Clinical trial NCT03196349
Conditions: Venous Thromboembolism
Sponsor: Duke University
Start date: 2018-08-01; Completion date: 2019-05-01
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Comparison of Oral anticoagulants (warfarin, apixaban and rivaroxaban) for extended VEnous Thromboembolism.

Detailed description:
Determine if apixaban is superior to warfarin in the reduction of clinically relevant bleeding. Determine if rivaroxaban is superior to warfarin in the reduction of clinically relevant bleeding. Determine if apixaban is non-inferior to warfarin in the prevention of recurrent venous thromboembolism. Determine if rivaroxaban is non-inferior to warfarin in the prevention of recurrent venous thromboembolism. An exploratory comparison of apixaban versus rivaroxaban for the prevention of clinically relevant bleeding and recurrent Venous Thromboembolism (VTEs) as a secondary objective.

Arms: arm 1: Subjects randomized to Warfarin will have warfarin administered daily in order to maintain a target INR of 2-3 arm 2: Subjects randomized to Apixaban will have apixaban administered study drug of 2.5mg twice daily arm 3: Subjects randomized to Rivaroxaban will have rivaroxaban administered study drug of 10 mg daily
Interventions: intervention 1: Warfarin intervention 2: Apixaban 2.5 MG intervention 3: Rivaroxaban 10 MG
Intervention descriptions: intervention 1: Will be randomized to receive open label warfarin daily to achieve a target INR of 2-3 intervention 2: Will be randomized to receive open label apixaban of 2.5 mg twice daily intervention 3: Will be randomized to receive open label rivaroxaban of 10mg daily

Protocol documents:
SAP_002.pdf: 
Final SAP Version 1.0, 11 July 2018 
    
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Comparison of Oral anticoagulants for extended Venous 
Thromboembolism 
 (COVET) 
 
Statistical Analysis Plan  
NCT 03196349 
July 11, 2018 
 
Prepared by Anna Giczewska 
 
Duke Clinical Research Institute 


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Table of contents 
 
 
Background ............................................................................................................... 3 
 
Study Design .............................................................................................................. 3 
 
Study Objectives ....................................................................................................... 4 
 
Analysis Population .................................................................................................. 4 
 
Data Sources .............................................................................................................. 4 
 
Endpoints ................................................................................................................... 4 
6.1 Primary Endpoints .............................................................................................4 
6.1.1 Primary Safety Endpoints ............................................................................4 
6.1.2 Primary Efficacy Endpoint ..........................................................................5 
6.1.3 Other Study Endpoints .................................................................................5 
6.2 Secondary Objectives.........................................................................................6 
 
Sample Size Justification .......................................................................................... 6 
 
Data Safety Monitoring Board (DSMB) ................................................................. 7 
8.1 Interim Analysis .................................................................................................7 
 
Statistical Methodology ............................................................................................ 7 
9.1 General Analysis Conventions ..............................................................................7 
9.1.1 Statistical significance .................................................................................7 
9.1.2 Assumption checks ......................................................................................7 
9.1.3 Descriptive statistics ....................................................................................7 
9.1.4 Study Tables and Listings ............................................................................7 
9.1.5 Validation procedures ..................................................................................7 
9.1.6 Subgroup analyses .......................................................................................7 
9.1.7 Timing of analyses .......................................................................................8 
9.1.8 Visit Windows .............................................................................................8 
9.2 Analysis of Baseline Data ..................................................................................8 
9.3 Analysis of Time to “Response” Data ...............................................................8 
9.3.1 Primary and Secondary Endpoint Analysis .................................................8 
 
 
 


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 Background 
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is a common, potentially fatal, yet treatable condition and is the third leading 
cause of mortality by cardiovascular disease. The standard therapy for patients with VTE is 
anticoagulation for 3-6 months; the most common oral anticoagulants used are vitamin K 
antagonists (VKA) and direct oral anticoagulants (DOACs). After completing 3-12 months of 
anticoagulation, patients, clinicians and policy makers are faced with the crucial decision of 
whether or not to continue anticoagulation lifelong and which anticoagulant to choose. Vitamin 
K antagonists were the only oral anticoagulants available for many years and DOACs have 
expanded the choices now available.  
To compare a DOACs (apixaban and rivaroxaban) to VKA (warfarin) for extended 
anticoagulation for safety and efficacy, we propose a pragmatic clinical trial in which 3000 
patients who have confirmed acute symptomatic and unprovoked DVT/PE, have completed 
initial treatment of oral anticoagulation therapy for 3-12 months and are at high risk for recurrent 
VTE will be randomly assigned in a 1:1:1 ratio to warfarin, apixaban or rivaroxaban. Maximum 
follow-up will be 12 months. The primary efficacy endpoint is rate of recurrent VTE. The 
primary safety endpoint is clinically relevant bleeding and/or clinically relevant non major 
bleeding.  
Further details on the background and significance of this trial can be found in the clinical trial 
study protocol.  
 Study Design 
The COVET study is a multi-center, randomized, open-label study conducted in the United 
States and Canada of approximately 3000 patients who have confirmed acute symptomatic and 
unprovoked DVT/PE, have completed initial treatment of oral anticoagulation therapy for 3-12 
months and are at high risk for recurrent VTE.  Eligible patients who consent to participate in the 
study will be randomized to warfarin, apixaban, or rivaroxaban (see Figure). 
 
 


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 Study Objectives 
The DCRI statistics group will investigate the following objectives:  
 
Primary Safety Objectives: 
 Determine if apixaban is superior to warfarin in the reduction of clinically relevant 
bleeding. 
 Determine if rivaroxaban is superior to warfarin in the reduction of clinically relevant 
bleeding 
 
Primary Efficacy Objectives: 
 Determine if apixaban is non-inferior to warfarin in the prevention of recurrent venous 
thromboembolism. 
 Determine if rivaroxaban is non-inferior to warfarin in the prevention of recurrent venous 
thromboembolism. 
 
Exploratory Objective: 
 An exploratory descriptive comparison of apixaban versus rivaroxaban for the prevention 
of clinically relevant bleeding and recurrent VTEs as a secondary objective. 
 Analysis Population 
All-randomized (Intention To Treat - ITT) – this population includes all randomized participants 
regardless of the actual treatment received. This population will be used for the primary analysis 
of the primary safety and efficacy endpoints and a secondary analysis of the primary safety 
endpoints. 
 
Per protocol population – this population excludes participants who have not started the assigned 
therapy by the time of the 1 month telephone interview. For time-to-event analyses, participants 
who stop taking the assigned treatment will be censored after permanently stopping the assigned 
treatment.  This population will be used for the primary analysis of the primary safety endpoints 
and a secondary analysis of the primary efficacy endpoints. 
 Data Sources  
There will be only one data source eClinical Operating System (eCOS), which will include: 
 electronic Case Report Form (eCRF) which will complete by sites representatives and 
DCRI Call Center 
 CEC database which will be completed by CEC reviewers.  
 Endpoints  
6.1  Primary Endpoints 
6.1.1 Primary Safety Endpoints  
Clinically relevant bleeding (composite of major bleeding (MB) and/or clinically relevant 
non major bleeding (CRNMB)) is the primary safety outcome which specifically addresses 


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concerns relevant to all patients with VTE. For health care providers and stakeholders, this 
outcome is relevant as it has been the source of recent law suits in the U.S. concerning 
DOAC-associated bleeding. Our criteria to define clinically relevant bleeding are consistent 
with those in the aforementioned VTE trials and published by the International Society on 
Thrombosis and Haemostasis (ISTH) (Kaatz 2015). 
 
Primary safety objectives in patients at high-risk for recurrent VTE, the COVET trial will: 
 Determine if apixaban is superior to warfarin, target INR 2-3, in the reduction of 
clinically relevant bleeding. 
 Determine if rivaroxaban is superior to warfarin, target INR 2-3 in the reduction of 
clinically relevant bleeding. 
 
6.1.2 Primary Efficacy Endpoint 
Recurrent VTE is the primary efficacy outcome, defined according to criteria described in the 
2012 Chest Guidelines for Diagnosis of DVT (Bates 2012) and 2014 European Society of 
Cardiology Guidelines for Diagnosis of PE (Konstaninides 2014). This outcome is patient 
centered and important for all stakeholders given the clinical (symptoms of pain and 
discomfort), social, and economic burden associated with it. 
 
Primary sefficacy objectives in patients at high-risk for recurrent VTE, the COVET trial will: 
 Determine if apixaban is non-inferior to warfarin, target INR 2-3, in the prevention of 
recurrent venous thromboembolism. 
 Determine if rivaroxaban is non-inferior to warfarin, target INR 2-3, in the prevention of 
recurrent venous thromboembolism. 
 
6.1.3 Other Study Endpoints 
 All-cause mortality 
 Major bleeding 
 Clinically relevant non-major bleeding 
 Premature termination of study medication 
 Vascular events (myocardial infarction, ischemic stroke) 
These study endpoints will be defined in detail in the Clinical Event Classification (CEC) 
charter. 
 
 


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6.2 Secondary Objectives  
In patients at high-risk for recurrent VTE, the COVET trial will 
 Compare the rates of clinically relevant bleeding between apixaban and rivaroxaban. 
 Sample Size Justification 
The planning and sample size calculations for the COVET study were designed to compare 
warfarin vs. apixaban and warfarin vs. rivaroxaban. A direct exploratory and descriptive 
comparison of the two DOACs will be conducted but the study was not sized to be adequately 
powered to detect statistically significant differences between those treatment groups. 
 
For the primary safety endpoint, there will be two comparisons, apixaban versus warfarin and 
rivaroxaban versus warfarin, each of which will be tested at the two-sided 0.05 level of significance 
to detect a 50% reduction (HR=0.50) in clinically relevant bleeding compared to warfarin. For the 
primary efficacy endpoint, there will be two comparisons, apixaban versus warfarin and 
rivaroxaban versus warfarin to determine is the DOACs are non-inferior to warfarin in the 
prevention of recurrent venous thromboembolism. The non-inferiority assessments will be based 
on comparing the one-sided 95% upper confidence interval with a 2% increase in recurrent VTE. 
The type I error rates for the non-inferiority and superiority analyses have been set at 0.05 one-
sided and 0.05 two-sided, respectively. These are considered standard values for two arm studies. 
We have elected to not alter them for this three-arm design because the clinical questions of interest 
are the two comparisons of the DOACs versus warfarin. 
For the primary efficacy analysis, using an outcome of recurrent VTE, we expect 12-month rate 
of 0.87% for the warfarin arm compared with 1.5% for the DOACs (Einstein Investigators 2010; 
Agnelli 2013). Sample sizes of 950 per arm are sufficient to provide 80% power to have the upper 
95% one-sided confidence interval less than 2%. The proposed sample size of 1000 participants 
per arm allows for 5% missing data due to loss-to-follow-up, deaths not related to VTE, and lack 
of starting the assigned study drug. These calculations were obtained using a simulation method 
with nQuery Advisor 7.0 software. 
For the primary safety analysis, the RE-MEDY study reported clinically relevant bleeding rates of 
10.2% for the warfarin treated patients (Schulman 2013). Using a 12-month rate of 6.8%, a per 
group sample size of 950 participants (or 1000 / group with an allowance for 5% missing data) 
will provide greater than 90% power to detect a 50% event rate reduction for the DOAC arm. 
Similarly, assuming a lower 12-month event rate of 6.0% for the warfarin arm, the sample size of 
950 participants per group will provide 88% power to detect a 50% event rate reduction for the 
DOAC arm. These calculations assume a two-sided 0.05 type I error rate and are based on a Cox 
model. 
 
