for magnet strength and exposure to radio waves, and 
the physicians performing these tests carefully observe those guidelines.  
You will be watched closely throughout the MR study.  Some people may feel uncomfortable or 
anxious. If this happens to you, you may ask to stop the procedure at any time and we will take 
you out of the MR scanner.  On rare occasions, some people might feel dizzy, get an upset stomach, 
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ICF-03 (0.2) date: February 23, 2021
have a metallic taste or feel tingling sensations or muscle twitches. These sensations usually go 
away quickly but please tell the study staff if you have them.  
During the MRI scan, patient lies in a closed area inside the magnetic tube. Some patients can 
experience a claustrophobic sensation during the procedure. Therefore, patients with any history 
of claustrophobia should relay this information to the practitioner to the study staff.  It is customary 
that the MRI staff will be nearby during MRI scan. Furthermore, there is usually a means of 
communication with the staff (such as a buzzer held by the patient) which can be used for 
contacting the practitioner performing the scan if you find that you cannot tolerate the scan.
There are some risks with an MR study for certain people.  If you have a pacemaker or some metal 
objects inside your body, you will not be eligible to join this study because the strong magnets in 
the MR scanner might harm you. Another risk is a metallic object flying through the air toward 
the magnet and hitting you. To reduce this risk, we require that all people undergoing the MR 
imaging procedure remove all metal from their clothing and all metal objects from their pockets.  
Nothing metal can be brought into the magnet room at any time.  Also, once you are in the magnet, 
the door to the room will be closed so that no one from outside accidentally goes near the magnet.
This MR study is for research purposes only and is not in any way a clinical examination of the 
heart. The scans performed in this study are not designed to find abnormalities. The primary 
investigator, the MR technologist, and the Magnetic Resonance Research Center are not qualified 
to interpret the MR scans and are not responsible for providing a diagnostic evaluation of the 
images. If a worrisome finding is seen on your scan, a radiologist or another physician will review 
the relevant images. Based on his or her recommendation (if any), the primary investigator or 
consulting physician will contact you, inform you of the finding, and recommend that you seek 
medical advice as a precautionary measure.  The decision for additional examination or treatment 
would lie solely with you and your doctor.  
Benefits
You may or may not receive direct benefit from taking part in this study. However, your taking 
part in this research may benefit patients with coronavirus infection in the future. If you receive 
treatment with the study drug, you may benefit from participating in this research by having less 
inflammation and better outcomes. 
Economic Considerations
The medications (colchicine+rosuvastatin) and procedures (Cardiac MRI) done solely for the 
purposes of this study will be covered by the sponsor of the study. All other tests and procedures 
performed if you were not in the study will be the responsibility of you or your insurance provider 
to pay for. Your doctor and the study team will go over what you may be expected to pay for and 
what will be covered as a part of the study with you. You will not be paid or receive financial 
compensation to take part in the study. 
Treatment Alternatives/Alternatives
The current alternative to this study is to decline to take part in the study and to undergo usual care 
as recommended by your doctor. 
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ICF-03 (0.2) date: February 23, 2021
Confidentiality
Any identifiable information that is obtained in connection with this study will remain confidential 
and will be disclosed only with your permission or as permitted by U.S. or State law. Examples of 
information that we are legally required to disclose include abuse of a child or elderly person, or 
certain reportable diseases. To safeguard the confidentiality of subjects’ data, we will code data 
with numbers (and remove identifying information), store research materials in locked cabinets, 
and use computers with password-protection. When the results of the research are published or 
discussed in conferences, no information will be included that would reveal your identity unless 
your specific consent for this activity is obtained.  
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information. If you decide to be in this 
study, the researcher will get information that identifies you and your personal health information.  
This may include information that might directly identify you, such as your name and telephone 
number.  This information will be de-identified at the earliest reasonable time after we receive it, 
meaning we will replace your identifying information with a code that does not directly identify 
you. Any information that can identify you will remain confidential. The research team will only 
give this coded information to others to carry out this research study. 
The information about your health that will be collected in this study includes: 

Research study records

All information in your medical record, the results of physical exams, laboratory test 
results, MRI and CT scan results, medication records and other tests, your medical history 
and other data collected during the study

The following study-related information: 
o
Records about phone calls made as part of this research
o
Records about your study visits
o
Diaries or questionnaires
Information about you and your health which might identify you may be reviewed, used by or 
given to: 

The Principal Investigator: 

The study sponsor or the sponsor’s designee who may be conducting parts of the study on 
behalf of the sponsor

Health care providers who provide services to you in connection with this study

Laboratories and other individuals and organizations that analyze your health 
information in connection with this study, according to the study plan

Individuals who review your medical records for billing purposes

Co-Investigators and other members of the study team 
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ICF-03 (0.2) date: February 23, 2021

Representatives of the Food and Drug Administration and the Yale Institution Review 
Board (the committee that reviews, approves, and monitors research on human subjects), 
who are responsible for ensuring research compliance and protection of research subjects