 


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 Data Safety Monitoring Board (DSMB) 
The Data Safety and Monitoring Board (DSMB) will convene approximately every 6 months to 
evaluate the progress of the trial and review accumulating safety data. Details on the roles and 
responsibilities of the DSMB are outlined in the DSMB charter. Summary reports and 
recommendations from the meetings will be distributed to the PIs within a reasonable period of 
time following the meeting. There are no formal stopping rules for safety in the trial. 
8.1 Interim Analysis 
There is no interim analysis planned for this trial.  
 Statistical Methodology 
9.1 General Analysis Conventions 
9.1.1 Statistical significance 
Statistical comparisons will be performed using two-sided significance tests. The level of 
significance for all secondary efficacy and safety analyses will be set at an alpha level of 
0.05.  
9.1.2 Assumption checks  
Before final analysis, the basic assumptions underlying the planned approach, including the 
validity of the proportional hazards assumption for the Cox model, will be checked and 
transformations or nonparametric tests will be used as needed.  
9.1.3 Descriptive statistics 
Mean, standard deviation, median, 25th percentile, 75th percentile, minimum, and maximum 
will be presented for continuous variables. Categorical variables will be presented as a simple 
count and percentage. Other descriptive statistics may be provided where appropriate. If 
necessary, plots of descriptive statistics will also be provided. 
9.1.4 Study Tables and Listings  
Most study data will be presented by treatment group and overall. Data may also be listed by 
subject id and by site where appropriate. 
9.1.5 Validation procedures 
All programs to create analysis datasets and perform analyses will be generated and validated 
under the guidance of the DCRI Statistical SOPs. 
9.1.6 Subgroup analyses 
The study investigators have identified several pre-specified subgroups of interest. Those 
subgroups include: initial anticoagulant, race, sex, renal impairment, obesity, and antiplatelet 
use (Buckner 2012; Liao 2014; White 2009). Given the expected low number of events for 
both primary endpoints, the subgroups will need to be interpreted cautiously. For each 
subgroup we will compute an interaction p-value and then estimate hazard ratios for each 
subgroup. 


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9.1.7 Timing of analyses 
The need for more than one database lock is not anticipated for this trial. The analyses of the 
safety and efficacy data will be conducted within a reasonable time following the database 
lock. 
9.1.8 Visit Windows 
Subjects should be seen for baseline evaluation and randomization. All visits except baseline 
visit will be phone calls.  
 
 
 
   
 
 
 
*Canadian participants will be contacted by the Canadian enrolling centers to complete phone assessments.  
**If the participant is not reached within the +/- 1 week window, please attempt contact until Month 3. 
***If the participant is not reached within the +/- 4 week window, please attempt contact until Month 9. 
9.2 Analysis of Baseline Data 
Baseline demographic and clinical characteristic descriptive data will be summarized in 
accordance with the general analysis conventions. If treatment group comparisons are 
warranted, differences will be examined using a two-sample Student t-test for continuous 
variables (or Wilcoxon rank sum test if the assumptions are not met) and chi-square test for 
categorical variables (or Fisher’s exact test). 
 
The following baseline data will be included in the final report: 
 
  Demographic characteristics (e.g. sex, ethnicity, race, and age) 
 Medical History characteristics (e.g. unprovoked deep vein thrombosis, unprovoked 
pulmonary embolism, GI bleed) 
 Prior medications (e.g. Ketoconazole, Iitraconazole, Aspirin, Clopidogrel) 
9.3 Analysis of Time to “Response” Data 
9.3.1 Primary and Secondary Endpoint Analysis  
The primary analyses for safety primary endpoint will be based on a stratified Cox model. 
The ascertainment time will be based on the time of the first event or censoring time. 
Stratification will be based on the anticoagulant used during the screening period. The all-
randomized analysis dataset will be used for the primary analyses. The treatment effect for 
each DOAC compared to warfarin will be computed using the estimated hazard ratio and 
Time (Day) 
Screening / 
Randomization 
Month 1* 
Month 6* 
Month 12* 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit Window 
30 days 
(+/- 1 week)** 
(+/- 4 
week)*** 
(+ 8weeks) 
Type of Visit 
In-person 
Phone call 
Phone call 
Phone call 


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associated 95% confidence intervals. Secondary analyses will be based on a Kaplan-Meier 
estimates on the all-randomized and per-protocol populations. 
 
For the efficacy primary endpoint, the primary analysis will be based on a Kaplan-Meier 
analysis using the all-randomized analysis dataset. The 12-month event rates differences 
between the DOACs versus warfarin will be based on the difference in the Kaplan-Meier 
estimates and the one-sided upper 95% confidence interval will be based on a bootstrap 
estimator. Secondary analyses of the recurrent VTE endpoint will be based on the Cox 
regression model. Exploratory analyses will directly compare the two DOACs for both safety 
and efficacy endpoints. Additionally, an exploratory analysis will pool the two DOAC arms 
and compare those estimates with the warfarin treatment group. 
 
For secondary endpoints, the estimated differences between the DOACs and warfarin treated 
groups will be based on linear models, logistic regression, and Cox models depending on the 
endpoint. Efforts will be made to limit the amount of missing data for the key endpoints and 
adherence measures. When necessary, multiple imputation will be used to account for 
missing covariate information.  
  


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References 
 
Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of 
Anticoagulation. Definition of clinically relevant non-major bleeding in studies of 
anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical 
patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015 
Nov;13(11):2119-26. 
 
Bates SM, Jaeschke R, Stevens SM et al. Diagnosis of DVT: Antithrombotic Therapy and 
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based 
Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e351S‐e418S. 
 
Buckner TW, Key NS. Venous thrombosis in blacks. Circulation 2012;125(6):837‐839. 
 
Liao S, Woulfe T, Hyder S, Merriman E, Simpson D, Chunilal S. Incidence of venous 
thromboembolism in different ethnic groups: a regional direct comparison study. J Thromb 
Haemost 2014;12(2):214‐219. 
 
White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous 
thromboembolism. Thromb Res 2009;123 Suppl 4:S11‐S17. 
 
 
 

Prot_003.pdf: 
 
Confidential 
Amendment 3, version date 21Sep2018 
 
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. 
COVET 
Study Protocol 
Amendment 3 
 
Comparison of Oral anticoagulants for extended VEnous Thromboembolism (COVET) 
NCT03196349 
 
 
Original Protocol Version Date: May 15, 2017 
Amendment 1 Version Date: October 10, 2017 
Amendment 2 Version Date: December 08, 2017 
Amendment 3 Version Date: September 21, 2018 
 
Principal Investigator: Thomas Ortel, MD 
Co-Principal Investigator: Lana Castellucci, MD 
Co-Principal Investigator: David Garcia, MD 
Statistical Investigator: Kevin Anstrom, PhD 
 
Funded by Patient Centered Outcomes Research Institute (PCORI) NOACs 1511-33599 
CONFIDENTIALITY STATEMENT 
 
The information contained in this document is the property or under control of DUKE CLINICAL 
RESEARCH INSTITUTE (DCRI) and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review Board or 
Independent Ethics Committee.  The information is only to be used by you in connection with the clinical 
study described in the protocol.  You will not disclose any of the information to others without written 


 
Confidential 
Amendment 3, version date 21Sep2018 
 
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authorization from DCRI. 


 
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PROTOCOL VERSION AND AMENDMENT TRACKING 
Version Number/Amendment 
Approval Date 
Version 1 
15May2017 
Amendment 1 
10October2017 
Amendment 2   
08December2017 
Amendment 3 
21Sep2018 
 
 
 
 


 
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PROTOCOL SYNOPSIS 
Protocol Title 
Comparison of Oral anticoagulants for extended VEnous 
Thromboembolism (COVET)  
Main Criteria for Inclusion 
Age 18 years and older; confirmed acute, symptomatic first 
unprovoked lower extremity proximal DVT and/or PE, 
completed initial course of oral anticoagulation therapy for 3-
12 months and recommended for continued anticoagulation, 
under the care of a healthcare provider for treatment of VTE 
during study participation  
Study Objectives 
Primary Safety Objectives: 
 
Determine if apixaban is superior to warfarin in the 
reduction of clinically relevant bleeding. 
 
Determine if rivaroxaban is superior to warfarin in the 
reduction of clinically relevant bleeding 
Primary Efficacy Objectives: 
 
Determine if apixaban is non-inferior to warfarin in 
the prevention of recurrent venous thromboembolism. 
 
Determine if rivaroxaban is non-inferior to warfarin 
in 
the 
prevention 
of 
recurrent 
venous 
thromboembolism. 
Exploratory Objective: 
 
An exploratory descriptive comparison of apixaban 
versus rivaroxaban for the prevention of clinically 
relevant bleeding and recurrent VTEs as a secondary 
objective. 
Study Design 
Randomized, open label, active comparator 
Treatment Regimen 
Warfarin, apixaban, or rivaroxaban 
Duration of Study Participation 
12 months 
Number of Patients 
Approximately 3000 
Number of Sites 
Approximately 60 sites in the US and Canada 
Primary Efficacy Endpoint 
Recurrent venous thromboembolism 
Primary Safety Endpoint 
Clinically relevant bleeding 
Interim Analyses 
There will be no formal interim analyses for the primary 
efficacy or safety endpoints.  The Data and Safety Monitoring 
Board will meet regularly to review patient safety and overall 
study conduct. 
 


 
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TABLE OF CONTENTS 
 
Protocol Version and Amendment Tracking .......................................................................3 
Protocol Synopsis.................................................................................................................4 
Table of Contents .................................................................................................................5 
Abbreviations .......................................................................................................................7 
1. 
Introduction ..............................................................................................................9 
1.1 
Background ..................................................................................................9 
1.2 
Preclinical Findings .....................................................................................9 
1.3 
Long-term prevention of recurrent VTE (after treatment of acute event) .10 
1.4 
Clinical Experience with Study Agents .....................................................11 
1.5 
Rationale for COVET ................................................................................12 
2. 
Objectives and Endpoints ......................................................................................13 
2.1 
Primary Safety Objectives .........................................................................13 
2.2 
Primary Efficacy Objectives ......................................................................13 
2.3 
Secondary Objectives.................................................................................13 
2.4 
Primary Safety Endpoint ............................................................................13 
2.5 
Primary Efficacy Endpoint ........................................................................13 
2.6 
Other Study Endpoints ...............................................................................13 
3. 
Patient Selection.....................................................................................................15 
3.1 
Inclusion Criteria .......................................................................................15 
3.2 
Exclusion Criteria ......................................................................................15 
4. 
Study Design ..........................................................................................................18 
4.1 
Overview of Study .....................................................................................18 
4.2 
Treatment Arms .........................................................................................18 
4.3 
Study Procedures .......................................................................................20 
4.4 
Schedule of Follow-Up Assessments.........................................................22 
4.5 
Screening and Pre-randomization Procedures ...........................................23 
4.6 
Randomization ...........................................................................................23 
4.7 
Post-randomization Procedures .................................................................24 
5. 
Treatment Arms .....................................................................................................25 
5.1 
Study Drug Administration ........................................................................25 
5.2 
Potential Benefits/Risks of Study Medications..........................................25 
5.3 
Procedure to Assess Medication Adherence ..............................................25 
5.4 
Concomitant Medications ..........................................................................25 


 
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5.5 
Patient Reported Outcomes/Quality of Life Assessments .........................25 
5.5.1 
Anti-coagulant Treatment Scale .................................................25 
5.5.2 
EQ-5D-5L ...................................................................................26 
5.6 
Prohibited Medications ..............................................................................26 
5.7 
Peri-Procedural anticoagulation management ...........................................26 
6. 
Safety Assessments ................................................................................................27 
6.1 
Safety Assessments and Reporting ............................................................27 
6.2 
Adverse Events ..........................................................................................27 
6.3 
Pregnancy ...................................................................................................27 
6.4 
Criteria for Withdrawal of Patients from Study .........................................28 
7. 
Statistical Considerations .......................................................................................29 
7.1 
General Design Issues ................................................................................29 
7.2 
Sample Size Justification ...........................................................................29 
7.3 
Definition of Analysis Populations ............................................................30 
7.4 
Interim Analyses and Stopping Rules ........................................................30 
7.5 
Data Analyses ............................................................................................31 
8. 
Follow-up Data Collection and Clinical Event Classification ...............................33 
9. 
Data Management and Quality Assurance .............................................................34 
9.1 
Data Management ......................................................................................34 
9.2 
Quality Assurance ......................................................................................34 
10. 
Study Responsibilities ............................................................................................36 
10.1 
Investigator Responsibility/Performance ...................................................36 
10.2 
Training ......................................................................................................36 
10.3 
Monitoring the Investigational Sites ..........................................................36 
10.4 
Study Documentation.................................................................................37 
10.5 
Source Documentation ...............................................................................37 
10.6 
Protocol Deviations ....................................................................................37 
10.7 
Data Transmittal and Record Retention .....................................................38 
10.8 
Study Closeout ...........................................................................................38 
10.9 
Audit/Inspections .......................................................................................38 
10.10 Publication Policies ....................................................................................38 
11. 
Ethical Considerations ...........................................................................................39 
11.1 
Informed Consent.......................................................................................39 
11.2 
Confidentiality of Patients .........................................................................39 
11.3 
Authorization for Use and Disclosure of Protected Health Information ...39 
11.4 
Human Subject Protections ........................................................................39 
11.4.1 
Research Subject Selection and Justification of Exclusions .......39 
11.4.2 
Risks/Discomforts of Study Participation...................................40 
11.5 
Institutional Review Board/Ethics Committee Review .............................40 
11.6 
Steering Committee ...................................................................................40 
11.7 
Study Advisory Committee (SAC) ............................................................40 


 
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11.8 
Data and Safety Monitoring Board ............................................................41 
11.9 
Independent Clinical Events Classification (CEC) ....................................41 
11.10 Role of PCORI as a Funding Source .........................................................41 
12. 
References ..............................................................................................................42 
 
ABBREVIATIONS 
ACTS 
Anti-coagulation Treatment Scale 
AE 
Adverse Event 
CEC  
Clinical Events Committee 
CI 
Confidence Interval 
CRCL 
Creatinine Clearance 
CRNMB 
Clinically Relevant Non Major Bleeding 
DCRI 
Duke Clinical Research Institute 
DL 
Deciliter 
DOACs 
Direct Oral Anticoagulants 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EQ-5D-5L 
EuroQoL-5D-5L 
FDA 
Food and Drug Administration 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
INR 
International Normalized Ratio 
IPW 
Inverse Probability Weighted 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
MB 
Major Bleeding 
NBCA 
National Blood Clot Alliance 
PCORI 
Patient Centered Outcomes Research Institute  
PE 
Pulmonary Embolism 
PI 
Principal Investigator 
RCT 
Randomized Clinical Trial 
RR 
Relative Risk 
SAC 
Study Advisory Committee 
VTE 
Venous Thromboembolism 
VKA 
Vitamin K Antagonists 


 
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V/Q 
Ventilation Perfusion  
 


 
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1. 
INTRODUCTION 
1.1 
Background 
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is a common, potentially fatal, yet treatable condition and is the third leading 
cause of mortality by cardiovascular disease (White 2003; Heit 2006; Kyrle 2004).  It represents 
an important health care issue due to its high rate of hospital admission and potential reduction in 
functional status of survivors due to VTE related complications such as post-thrombotic 
syndrome and chronic thromboembolic pulmonary hypertension. Up to 5% of the population will 
experience VTE in their lifetime and the majority of these events will be unprovoked (White 
2003). VTE is predominantly a disease of the elderly with incidence rates increasing 
exponentially with age for both men and women (White 2003; Heit 2006; Kyrle 2004). The 
standard therapy for patients with VTE is anticoagulation for 3-6 months; the most common oral 
anticoagulants used are vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) 
(Kearon 2012).  
After completing 3-12 months of anticoagulation, patients, clinicians and policy makers are 
faced with the crucial decision of whether or not to continue anticoagulation lifelong. In patients 
with unprovoked VTE, the risk of recurrent VTE is substantial, reaching 5%-10.8% in the first 
year after stopping 3-6 months of VKA, 5% in the subsequent year (Agnelli 2001) and 2-3% per 
year thereafter (Agnelli 2001; Prandoni 1996; Kearon 1999; Schulman 1995; Research 
Committee 1992), with a case-fatality rate for recurrent VTE of 3.6% (Carrier 2010). Since up to 
75% of unprovoked VTE patients would benefit from continuing anticoagulants lifelong (Rodger 
2008), current guidelines recommend indefinite anticoagulant therapy for patients in this 
category (Kearon 2016). With this decision, the next crucial question becomes which 
anticoagulant to choose. Treatment with VKA presents many challenges including drug and food 
interactions, and a narrow therapeutic window requiring regular laboratory monitoring; these can 
be particularly burdensome for elderly patients and those with many co-morbidities who require 
intensive monitoring, frequent trips to the laboratory and subsequent dosing changes.  DOACs 
are simpler to use as they have more predictable pharmacokinetic properties (Vilchez 2014) and 
do not require monitoring. A major limitation of DOACs however, is the lack of comparison 
trials demonstrating a favorable benefit-to-risk ratio of DOACs over VKAs for long term 
anticoagulation in VTE patients. This gap in the evidence highlights the decisional dilemma 
patients, clinicians, and stakeholders are faced with when choosing which anticoagulant to use 
for long-term prevention of recurrent VTE.  
1.2 
Preclinical Findings 
The information on comparative effectiveness between rivaroxaban or apixaban and warfarin 
(target INR 2-3) is derived from industry-sponsored trials for treatment of acute VTE (Einstein 
Investigators 2010; Buller 2012; Agnelli 2013a). The duration of treatment in these trials was 
defined as the initial 3-12 months of anticoagulation after diagnosis of acute VTE. Einstein-DVT 
included nearly 3500 patients with proximal DVT and no symptomatic PE (Einstein 
Investigators 2010). Rivaroxaban was shown to be non-inferior to warfarin for the primary 
efficacy outcome of recurrent VTE with an event rate of 2.1% in the rivaroxaban arm and 3.0% 
in the warfarin arm (hazard ratio (HR), 0.68; 95% confidence interval (CI), 0.44 to 1.04). The 


 
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primary safety outcome was clinically-relevant bleeding, a composite of major bleeding or 
clinically-relevant non-major bleeding events, occurred in 8.1% of patients in each group. 
Einstein-PE enrolled 4800 patients with acute PE with or without DVT (Buller 2012). The 
primary efficacy and safety outcomes were identical to the Einstein-DVT trial. Rivaroxaban was 
similarly shown to be non-inferior to warfarin for the primary efficacy outcome with 2.1% of 
patients in the rivaroxaban arm versus 1.8% in the warfarin having recurrent events (HR 1.12; 
95% CI, 0.75 to 1.68). Bleeding occurred in 10.3% of patients in the rivaroxaban group and 
11.4% in the warfarin group. The Amplify RCT compared apixaban to warfarin in 5400 patients 
with acute VTE (Agnelli 2013a). The primary efficacy outcome of recurrent VTE occurred in 
2.3% of patients in the apixaban group and 2.7% in the warfarin group (Relative risk (RR), 0.84; 
95% CI, 0.60 to 1.18), demonstrating non-inferiority of apixaban to warfarin. The primary safety 
outcome of major bleeding occurred in 0.6% of patients in the apixaban group compared to 1.8% 
in the warfarin group, meeting pre-specified criteria for superiority.  
1.3 
Long-term prevention of recurrent VTE (after treatment of acute event) 
 
Rivaroxaban and apixaban have each been compared to placebo for extended anticoagulation in 
patients who had completed 6 to 12 months of anticoagulation for the index VTE event (Einstein 
Investigators 2010; Agnelli 2013b). In both trials, extended anticoagulation treatment was for 12 
months duration, the primary efficacy outcome was recurrent VTE and the primary safety 
outcome was major bleeding. In the Einstein-EXT RCT, 1200 patients were included and 
rivaroxaban was superior to placebo for preventing recurrent VTE (1.3% for rivaroxaban and 
7.1% for placebo; HR, 0.18; 95% CI, 0.09 to 0.39) (cf. Table 1). Major bleeding events occurred 
in 0.7% of patients in the rivaroxaban group compared to no bleeding events in those on placebo. 
Clinically relevant bleeding (MB or CRNMB) events occurred in 6.0% of patients receiving 
rivaroxaban and 1.2% of those on placebo (cf. Table 2). The Amplify-EXT RCT compared two 
doses of apixaban (5 mg and 2.5 mg, twice daily) to placebo (Agnelli 2013b). Both doses of 
apixaban were superior to placebo in this trial of 2500 patients. The rates of recurrent VTE were 
1.7% in each apixaban group compared to 8.8% in the placebo group (Table 1).  Major bleeding 
events occurred in 0.2% in the 2.5 mg apixaban group, 0.1% in the 5 mg apixaban group, and in 
0.5% of the placebo group. Clinically relevant bleeding (MB or CRNMB) events occurred in 
3.2% of patients receiving apixaban 2.5 mg and 2.7% of those on placebo (cf. Table 2).  
 
Table 1: Recurrent VTE event rates in Phase III VTE Secondary Prevention Trials 
 
Study 
Outcome 
Comparator 1 
Comparator 2 
Hazard Ratio (95% CI) 
RE-MEDY 
Recurrent 
VTE 
or 
VTE-related death 
Dabigatran: 1.2% 
Warfarin: 
0.87% 
1.44 (0.78-2.64) 
EINSTEIN-
EXT 
Recurrent VTE 
Rivaroxaban: 
1.3% 
Placebo: 7.1% 
0.18 (0.09-0.39) 
AMPLIFY-
EXT 
Recurrent 
VTE 
or 
VTE-related death 
Apixaban 2.5 mg 
BID: 1.7% 
Placebo: 8.8% 
Relative Risk: 0.19 (0.11-
0.33) 
AMPLIFY-
EXT 
Recurrent 
VTE 
or 
VTE-related death 
Apixaban 2.5 mg 
BID: 1.7% 
Apixaban 5 mg 
BID: 1.7% 
 Relative Risk: 0.97 (0.46-
2.02) 
 


 
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Table 2: Clinically Relevant Bleeding (Major Bleeding [MB] and clinically relevant non-major 
bleeding [CRNMB]) event rates in Phase III VTE Secondary Prevention Trials 
 
Study 
Outcome 
Comparator 1 
Comparator 2 
Hazard Ratio (95% CI) 
RE-MEDY 
MB or CRNMB 
Dabigatran: 5.6% 
Warfarin: 10.2% 
0.54 (0.41-0.71) 
EINSTEIN-
EXT 
MB or CRNMB 
Rivaroxaban: 6.0% 
Placebo: 1.2% 
5.19 (2.3-11.7) 
AMPLIFY-
EXT 
MB or CRNMB 
Apixaban 2.5 mg 
BID: 3.2% 
Placebo: 2.7% 
Relative Risk: 1.20 (0.69-
2.10) 
AMPLIFY-
EXT 
MB or CRNMB 
Apixaban 2.5 mg 
BID: 3.2% 
Apixaban 5 mg 
BID: 4.3% 
 Relative Risk: 0.74 (0.46-
1.22) 
 
1.4 
Clinical Experience with Study Agents 
The standard oral anticoagulant that has long been used for extended treatment of VTE has been 
VKAs. Warfarin is the most common VKA available in North America and it is an effective 
anticoagulant that reduces the risk of recurrent VTE by >90% (Castellucci 2013).  We have set 
the outcome of our comparative effectiveness study for superiority relative to warfarin.  Despite 
its effectiveness, there are several limitations of warfarin use including the narrow therapeutic 
window, frequent INR monitoring to ensure patients remain in target range of 2-3, and many 
food and drugs interactions. The need to monitor INRs can be burdensome for patients and 
interfere with regular activities and functioning. DOACs have simplified anticoagulation 
treatment for many patients because they do not require laboratory monitoring for dosing 
adjustments. There are four DOACs available for treatment of VTE in the United States and 
Canada – dabigatran, edoxaban, rivaroxaban and apixaban. Edoxaban has not been studied for 
extended anticoagulation in VTE so we have excluded it from the trial. Dabigatran has been 
associated with higher rates of acute coronary syndromes in previous VTE trials and we 
excluded it from our proposed trial (Schulman 2012; Connolly 2009).  
The DOACs rivaroxaban and apixaban were chosen as the intervention anticoagulants for the 
proposed trial. Rivaroxaban and apixaban are two Factor Xa inhibitors that are at least as 
effective and safe as warfarin for treatment of acute VTE (Einstein Investigators 2010; Buller 
2012; Agnelli 2013a). Each DOAC has also been compared to placebo for extended 
anticoagulation in patients with VTE, demonstrating significantly lower rates of recurrent VTE 
and similar or lower rates of major bleeding events (Einstein Investigators 2010; Agnelli 2013b). 
The differences between the medications are in their dosing frequency as rivaroxaban is once 
daily and apixaban is twice daily. Both medications are currently approved by the FDA and 
Health Canada and are widely available from commercial pharmacies. Direct comparison of 
these anticoagulants to warfarin will enable us to determine whether they are as efficacious and 
as safe as warfarin for extended VTE treatment.  