Representatives of the Department of Health and Human Services (DHHS)
By signing this form, you authorize the use and/or disclosure of the information described above 
for this research study.  The purpose for the uses and disclosures you are authorizing is to ensure 
that the information relating to this research is available to all parties who may need it for 
research purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information. The research staff at the Yale New 
Haven Health System are required to comply with HIPAA regulations and to ensure the 
confidentiality of your information. Some of the individuals or agencies listed above may not 
be subject to HIPAA and therefore may not be required to provide the same type of 
confidentiality protection. They could use or disclose your information in ways not mentioned 
in this form.  However, to better protect your health information, agreements are in place with 
these individuals and/or companies that require that they keep your information confidential. 
The sponsor will see the research information we collect about you when we monitor the conduct of 
this research study. The “Sponsor” includes any persons that work for or are hired by the sponsor to 
conduct research activities related to this study.  For this study, the sponsor is Yale University.  
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies. 
This authorization to use and disclose your health information collected during your taking part in 
this study will never expire.
In Case of Injury
If you believe that the illness or injury is a result of the research, please contact your study doctor, 
Alexandra Lansky, MD at 203-737-2142 as soon as possible. 
If you become ill or are hurt while you are in the study, get the medical care that you need right 
away. You or your insurance company will be responsible for medical costs of treatment and care 
that occur during the study. However, if you experience an illness or injury resulting from the 
study drug, you and/or your insurance company will not be billed for diagnosis, care and treatment 
as long as the study protocol was followed by your study doctor, instructions provided to you by 
your study doctor were followed, and the illness or injury was not a result of a pre-existing 
condition or was not an expected risk from standard treatments for your condition.
For the treatment of injuries sustained as a direct result of participation in the study, the study 
sponsor will cover the expenses. No additional financial compensation for injury or lost wages is 
available. 
You do not give up any of your legal rights by signing this form. If you have any questions 
regarding research related injury, or where to obtain care, you should contact your research study 
doctor Alexandra Lansky, MD at 203-737-2142.
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Page 7 of 9
ICF-03 (0.2) date: February 23, 2021
Voluntary Participation and Withdrawal
You are free to choose not to take part in this study. Your participation in this study is voluntary 
and deciding not to participate will involve no penalty or loss of benefits to which you are entitled. 
Withdrawing from the Study
If you choose to participate and later change your mind, you are free to stop and withdraw from 
this study at any time during its course. If you choose to withdraw, data collected up until your 
withdrawal may still be used in the research study. All identifying information will be destroyed 
upon your withdrawal. To withdraw from the study, you can call a member of the study team at 
any time and tell them that you no longer want to take part. Your study doctor will advise you if 
there are any precautions to be taken should you withdraw from the study prior to completion of 
all study follow-ups.
Involuntary Withdrawal from the Study
The researchers may withdraw you from participating in the research if necessary. Your study 
doctor may end your participation if he/she determines that it is not in your best medical interest 
to continue taking part in the study.  The sponsor of the study may decide not to continue the study 
resulting in early withdrawal of subjects from the study. Your study doctor will advise you of any 
special precautions that may need to be taken should this occur.
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time.  You do this by sending written notice to the study doctor:
Alexandra Lansky, MD
Yale Internal Medicine/Cardiology
PO Box 208017
New Haven, CT 06520-8017
If you withdraw your permission, you will not be able to stay in this study. When you withdraw 
your permission, no new health information identifying you will be gathered after that date.  
Information that has already been gathered may still be used and given to others until the end of 
the research study, as necessary to insure the integrity of the study and/or study oversight.  
New Findings
If significant new findings develop during the course of this study which may relate to your 
willingness to continue participating, your study doctor will provide this information to you. You 
may be asked to sign a revised consent form if this occurs. You do not waive any of your legal 
rights by signing a revised consent form.
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Questions
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this web site at any time.
If you have further questions about this project or if you have a research-related problem, you 
may contact the Principal Investigator Dr. Alexandra Lansky at 203-737-2142.  
If you would like to talk with someone other than the researchers to discuss problems, concerns, 
or questions you may have concerning this research, or to discuss your rights as a research 
subject, you may contact the Yale Human Investigation Committee at 203-785-4866.
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ICF-03 (0.2) date: February 23, 2021
Authorization
I have read (or someone has read to me) this form and have decided to participate in the COLSTAT 
Trial described above. Its general purposes, the particulars of my involvement and possible hazards 
and inconveniences have been explained to my satisfaction. My signature also indicates that I have 
received a copy of this consent form. By signing this form, I give permission to the researchers to 
use and give out information about me for the purposes described in this form.
Printed Name of Patient: ________________________________________________________
Signature of Patient: ____________________________________________________________
Date: ______________________________                            Time: _______________________
Printed Name of Legally Authorized Representative of Patient: 
______________________________________________________________
Signature of Legally Authorized Representative of Patient: 
____________________________________________________________
Date: ______________________________                            Time: _______________________
Printed Name of Investigator Obtaining Consent: ______________________________________
Signature of Investigator Obtaining Consent: _________________________________________ 
Date: _______________________________                         Time: ________________________
                                      or
Printed Name of Person Obtaining Consent: __________________________________________
Signature of Person Obtaining Consent:  ____________________________________________           
Date: _____________________________                             Time: ________________________
APPROVED BY THE YALE UNIVERSITY IRB 4/6/2021