 
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1.5 
Rationale for COVET 
Vitamin K antagonists were the only oral anticoagulants available for many years and DOACs 
have expanded the choices now available. Although the Einstein and Amplify trials have 
changed clinical practice management for patients with acute VTE, generalizability of their 
results for extended anticoagulation are limited for the following reasons: a) treatment duration 
was shorter than what would be expected for extended anticoagulation; b) the trials contained 
patients with both provoked and unprovoked VTE; c) the patients were highly selected from 
populations that do not reflect clinical practice; d) lack of head-to-head comparisons of DOACs. 
Only one trial comparing a DOAC (dabigatran) to VKA for extended anticoagulation has been 
done (Schulman 2012) and no comparative efficacy or safety data exists for rivaroxaban and 
apixaban relative to warfarin for extended anticoagulation; and e) previous clinical trials were 
sponsored by industry and there is no interest by the manufacturers to conduct head-to-head 
comparisons of anticoagulants. Our study will advance knowledge in this field as it is a 
pragmatic comparison trial that will potentially change practice and resolve the decisional 
uncertainty patients and clinicians face when choosing an anticoagulant for extended treatment.  


 
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2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Safety Objectives 
In patients at high-risk for recurrent VTE, the COVET trial will 
 Determine if apixaban is superior to warfarin, target INR 2-3, in the reduction of 
clinically relevant bleeding. 
 Determine if rivaroxaban is superior to warfarin, target INR 2-3 in the reduction of 
clinically relevant bleeding. 
2.2 
Primary Efficacy Objectives 
In patients at high-risk for recurrent VTE, the COVET trial will 
 Determine if apixaban is non-inferior to warfarin, target INR 2-3, in the prevention of 
recurrent venous thromboembolism. 
 Determine if rivaroxaban is non-inferior to warfarin, target INR 2-3, in the prevention of 
recurrent venous thromboembolism. 
2.3 
Secondary Objectives 
In patients at high-risk for recurrent VTE, the COVET trial will 
 Compare the rates of clinically relevant bleeding between apixaban and rivaroxaban. 
2.4 
Primary Safety Endpoint 
Clinically relevant bleeding (composite of major bleeding (MB) and/or clinically relevant non 
major bleeding (CRNMB)) is the primary safety outcome which specifically addresses concerns 
relevant to all patients with VTE. Our criteria to define clinically relevant bleeding are consistent 
with those in the aforementioned VTE trials and published by the International Society on 
Thrombosis and Haemostasis (ISTH) (Kaatz 2015). 
2.5 
Primary Efficacy Endpoint 
Recurrent VTE is the primary efficacy outcome, defined according to criteria described in the 
2012 Chest Guidelines for Diagnosis of DVT (Bates 2012) and 2014 European Society of 
Cardiology Guidelines for Diagnosis of PE (Konstaninides 2014). This outcome is patient 
centered and important for all stakeholders given the clinical (symptoms of pain and discomfort), 
social, and economic burden associated with it. 
2.6 
Other Study Endpoints 
 All-cause mortality 
 Major bleeding 
 Clinically relevant non-major bleeding 


 
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 Premature termination of study medication 
 Vascular events (myocardial infarction, ischemic stroke) 
These study endpoints will be defined in detail in the Clinical Event Classification (CEC) 
charter. 


 
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3. 
PATIENT SELECTION 
3.1 
Inclusion Criteria 
To be eligible for this trial, patients must meet all of the following criteria: 
 
Have confirmed acute, symptomatic, first lower extremity proximal DVT and/or PE that 
is NOT associated with a transient risk factor. (See Table 2 for list of transient risk 
factors that would exclude the patient) 
 Have completed an initial treatment course of oral anticoagulant therapy for 3-12 months 
and have a recommendation from their provider to continue anticoagulation indefinitely. 
 Have the capacity to understand and sign an informed consent form. 
 Be 18 years of age and older. 
 Under the direct care of a healthcare provider for treatment of VTE for the length of time 
in the study. 
3.2 
Exclusion Criteria 
If a patient meets any of the following criteria, he or she may not be enrolled in the study: 
 Creatinine clearance (CrCl) < 30 mL/min as determined by Cockcroft-Gault formula 
documented within 3 months from date of consent 
 Significant liver disease (Child-Pugh B or C) 
 Concomitant use of medications that are strong P-glycoprotein or CYP3A4 
inducers/inhibitors 
 Another indication for chronic therapeutic-dose anticoagulation, such as atrial fibrillation 
(i.e., rivaroxaban, 10 mg daily, or apixaban, 2.5 mg twice daily, would not be appropriate 
therapy) 
 A clinical indication for a specific anticoagulant regimen (e.g., warfarin with a target INR 
of 2-3 is recommended for patients with ‘triple-positive’ antiphospholipid syndrome). 
 Life expectancy < 3 months  
 Currently pregnant or breast feeding 
 Unable / unwilling to pay for one (or more) of the treatment options 
 Active Cancer defined as: 
 Diagnosed with cancer within the past 6 months; or 
 Recurrent, regionally advanced or metastatic disease; 
 Currently receiving treatment or have received any treatment for cancer 
during the 6 months prior to randomization; or 
 A hematologic malignancy not in complete remission 
 Unwilling / unlikely to agree to follow up 
 


 
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These exclusion criteria are less stringent than the phase III RCTs (Einstein Investigators 2010; 
Agnelli 2013) and are pragmatic and reflective of real world patients who would receive DOACs 
(Thorpe 2009).  


 
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Table 2.  Transient risk factors* 
For a patient to be eligible to participate in COVET, the following transient risk factors should 
NOT have been present during the 3 months preceding the diagnosis of the qualifying VTE: 
 
• Surgery with general anesthesia for greater than 30 min. 
• Confined to bed in hospital (only ‘bathroom privileges’) for at least 3 days with an acute 
illness. 
• Caesarean section. 
• Estrogen therapy. 
• Pregnancy or puerperium. 
 
* Adapted from (Kearon 2016, J Thromb Haemost 2016) 
 
 


 
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4. 
STUDY DESIGN 
The COVET study is a multi-center, randomized, open-label study of approximately 3000 
patients who have confirmed acute symptomatic and unprovoked DVT/PE, have completed 
initial treatment of oral anticoagulation therapy for 3-12 months and are at high risk for recurrent 
VTE.  Eligible patients who consent to participate in the study will be randomized to warfarin, 
apixaban, or rivaroxaban. 
4.1 
Overview of Study 
This will be a multi-center trial conducted in the United States and Canada. Patients will be 
treated for a period of 12 months (see Figure). Treatment beyond this will be at the discretion of 
the treating physician. 
 
 
Figure. Study Design Schematic 
4.2 
Treatment Arms 
After completion of an initial 3 to 12 months of anticoagulant therapy as standard of care, the 
patient will be randomized to receive one of the following therapies: 
• 
Warfarin, target INR of 2-3 
• 
Rivaroxaban, 10 mg daily 
• 
Apixaban, 2.5 mg twice daily 


 
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Each study participant will be provided with detailed information describing how to switch from 
the anticoagulant that he/she was taking for their initial treatment, to the therapy that he/she will 
be taking for the study. The patient should start on the study-assigned anticoagulant within one 
week of randomization. 
The possible transitions are described below: 
a) Switching from warfarin to rivaroxaban 
To switch from warfarin to rivaroxaban, stop the warfarin and determine the international 
normalized ration (INR).  If the INR is ≤ 2.5, start rivaroxaban. If the INR is > 2.5, delay the 
start of rivaroxaban until the INR is ≤ 2.5. (Adapted from Rivaroxaban Product Monograph). 
b) Switching from warfarin to apixaban 
When switching patients from warfarin to apixaban, discontinue warfarin and start apixaban 
when the INR is below 2.0. (Adapted from the Apixaban Product Monograph). 
c) Switching from rivaroxaban to warfarin 
Rivaroxaban should be continued concurrently with warfarin until the INR is ≥ 2.0. For the 
first 2 days of the conversion period, the warfarin can be given in the usual starting doses 
without INR testing. Thereafter, while on concomitant therapy, the INR should be tested just 
prior to the next dose of rivaroxaban, as appropriate. Rivaroxaban can be discontinued once 
the INR is >2.0. Once rivaroxaban is discontinued, INR testing may be done at least 24 hours 
after the last dose of rivaroxaban, and should then reliably reflect the anticoagulant effect of 
the warfarin. (Adapted from Rivaroxaban Product Monograph). 
d) Switching from apixaban to warfarin 
Apixaban should be continued concurrently with warfarin until the INR is ≥ 2.0. For the first 
2 days of the conversion period, the warfarin can be given in the usual starting doses without 
INR testing. Thereafter, while on concomitant therapy, the INR should be tested just prior to 
the next dose of apixaban, as appropriate. Apixaban can be discontinued once the INR is > 
2.0. Once apixaban is discontinued, INR testing may be done at least 12 hours after the last 
dose of apixaban, and should then reliably reflect the anticoagulant effect of the warfarin. 
(Adapted from the Apixaban Product Monograph) 
e) Switching from apixaban to rivaroxaban, or from rivaroxaban to apixaban 
Switching from apixaban to rivaroxaban involves stopping the apixaban and beginning the 
rivaroxaban at the time of the next scheduled dose.  Similarly, switching from rivaroxaban to 
apixaban involves stopping the rivaroxaban and beginning the apixaban at the next scheduled 
dose. (Recommendation by Principal Investigators consensus). 
It is possible that some patients will be taking dabigatran or edoxaban for the initial treatment of 
their VTE.  Transitions from these drugs would be performed as follows. 
f) Switching from dabigatran to warfarin 
Warfarin should be started while the patient is still taking dabigatran, adjusted according to 
the patient’s calculated creatinine clearance (CrCl) as follows:  CrCl ≥50 mL/min, start 
warfarin 3 days before discontinuing dabigatran; CrCl ≥30 to <50 mL/min, start warfarin 2 
days before discontinuing dabigatran.  Once dabigatran is discontinued, INR testing may be 


 
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done at least 48 hours after the last dose of dabigatran, and should then reliably reflect the 
anticoagulant effect of the warfarin. (Adapted from the Dabigatran Product Monograph) 
g) Switching from edoxaban to warfarin 
Warfarin should be started while the patient is still taking edoxaban.  For the first 2 days of 
the conversion period, the warfarin can be given in the usual starting doses without INR 
testing. Thereafter, while on concomitant therapy, the INR should be tested just prior to the 
next dose of edoxaban, as appropriate. Edoxaban can be discontinued once the INR is > 2.0. 
Once edoxaban is discontinued, INR testing may be done at least 24 hours after the last dose 
of edoxaban, and should then reliably reflect the anticoagulant effect of the warfarin. 
(Recommendation by Principal Investigators consensus). 
h) Switching from dabigatran to rivaroxaban (or apixaban) 
Switching from dabigatran to rivaroxaban (or apixaban) involves stopping the dabigatran and 
beginning the rivaroxaban (or apixaban) at the time of the next scheduled dose.  
(Recommendation by Principal Investigators consensus). 
i) Switching from edoxaban to rivaroxaban (or apixaban) 
Switching from edoxaban to rivaroxaban (or apixaban) involves stopping the edoxaban and 
beginning the rivaroxaban (or apixaban) at the time of the next scheduled dose.  
(Recommendation by Principal Investigators consensus). 
Similarly, at the end of the study, each study participant will receive information from their 
primary physician on how to switch from the anticoagulant that they were on for the study to a 
post-study treatment plan. 
4.3 
Study Procedures 
The follow-up schedule for research purposes will not require any in-person clinic visits (Table 
3-Schedule of follow-up assessments). The only study related visit will be at the time of 
enrollment into the trial when the local research coordinator and investigator will review 
eligibility, obtain consent after answering questions, and proceed with randomization. All other 
trial related follow-up will be conducted remotely via structured telephone interviews at 1, 6, and 
12 months. During regularly scheduled follow-up, patients will provide relevant information 
about events and if contact with a physician was made, medical records will be requested for 
review by the blinded CEC. The DCRI call center will contact the participants in the US. 
Canadian sites will contact the participants enrolled in Canada to complete the phone follow up 
and to collect medical records for CEC.  Patients will also participate in two Patient Reported 
Outcomes measures, the Anti-Clot Treatment Scale (ACTS) and the EuroQol-5D-5L (EQ-5D-
5L).  These will be collected at Baseline, Month 1, Month 6 and Month 12. Regular clinic visits 
will be in keeping with local practices and at the discretion of the treating physician. Patients will 
be provided with a study participation journal to capture event information between scheduled 
study visits.  
Our primary safety and main efficacy outcomes are important patient-reported outcomes 
measures (clinically relevant bleeding and recurrent VTE, respectively). Concerns for recurrent 
VTE or bleeding may require investigations that will be consistent with standard of care. Patients 
will be instructed on when to seek medical attention and local practices will determine 


 
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investigations and further management. Diagnosis of DVT will be confirmed by 
ultrasonography. If a patient experiences signs or symptoms suggestive of bleeding or recurrent 
VTE, and diagnostic tests are performed, all events will be treated according to the standard of 
care at the local institution by the primary physician.  


 
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4.4 
Schedule of Follow-Up Assessments 
Table 3: Schedule of Follow-up Assessments for Enrolled Participants 
 
*Canadian participants will be contacted by the Canadian enrolling centers to complete phone 
assessments.  
**If the participant is not reached within the +/- 1 week window, please attempt contact until Month 3. 
*** If the participant is not reached within the +/- 4 week window, please attempt contact until Month 9. 
 
 
Time (Day) 
Screening / 
Randomization 
Month 1* 
Month 6* 
Month 12* 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit Window 
30 days 
(+/- 1 week)** (+/- 4 week)*** 
(+ 8weeks) 
Type of Visit 
In-person 
Phone call 
Phone call 
Phone call 
Patient consent 
X 
 
 
 
Height and Weight 
X 
 
 
 
Medical history 
X 
 
 
 
Event assessment 
 
X 
X 
X 
Concomitant medication review/ 
Medication Compliance 
X 
X 
X 
X 
ACTS 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 


 
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4.5 
Screening and Pre-randomization Procedures 
Patients will be identified in outpatient clinical settings of hematologists and general 
internists in the U.S. and Canada. Recruitment of patients from such a setting is 
intentional so that we may enroll patients seen in daily practice to ensure generalizability 
of results at conclusion of the trial. The annual volume of patients at each participating 
center is variable with up to 10,000 patient visits, based on administrative data at each 
participating site. Daily clinic logs will be used to identify eligible patients, and patients 
who do not meet exclusion criteria will be approached to participate in the proposed trial. 
Many of these practice settings will also be affiliated with an anticoagulation clinic.  
Patients who satisfy eligibility criteria will be approached to consider participation in the 
trial. A research coordinator or delegated site personnel will supply the patient with 
information and informed consent about the trial. The site personnel will also review with 
the patient anticipated out-of-pocket/copay costs for each of the study drugs. If the patient 
incurs a cost for any of the three treatment arms (either full cost of the medication, or a 
copay) that is not sufficiently off-set by the copay provided through the study, and the 
patient is unable and/or unwilling to cover that cost, then the patient should not be 
enrolled into the trial. As a pragmatic, real world study, the patient and his/her insurance 
company is responsible for the cost of the medical care (including labs such as INR, 
doctor visits, etc), as well as any medication costs not covered by the study.  
After an appropriate amount of time to read the information and informed consent form 
has elapsed, the research coordinator and/or physician will answer any questions the 
patient and their family members may have. Patients agreeing to participate will then be 
enrolled, randomized and followed as outlined in the study protocol.  
4.6 
Randomization 
We will use permuted block randomization with randomly selected block sizes through a 
central randomization system in a 1:1:1 ratio for the three treatments. The randomization 
scheme will be generated by an independent statistician. Blocks will be stratified by 
anticoagulant used (e.g. warfarin, apixaban, rivaroxaban, or other) to treat acute VTE 
event prior to randomization. The randomization process will be initiated by the local 
study coordinator/site investigator who will access the web-based system and enter the 
patient’s unique identifier, center number, confirmation of eligibility and informed 
consent. Patient allocation will then be electronically delivered to the study coordinator 
and site investigator so that a prescription may be written for the corresponding 
anticoagulant. The patient will have the prescription dispensed at a local pharmacy as 
these are all commercially available medications. Co-pay assistance will be provided by 
the study through the use of the RxStudy CardTM (administered through RxSolutions). 
The cards will be available to all non-VA sites (unless prohibited by institutional policy). 
VA sites will not participate in the co-pay assistance program. Medication for the VA 
sites’ patients will be provided by the affiliated VA pharmacies. 
 
 


 
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4.7 
Post-randomization Procedures 
The follow-up schedule for research purposes will not require any in-person clinic visits. 
The only study related visit will be at the time of enrollment into the trial when the local 
research coordinator and investigator will review eligibility, obtain consent after 
answering questions, and proceed with randomization. All other trial related follow-up 
will be conducted remotely via structured telephone interviews at 1, 6, and 12 months.  
During regularly scheduled follow-up phone calls, patients will provide relevant 
information about any outcome event and if contact with a physician was made, medical 
records will be requested by the DCRI Call Center / Canadian site for review by the CEC.  
Regular clinic visits will be in keeping with local practices and at the discretion of the 
treating physician. Unscheduled study visits are not expected during this study. Patients 
will be provided with a study participation journal to capture event information between 
scheduled study contacts. These journals are provided to the patients as a tool to assist in 
reporting only and use is optional. The journals will not be used as a source document. 


 
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5. 
TREATMENT ARMS 
Warfarin, rivaroxaban and apixaban will be prescribed and administered according to the 
approved dosages and indications. 
5.1 
Study Drug Administration 
Patients will be randomized to receive either warfarin, rivaroxaban or apixaban.  
Warfarin will be given as needed to obtain a target INR of 2-3. Rivaroxaban will be 
prescribed at 10mg daily and  apixaban will be prescribed at 2.5mg twice daily. Patients 
on once daily medications will have flexibility in determining the daily dosing timing. 
Patients will receive a prescription for the medication to which they are assigned.. The 
assigned medication will be dispensed at a local pharmacy. 
5.2 
Potential Benefits/Risks of Study Medications 
All three of the anticoagulant agents included in this study have been shown to be 
efficacious in the secondary prevention of recurrent VTE (cf. Table 1). These three 
agents have not been directly compared, but indirect comparisons suggest that 
rivaroxaban and apixaban are not inferior to warfarin, target INR 2-3, in the prevention of 
recurrent VTE. In contrast, clinically relevant bleeding (combination of major bleeding 
and clinically relevant, non-major bleeding) appear to be lower for the direct oral 
anticoagulants compared to warfarin, target INR 2-3 (cf. Table 2). This study will address 
both of these issues with sufficient power to provide high-quality data to inform 
decisions. 
The direct oral anticoagulants also offer several potential benefits to patients compared to 
warfarin, including no dietary restrictions affecting the efficacy of rivaroxaban and 
apixaban, and therapy with these two agents does not need to be monitored by laboratory 
testing. Conversely, concerns have been expressed by patients about the lack of a reversal 
agent for the factor Xa-specific agents in contrast to warfarin, where the anticoagulant 
effect can be reversed by administration of a prothrombin complex concentrate and/or 
vitamin K. Strategies have been developed for the treatment of bleeding complications in 
patients taking rivaroxaban and apixaban, however, and studies are ongoing with a 
specific reversal agent. 
5.3 
Procedure to Assess Medication Adherence 
We will evaluate medication adherence by self-report from the participant. Medication 
adherence information will be collected at 1 month, 6 months, and 12 months. 
5.4 
Concomitant Medications 
Concomitant 
medications 
will 
be 
assessed 
by 
site 
personnel 
during 
the 
screening/randomization visit (visit 1). Concomitant mediations will also be assessed 
during the follow-up period phone contact at 1 month, 6 months and 12 months. 
5.5 
Patient Reported Outcomes/Quality of Life Assessments 
5.5.1 Anti-coagulant Treatment Scale 
 


 
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The patient satisfaction question that will be addressed by COVET is whether patients are 
more satisfied with chronic anticoagulant therapy with apixaban or rivaroxaban compared 
to warfarin with a target INR of 2-3.  To address this question, we will use the Anti-Clot 
Treatment Scale (ACTS), a 15-item patient-reported instrument that includes a 12-item 
ACTS Burdens scale and a 3-item ACTS Benefits scale.  Patients are asked to rate their 
experiences of anticoagulant treatment during the preceding 4 weeks on a 5-point scale of 
intensity (1 = not at all, 2 = a little, 3 = moderately, 4 = quite a bit, 5 = extremely). The 
ACTS Burdens total score ranges from 12 to 60, and the ACTS Benefits total score 
ranges from 3 to 15. In this study, the ACTS scale will be administered at baseline, 1 
month, 6 months, and 12 months. In the US, the baseline ACTS scale will be performed 
by the site enrolling the patient, and the scales for the 1, 6, and 12 month calls will be 
administered by the Call Center. In Canada, all of the scales will be performed at the site 
enrolling the patient. 
5.5.2 EQ-5D-5L 
 
The economic research question is whether using apixaban and rivaroxaban for treatment 
of acute VTE is cost-effective compared to warfarin. In this study, the EQ-5D-5L will be 
administered at baseline, 1 month, 6 months, and 12 months. In the US, the baseline EQ-
5D-5L scale will be performed by the site enrolling the patient, and the scales for the 1, 6, 
and 12 month calls will be administered by the Call Center. In Canada, all of the scales 
will be performed at the site enrolling the patient. 
 
5.6 
Prohibited Medications 
The concomitant use of medications that are strong P-glycoprotein or CYP3A4 
inducers/inhibitors is prohibited due to interactions with rivaroxaban and apixaban. 
Examples include: all human immunodeficiency virus protease inhibitors and the 
following 
azole-antimycotics 
agents: 
fluconazole, 
ketoconazole, 
itraconazole, 
voriconazole, posaconazole, if used systemically.  
Use of single or dual antiplatelet agents is not prohibited. 
5.7 
Peri-Procedural anticoagulation management 
Please refer to the following resources for recommendations regarding anticoagulant 
interruption. 
1) Thrombosis Canada: 
(http://thrombosiscanada.ca/?page_id=502&calc=perioperativeAnticoagulantAlgo
rithm) 
2) Spyropoulos AC, Douketis, JD.  “How I treat anticoagulated patients undergoing 
an elective procedure or surgery” Blood, 2012; 120: 2954-62. 
3) Douketis JD, Spyropoulos AC, et al. “Perioperative management of 
antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 
9th ed: American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines” Chest, 2012; 141 (2 Suppl): e326S-50S. 


 
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6. 
SAFETY ASSESSMENTS 
6.1 
Safety Assessments and Reporting 
All study medications will be prescribed and administered per the approved package 
insert.  For this trial the defined safety outcome events of interest will be recorded in the 
electronic case report form (eCRF) by site personnel and/or the follow-up call center 
personnel. If site personnel become aware of a treatment-related event that is considered 
serious and unexpected, the site investigator should report the event to the local 
IRB/ethics committee per local policy. 
6.2 
Adverse Events 
The COVET study is designed to be a pragmatic trial comparing three therapeutic agents 
approved by the regulatory agencies in the United States (Food and Drug Administration) 
and Canada (Health Canada) for the extended treatment of patients with an unprovoked 
DVT or PE to prevent recurrent thromboembolism. We will be collecting adjudicated 
outcome events, including bleeding, that have been shown to account for the majority of 
SAE’s based on a large number of patients treated in several clinical studies. These 
outcome events, listed above in Section 2, include the following: 
 
 Clinically relevant bleeding, which is the composite of major bleeding and/or 
clinically-relevant, non-major bleeding, as defined by ISTH criteria (Kaatz, 2015) 
 Recurrent VTE, as defined above (Section 2.5), representing failure in efficacy 
 All-cause mortality 
 Vascular events, including myocardial infarction and ischemic stroke 
 
All study endpoints will be identified during scheduled contact with the study participants 
at 1 month, 6 months, and 12 months (see Table 3) and reported to the P.I., co-P.I.’s, and 
study leadership at DCRI within 24 hours. All events will then be independently 
adjudicated by the Clinical Event Classification committee (section 11.9). 
 
Pregnancy is also collected as part of the COVET study (section 6.3) and will be reported 
within 24 hours as described for the outcome events documented above. 
 
Study drug discontinuation is also collected as part of the COVET study, including the 
reason for discontinuation of the study drug.  Laboratory tests are not being collected in 
the COVET study. 
6.3 
Pregnancy 
If a participant becomes pregnant during the course of the study and they elect to carry 
the pregnancy to term, the following actions should be taken: 
1. The patient should notify the site investigator immediately 
2. The  study anticoagulant will be discontinued 
3. The local investigator will decide what (if any) ongoing anticoagulation therapy 
will be prescribed (off study) 
4. The patient may continue with the follow-up telephone calls only. 
 


 
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A separate document for women of childbearing age regarding instructions if she 
becomes pregnant will be provided at enrollment into the trial.  These instructions will 
include discussing discontinuation of the study anticoagulant with their primary care 
physician (PCP), notifying their study doctor (if different from their PCP) of the 
pregnancy and the ability to continue participation in the study once the study medication 
has been discontinued.  
6.4 
Criteria for Withdrawal of Patients from Study 
Participants have the right to withdraw from the study at any time and for any reason 
without prejudice to future medical care. In the case of participant withdrawal, the 
investigator will discuss with the patient the most appropriate way to terminate study 
participation to ensure the patient’s health. All efforts will be made to complete and 
report the observations as thoroughly as possible up to the date of study termination. All 
applicable activities scheduled for the final study visit should be performed at the time of 
discontinuation. Randomized patients who withdraw from the study will not be replaced.  
 


 
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7. 
STATISTICAL CONSIDERATIONS 
7.1 
General Design Issues  
COVET is a 3-arm prospective, multi-center, open-label, active comparator, randomized 
study designed to compare the efficacy and safety of apixaban and rivaroxaban compared 
with standard warfarin therapy. All potential study endpoints will be reviewed by a 
central adjudication committee that is blinded to treatment assignment. For participants 
who withdraw consent for follow-up, all data obtained prior to the time of formal 
withdrawal will be used in data analyses. The duration of follow up from randomization 
is expected to be twelve months, and all participants will be expected to remain in study 
until the 12-month follow-up telephone call regardless of whether they are taking their 
assigned study medication. Reporting of this prospective, randomized, open-label, 
blinded endpoint design will follow the CONSORT recommendations (Hansson 1992; 
Paggio 2012). 
The primary efficacy endpoint is rate of recurrent VTEs and the primary safety endpoint 
is clinically relevant bleeding. Secondary endpoints include components of the primary 
endpoints, all-cause mortality, and other events of interest. The primary efficacy and 
safety endpoints will be confirmed by a CEC. Participants will be randomized in a 1:1:1 
ratio to warfarin, apixaban, or rivaroxaban. Randomization will be stratified by the 
anticoagulant used during the screening period. For purposes of randomization, the 
screening anticoagulants will be classified as either warfarin, apixaban, rivaroxaban, or 
other. The relative open inclusion criteria, limited exclusions, and simple follow-up 
structure of COVET are an attempt to be pragmatic (Thorpe 2009). 
SAS software version 9.4 or higher will be used for all statistical analyses. P-values less 
than 0.05 will be considered statistically significant unless otherwise specified. Complete 
details of all planned analyses will be contained in a separate Statistical Analysis Plan 
(SAP). The SAP will include the planned tables, listings, and figures. In particular, 
special attention will be given the participants who do not have complete data. 
7.2 
Sample Size Justification 
The planning and sample size calculations for the COVET study were designed to 
compare warfarin vs. apixaban and warfarin vs. rivaroxaban. A direct exploratory and 
descriptive comparison of the two DOACs will be conducted but the study was not 
powered to detect statistically significant differences between those treatment groups. 
 
For the primary safety endpoint, there will be two comparisons, apixaban versus warfarin 
and rivaroxaban versus warfarin, each of which will be tested at the two-sided 0.05 level 
of significance to detect a 50% reduction (HR=0.50) in clinically relevant bleeding 
compared to warfarin. For the primary efficacy endpoint, there will be two comparisons, 
apixaban versus warfarin and rivaroxaban versus warfarin to determine if the DOACs are 
non-inferior to warfarin in the prevention of recurrent venous thromboembolism. The 
non-inferiority assessments will be based on comparing the one-sided 95% upper 
confidence interval with a 2% absolute risk increase for recurrent VTE. 
The type I error rates for the non-inferiority and superiority analyses have been set at 0.05 
one-sided and 0.05 two-sided, respectively. These are considered standard values for two 


 
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arm studies. We have elected to not alter them for this three-arm design because the 
clinical questions of interest are the two comparisons of the DOACs versus warfarin. 
For the primary efficacy analysis, using an outcome of recurrent VTE, we expect 12-
month rate of 0.87% for the warfarin arm compared with 1.5% for the DOACs (Einstein 
Investigators 2010; Agnelli 2013). Sample sizes of 950 per arm are sufficient to provide 
80% power to have the upper 95% one-sided confidence interval less than 2%. The 
proposed sample size of 1000 participants per arm allows for 5% missing data due to 
loss-to-follow-up, deaths not related to VTE, and lack of starting the assigned study drug. 
These calculations were obtained using a simulation method with nQuery Advisor 7.0 
software. 
For the primary safety analysis, the RE-MEDY study reported clinically relevant 
bleeding rates of 10.2% for the warfarin treated patients (Schulman 2013). Using a 12-
month rate of 6.8%, a per group sample size of 950 participants (or 1000 / group with an 
allowance for 5% missing data) will provide greater than 90% power to detect a 50% 
event rate reduction for the DOAC arm. Similarly, assuming a lower 12-month event rate 
of 6.0% for the warfarin arm, the sample size of 950 participants per group will provide 
88% power to detect a 50% event rate reduction for the DOAC arm. These calculations 
assume a two-sided 0.05 type I error rate and are based on a Cox model. 
7.3 
Definition of Analysis Populations 
All-randomized (Intention To Treat-ITT) population 
This population includes all randomized participants regardless of the actual treatment 
received. This population will be used for the primary analysis of the primary safety and 
efficacy endpoints. 
 
Per protocol population 
This population excludes participants who have not started the assigned therapy by the 
time of the 1 month telephone interview. For time-to-event analyses, participants who 
stop taking the assigned treatment will be censored after permanently stopping the 
assigned treatment.   
7.4 
Interim Analyses and Stopping Rules 
There will be no formal interim analyses for the primary efficacy or safety endpoints for 
futility. The Data and Safety Monitoring Board (DSMB) will meet regularly to review 
patient safety and overall study conduct. The independent DSMB will review the 
summaries of patient safety and self-reported adherence at regular intervals. 
Pooled event rates for the primary safety and primary efficacy and per-protocol 
anticoagulant adherence will be reviewed by the Steering Committee after 500, 1000, and 
1500 participants have completed the 12-month telephone contact. The overall sample 
size will be assessed based on a comparison of the observed rates with the rates used for 
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7.5 
Data Analyses 
Baseline characteristics will be presented using mean (standard deviation) and median 
(25th, 75th percentiles) for continuous variables and as frequencies (percentages) for 
categorical variables. No formal comparisons will be computed for baseline variables.  
 
The primary analyses for safety primary endpoint will be based on an un-stratified Cox 
model adjusting for the two treatment indicators and three stratification indicators. The 
ascertainment time will be based on the time of the first event or censoring time. 
Stratification will be based on the anticoagulant used during the screening period. The 
all-randomized (ITT) analysis dataset will be used for the primary analyses. The 
treatment effect for each DOAC compared to warfarin will be computed using the 
estimated hazard ratio and associated 95% confidence intervals. Secondary analyses will 
be based on a Kaplan-Meier estimates on the all-randomized (ITT) and per-protocol 
populations. 
 
For the efficacy primary endpoint, the primary analysis will be based on a Kaplan-Meier 
analysis using the all-randomized (ITT) analysis dataset. The 12-month event rates 
differences between the DOACs versus warfarin will be based on the difference in the 
Kaplan-Meier estimates and the one-sided upper 95% confidence interval will be based 
on a bootstrap estimator. Secondary analyses of the recurrent VTE endpoint will be based 
on the Cox regression model. Exploratory analyses will directly compare the two DOACs 
for both safety and efficacy endpoints. Additionally, an exploratory analysis will pool the 
two DOAC arms and compare those estimates with the warfarin treatment group. 
 
For secondary endpoints, the estimated differences between the DOACs and warfarin 
treated groups will be based on linear models, logistic regression, and Cox models 
depending on the endpoint. Efforts will be made to limit the amount of missing data for 
the key endpoints and adherence measures. When necessary, multiple imputation will be 
used to account for missing covariate information. 
 
The SAP will contain details on sensitivity analysis that will be done to support the 
previously described analyses. There are two particular issues that might create biased 
estimates – missing data and lack of adherence to the assigned treatment. For the missing 
data problem, we will impute data with higher, same, and lower event rates for the 
DOAC arms to estimate the impact of missingness on the study results. In addition to the 
analyses with the all randomized dataset, we will conduct analyses with the per-protocol 
dataset to determine the impact of participants not taking the assigned study drug. For the 
per-protocol analyses there is no guarantee that the comparisons are valid based on 
randomization. To account for this potential bias, inverse probability weighted (IPW) 
estimators will be used to re-weight the per-protocol population. The IPW weights will be 
obtained using logistic regression models predicting adherence at 1 month. The SAP will 
also address analysis of the Patient Reported Outcomes tools, the ACTS and the EQ-5D-
5L.  
 
The study investigators have identified several pre-specified subgroups of interest. Those 
subgroups include: initial anticoagulant, race, sex, renal impairment, obesity, and 
antiplatelet use (Buckner 2012; Liao 2014; White 2009). Given the expected low number 
of events for both primary endpoints, the subgroups will need to be interpreted 


 
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cautiously. For each subgroup we will compute an interaction p-value and then estimate 
hazard ratios for each subgroup. 


 
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8. 
FOLLOW-UP DATA COLLECTION AND CLINICAL EVENT 
CLASSIFICATION 
Participants will be provided with instructions to maintain a diary during the course of the 
study to facilitate reporting of events at the time of the follow-up calls. For participants in 
the US, the DCRI Call Center will attempt phone calls at 1 month, 6 months and 12 
months following randomization. For participants enrolled at Canadian sites, the 
enrolling site will contact the participant at the same time intervals. Information collected 
during these phone calls will be documented in the eCRF. If a participant reports that 
they are experiencing an event during a scheduled call, the Call Center agent will advise 
the participant to contact their health care provider or call 911 if it is an emergency. The 
event details would be captured at the next scheduled call. Medical records associated 
with all potential outcome events will be requested/obtained and sent to the blinded CEC 
for review. 
 
COVET is comparing treatment strategies that are already in standard clinical use, and it 
is not anticipated that outcomes beyond those that can be seen in any patient taking 
anticoagulant therapy will be encountered. For each outcome event, supporting 
documentation to include all radiographic imaging data, relevant laboratory data, and 
treatment records will be collected by the centralized call center for review and 
validation. All outcomes will be independently adjudicated by physician reviewers with 
expertise in thrombosis who will be blinded to the specific treatment arm to which the 
patient had been randomized. Outcome classification will follow an established protocol 
similar to prior studies conducted through the DCRI. Details of the clinical event 
adjudication process will be included in the CEC Charter. 
 


 
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9. 
DATA MANAGEMENT AND QUALITY ASSURANCE 
9.1 
Data Management 
All required data for this study will be entered into the electronic case report form 
(eCRF). This study will use Web-based e-CRFs developed through a validated, electronic 
reporting-electronic-signatures–compliant platform (21 Code of Federal Regulations Part 
11). For security reasons, and in compliance with regulatory guidelines, it is imperative 
that only the persons who own the user IDs and passwords access the system using their 
own unique access codes. Access codes are nontransferable. Site personnel who have not 
undergone training may not use the system and will not be issued user ID and password 
until appropriate training is completed. 
At the conclusion of the study, each enrolling site will be provided with a compact disc 
containing PDF files of both the individual patient's data and the audit trail (changes 
made to the database). This will be maintained at the site according to the requirements 
for records retention. 
Computerized data will be accessible only by password, and a centralized monitoring 
system will record and report all access to data. The DCRI computer network is protected 
by a firewall. To ensure participant anonymity, eCRFs will be identified by study number 
only. No participant identifiers will be used in the presentation of data. Except when 
required by law, participants will not be identified by name, personal identification 
number (e.g. social security number, social insurance number), address, telephone 
number, or any other direct personal identifier in study records. This information will be 
retained by each individual center and will not be disclosed to the DCRI except as needed 
for centralized follow-up of the participants. Participants will be informed that their 
records may be reviewed in order to meet federal, state or regional/local regulations. 
Reviewers may include the study monitors, IRBs or Ethics Committees, and other 
government regulators as dictated by local law, or their delegates. 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study 
product, regulatory documents, and other sponsor correspondence pertaining to the study 
must be kept in the appropriate study files at the site. Source documents include all 
recordings and observations or notations of clinical activities and all reports and records 
necessary for the evaluation and reconstruction of the clinical study. These records will 
be retained in a secure file for the period required by the institution or site policy.  Prior 
to transfer or destruction of these records, the DCC must be notified in writing and be 
given the opportunity to further store such records. 
9.2 
Quality Assurance  
Steps to be taken to ensure the accuracy and reliability of data include: 
 the selection of qualified investigators and appropriate study centers 
 review of protocol procedures with the investigator and associated personnel 
before the study 
 periodic monitoring visits to clinical sites 


 
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 electronic CRF completion guidelines will be provided and reviewed with study 
personnel before the start of the study. 
 The DCRI clinical research associate will review eCRFs for accuracy and 
completeness during site monitoring; any discrepancies will be resolved with the 
investigator or designee, as appropriate. 
At regular intervals, all data will be transferred from the study database to SAS for 
statistical summarization, data description, and data analysis. Further cross-checking of 
the data will be performed in SAS, and discrepant observations flagged and appropriately 
resolved through a data query system.  


 
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10. 
STUDY RESPONSIBILITIES 
10.1 
Investigator Responsibility/Performance 
The site principal investigator (PI) agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems to ensure that all work 
incidental to this protocol is conducted and data are generated, documented, and reported 
in compliance with the protocol; accepted standards of Good Clinical Practice (GCP); 
and all applicable federal, state, and local laws, rules and regulations relating to the 
conduct of the clinical study. 
The site PI will provide current copies of the study protocol to all sub-investigators or 
other site personnel responsible for study conduct. Additionally, the site PI will provide 
DCRI with copies of all institutional review board (IRB) or Ethics Committee actions 
regarding the study. 
10.2 
Training 
The initial training of appropriate clinical site personnel will be the responsibility of the 
DCRI. The PI is responsible for ensuring that staff conduct the study according to the 
protocol. To ensure proper administration of study agents, uniform data collection, and 
protocol compliance, the DCRI will present a formal training session to study site 
personnel, to include instructions for study procedures, the investigational plan, 
instructions on data collection, methods for soliciting data from alternative sources, and 
regulatory requirements.  
10.3 
Monitoring the Investigational Sites 
As part of a concerted effort to follow the study in a detailed and orderly manner in 
accordance with established principles of GCP and applicable regulations, a study 
monitor from the DCRI will visit the study sites as appropriate and will maintain frequent 
telephone and written communication. 
Remote monitoring will be used for this study. Site managers will schedule monitoring 
calls to review enrollment, EDC completion, informed consent and overall study 
management. During monitoring visits, the monitor will perform a review of 
inclusion/exclusion criteria, informed consent, HIPAA authorization, as well as safety 
and efficacy endpoints.  Sites may be required to provide at a minimum the informed 
consent and eligibility requirements for patients to the sponsor or designee via a secure 
system.  
Trends will be monitored and, if warranted, the frequency of onsite monitoring visits may 
be adjusted at sites. Details will be described in the clinical monitoring plan 
On-site monitoring visits may be performed at active investigational sites as needed to 
assure that the investigator obligations are being fulfilled and all applicable regulations 
and guidelines are being followed. These visits will be initiated based on the findings of 
monitoring calls and/or data review. The goal of these on-site visits are to assure the 
facilities are still acceptable, the protocol and investigational plan are being followed, the 
IRB or Ethics Committee has been notified of approved protocol changes as required, 
complete records are being maintained, appropriate reports have been made to the 


 
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sponsor or designee and the IRB or Ethics Committee, and the investigator is carrying out 
all agreed-upon activities. 
10.4 
Study Documentation 
Study documentation includes all electronic case report forms, source documents, 
monitoring logs and appointment schedules, sponsor-investigator correspondence, and 
regulatory documents (e.g., protocol and amendments, IRB or EC correspondence and 
approval, approved and signed patient consent forms, Patient contact forms and medical 
release forms). 
The site PI will prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable federal, state, and local laws, rules and 
regulations. For each patient participating in the study at the site, the investigator will 
promptly complete all eCRFs and such other reports as required by this protocol 
following completion or termination of the clinical study or as otherwise required 
pursuant to any agreement with the sponsor. 
The site PI acknowledges that, within legal and regulatory restrictions and institutional 
and ethical considerations, study documentation will be promptly and fully disclosed to 
the sponsor or designee by the investigator upon request and also shall be made available 
at the investigator’s site upon request for inspection, copying, review, and audit at 
reasonable times by representatives of the sponsor or responsible government agencies as 
required by law.  
The site PI agrees to promptly take any reasonable steps that are requested by the sponsor 
or designee as a result of an audit to cure deficiencies in the study documentation and 
eCRFs. 
10.5 
Source Documentation 
Source documents include all original recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical study. Accordingly, source documents include, but are not limited to, 
laboratory reports, electrocardiogram (ECG) tracings, x-rays, radiologist reports, patient 
diaries, biopsy reports, ultrasound photographs, patient progress notes, hospital charts, 
pharmacy records, and any other similar reports or records of any procedure performed in 
accordance with the protocol. Whenever possible, the original recording of an 
observation should be retained as the source document; however, a photocopy is 
acceptable provided that it is a clear, legible, and exact duplication of the original 
document. 
10.6 
Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel did 
not conduct the study according to the investigational plan. Site investigators must also 
follow the policy of the reviewing IRB for reporting such deviations to their reviewing 
IRB per local policy. 
The IRB or Ethics Committee will be informed of all protocol changes by the sponsor or 
the investigator in accordance with applicable regulations and the IRB or Ethics 


 
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Committee’s established procedures. No deviations from the protocol of any type will be 
made without complying with the IRB or Ethics Committee’s established procedures. 
Investigators will maintain documentation of the dates and reasons for each deviation 
from the protocol. 
10.7 
Data Transmittal and Record Retention 
Required data will be entered in the eCRF at the time of or as soon as possible after the 
patient call/visit or the availability of test results. The site PI will maintain final eCRFs, 
worksheets, and all other study-specific documentation (e.g., study file notebooks or 
source documentation) until notified by the sponsor that records may be destroyed. To 
avoid error, the investigator will contact the sponsor or designee before the destruction of 
any records pertaining to the study to ensure they no longer need to be retained. In 
addition, the sponsor or designee will be contacted if the PI plans to leave the institution 
so that arrangements can be made for the transfer of records. The site PI takes 
responsibility for maintaining adequate and accurate source documents of all 
observations and data generated during this study. Such documentation is subject to 
inspection by the sponsor or designee as well as by federal, state, and local regulatory 
agencies. 
10.8 
Study Closeout 
Upon completion of the study (defined as all patients have completed all follow-up visits, 
all eCRFs are complete, and all queries have been resolved), the sponsor or designee will 
notify the site of closeout, and a study closeout visit will be performed via telephone. All 
unused study materials can be destroyed by the site when the study is completed. The 
sponsor or designee will ensure that the site PI’s regulatory files are up-to-date and 
complete and that any outstanding issues from previous visits have been resolved. Other 
issues to be reviewed at the closeout visit include discussing retention of study files, 
possibility of site audits, publication policy, and notifying the IRB of study closure. 
10.9 
Audit/Inspections 
Regulatory authorities from the U.S. or abroad may inspect the site during or after the 
study at a reasonable time and in a reasonable manner. The site PI should contact the 
sponsor immediately if contacted regarding an inspection. Site personnel are expected to 
cooperate with personnel from regulatory agencies (e.g., FDA and Health Canada).  
10.10 
Publication Policies 
Members of the Steering Committee will be primarily responsible for creation, review, 
and submission of publications and presentations relating to the major aspects of the 
study and approved ancillary analyses within a timely fashion after completion of the 
study. Details will be contained in the Publication Plan.  
 


 
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11. 
ETHICAL CONSIDERATIONS 
11.1 
Informed Consent 
The PI has both ethical and legal responsibility to ensure that each patient being 
considered for inclusion in this study is given a full explanation of the study. Written 
informed consent will be obtained from all patients (or, at the discretion of the local IRB, 
the patient’s guardian or legally authorized representative [LAR]) before any study-
related procedures are performed or given.  
Written informed consent will be documented on an informed consent form (ICF) 
approved by the local IRB/EC responsible for approval of this protocol. The ICF will 
conform to the applicable requirements of 45 CFR 46, ICH E6 and institutional 
requirements for informed consent.  The site investigator agrees to obtain approval from 
DCRI of any ICF intended for use in the study before submission of the ICF for IRB 
approval. 
11.2 
Confidentiality of Patients 
Patient confidentiality will be maintained throughout the clinical study in a way that 
ensures that study data can always be tracked back to the source data. Patient information 
collected in this study will comply with the standards for protection of privacy of 
individually identifiable health information as promulgated by the U.S. Health Insurance 
Portability and Accountability Act (HIPAA). All records will be kept confidential, and 
the patient’s name and contact information will not be released for US participants to 
persons other than the DCRI Call Center. Patient records will not be released to anyone 
other than DCRI or its designees and responsible regulatory authorities when requested. 
In all cases, caution will be exercised to assure the data are treated confidentially and that 
the patient’s privacy is guaranteed. The DCRI call center will contact the participants in 
the US. Canadian sites will contact the participants enrolled in Canada to complete the 
phone follow up and to collect medical records for CEC. Any records sent from the 
Canadian sites to DCRI for endpoint review will have PHI redacted prior to providing to 
DCRI.  
11.3 
Authorization for Use and Disclosure of Protected Health 
Information  
An authorization for use and disclosure of protected health information (PHI) under the 
HIPAA Privacy Rule will be obtained from every trial patient before enrollment. The 
investigator is responsible for obtaining patients’ (or their LARs’) authorizations and 
signatures and for explaining the elements of the HIPAA authorization form, if necessary. 
The site PI will promptly inform DCRI of any restrictions on the use or disclosure of any 
patient’s PHI. The site investigator will also promptly inform the sponsor of written 
revocation of any patient’s HIPAA authorization. 
11.4 
Human Subject Protections 
11.4.1 Research Subject Selection and Justification of Exclusions 


 
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Amendment 3, version date 21Sep2018 
 
40 
There will be no exclusion from participation in the study on the basis of ethnicity or 
race. Subjects younger than 18 years of age will be excluded from the study, as the target 
population is adults.  
 
11.4.2 Risks/Discomforts of Study Participation 
This study will evaluate the safety and efficacy of warfarin, apixaban and rivaroxaban in 
patients at high risk for recurrent VTE. These medications are standard of care for 
treatment of VTE.  
11.5 
Institutional Review Board/Ethics Committee Review 
The appropriate IRB or Ethics Committee must approve the protocol and informed 
consent documents, agree to monitor the conduct of the study, and agree to review study 
progress periodically, at intervals not to exceed 1 year. The investigator will provide 
DCRI with documentation that the IRB or Ethics Committee has approved the study 
before the study may begin. 
In addition, the investigator must provide the following documentation to DCRI: 
1. IRB or Ethics Committee annual re-approval of the protocol, 
2. IRB or Ethics Committee approval of revisions to the informed consent 
documents or any amendments to the protocol. The investigator will provide 
DCRI or designee with documentation of all approvals. 
11.6 
Steering Committee 
The Steering Committee will be the primary decision making body of the study and is 
responsible for its successful completion. The Steering Committee will be comprised of 
the study principal investigators, the project leader, and selected other investigators with 
expertise in venous thromboembolism, anticoagulation, biostatistics, and clinical trials.  
11.7 
Study Advisory Committee (SAC) 
Members of the SAC with include the PI, co-PIs, two patient partners, a patient partner 
physician leader, researchers, and several professional stakeholders (i.e. payers, industry, 
purchasers) who will act as consultants to the SAC. The SAC will be responsible for 
engagement 
activities 
to 
identify 
patient-oriented 
outcomes 
and 
provide 
recommendations based on each stakeholder member’s interests. They will be 
instrumental in providing updates on patient recruitment and milestones. Opinions and 
feedback from the professional stakeholders will reinforce that “real-world” concerns are 
addressed during the trial and that the results can be utilized by all stakeholder end-users. 
Members of the SAC will be instrumental in dissemination of the trial results to ensure 
they can be adopted by their respective end-users. The SAC will report to the Steering 
Committee any recommendations made from the SAC engagement activities and 
stakeholders.  For example, issues arising during the trial, such as slow recruitment rates, 
would be reviewed by the SAC for discussion and brainstorming with stakeholders. 
These recommendations would be brought to the Steering Committee for further 
consideration and approval before execution of a plan. 


 
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Amendment 3, version date 21Sep2018 
 
41 
11.8 
Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be appointed for the COVET trial, 
which will include individuals with pertinent expertise in anticoagulation, clinical trials, 
and biostatistics. The DSMB will advise the Steering Committee regarding participant 
reported safety events of interest for current participants.   
 
The composition of the DSMB will be specified in the overall DSMB Charter for the 
study. It is anticipated that the board will include a (1) chair with both clinical and 
research expertise in anticoagulant therapy, (2) a senior statistician with prior DSMB 
experience; and (3) a member of the community. A DSMB Charter for the studies will be 
developed detailing specific data tables to be provided and procedures to be followed. 
The DSMB Charter will also describe the overall mission, responsibilities, and meeting 
schedule of the board. The following outlines the procedures for the DSMB. The DCRI 
statistical team will be responsible for assuring that the DSMB Charter is developed and 
approved. The Charter will be distributed to the members of the Study Advisory 
Committee for their review.  
 
The goal of the DSMB will be to monitor patient safety and to review performance of the 
protocol. At the conclusion of each DSMB meeting, the DSMB Chair will make a 
recommendation to the Steering Committee and the Study Advisory Committee about the 
continuation of the study. Currently, we are planning that the DSMB will meet every six 
months via teleconference. If safety issues arise, additional conference calls can be 
requested by the DSMB chairman. 
 
Confidential Interim Data Reports will be prepared regularly by the protocol statistician 
as specified in the Charter. The report will include recruitment and retention rates, 
outcomes, and other information as requested by the DSMB Chair. We anticipate that in 
accordance with customary PCORI practices, there will be both an open and closed 
session for the DSMB meeting. 
11.9 
Independent Clinical Events Classification (CEC) 
The CEC committee will provide independent central adjudication of bleeds, recurrent 
VTE, and deaths.  The guidelines for the adjudication process will be reported in a 
separate document, the CEC Charter. The members of this Committee will not participate 
in the enrollment or treatment of patients in this trial, nor will they participate in the 
DSMB.  
11.10 
Role of PCORI as a Funding Source 
The Patient-Centered Outcomes Research Institute (PCORI) is an independent, nonprofit 
organization authorized by Congress in 2010. Its mission is to fund research that will 
provide patients, their caregivers, and clinicians with the evidence-based information 
needed to make better-informed healthcare decisions. PCORI is committed to continually 
seeking input from a broad range of stakeholders to guide its work. 


 
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Amendment 3, version date 21Sep2018 
 
42 
12. 
REFERENCES 
Agnelli G, Prandoni P, Santamaria MG et al. Three months versus one year of oral 
anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration 
Italian Trial Investigators. N Engl J Med 2001;345(3):165‐169. 
 
Agnelli G [2013a], Buller HR, Cohen A et al. Apixaban for extended treatment of venous 
thromboembolism. N Engl J Med 2013;368(8):699‐708. 
 
Agnelli G [2013b], Buller HR, Cohen A et al. Oral Apixaban for the Treatment of Acute 
Venous Thromboembolism. N Engl J Med 2013;369(9):799‐808. 
 
Apixaban:    http://packageinserts.bms.com/pi/pi_eliquis.pdf (May 15, 2017) 
 
Bates SM, Jaeschke R, Stevens SM et al. Diagnosis of DVT: Antithrombotic Therapy and 
Prevention of Thrombosis, 9th ed: American College of Chest Physicians 
Evidence‐Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e351S‐e418S. 
 
Buckner TW, Key NS. Venous thrombosis in blacks. Circulation 2012;125(6):837‐839. 
 
Buller HR, Prins MH, Lensin AW et al. Oral rivaroxaban for the treatment of 
symptomatic pulmonary embolism. N Engl J Med 2012;366(14):1287‐1297. 
 
Canadian Agency For Drugs And Technologies In Health. Guidelines for the economic 
evaluation of health technologies. 4th ed. Ottawa: CADTH, 2017. 
 
Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case‐fatality rates of 
recurrent venous thromboembolism and major bleeding events among patients treated for 
venous thromboembolism. Ann Intern Med 2010;152(9):578‐589. 
 
Castellucci LA, Cameron C, Le Gal G et al. Efficacy and safety outcomes of oral 
anticoagulants and antiplatelet drugs in the secondary prevention of venous 
thromboembolism: systematic review and network meta‐analysis. BMJ 2013;347:f5133. 
 
Chan AW, Tetzlaff JM, Altman DG et al. SPIRIT 2013 statement: defining standard 
protocol items for clinical trials. Ann Intern Med 2013;158(3):200‐207. 
 
Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus Warfarin in Patients with 
Atrial Fibrillation. N Engl J Med 2009;361(12):1139‐1151. 
 
Dabigatran:  
http://docs.boehringer-
ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf (May 15, 2017) 
 
Einstein Investigators, Bauersachs R, Berkowitz SD et al. Oral Rivaroxaban for 
Symptomatic Venous Thromboembolism. N Engl J Med 2010;363(26):2499‐2510. 
 


 
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Amendment 3, version date 21Sep2018 
 
43 
Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end‐point 
(PROBE) study. A novel design for intervention trials. Prospective Randomized Open 
Blinded End‐Point. Blood Press 1992;1(2):113‐119. 
 
Heit JA. The epidemiology of venous thromboembolism in the community: implications 
for prevention and management. J Thromb Thrombolysis 2006;21:23-29. PMID: 
16475038 
 
Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., Bonsel, G., Badia, 
X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-
5L). Quality of Life Research 2011 Dec; 20(10):1727–1736. 
 
Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of 
Anticoagulation. Definition of clinically relevant non-major bleeding in studies of 
anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical 
patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015 
Nov;13(11):2119-26. 
 
Kearon C, Gent M, Hirsh J et al. A comparison of three months of anticoagulation with 
extended anticoagulation for a first episode of idiopathic venous thromboembolism. N 
Engl J Med 1999;340(12):901‐907. 
 
Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: 
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of 
Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest 2012;141(2 
Suppl):e419S‐e494S. 
 
Kearon C, Akl EA, Ornelas J et al. Antithrombotic Therapy for VTE Disease: CHEST 
Guideline and Expert Panel Report. Chest 2016;149(2):315‐352. 
 
Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing G-J and Kyrle PA, for the 
Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables 
in Thrombotic Disease. Categorization of patients as having provoked or unprovoked 
venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 
14: 1480–3. 
 
Konstantinides SV, Torbicki A, Agnelli G et al. 2014 ESC Guidelines on the diagnosis 
and management of acute pulmonary embolism: The Task Force for the Diagnosis and 
Management of Acute Pulmonary Embolism of the European Society of Cardiology 
(ESC)Endorsed by the European Respiratory Society (ERS). Eur Heart J 
2014;35(43):3033‐3073. 
 
Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of 
recurrent venous thromboembolism in men and women. N Engl J Med 
2004;350(25):2558-2616. PMID: 15201412 
 


 
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44 
Liao S, Woulfe T, Hyder S, Merriman E, Simpson D, Chunilal S. Incidence of venous 
thromboembolism in different ethnic groups: a regional direct comparison study. J 
Thromb Haemost 2014;12(2):214‐219. 
 
Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG. Reporting of noninferiority 
and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 
2012;308(24):2594‐2604. 
 
Prandoni P, Lensing AWA, Cogo A et al. The long‐term clinical course of acute deep 
venous thrombosis. Ann Intern Med 1996;125(1):1‐7. 
 
Research Committee of the British Thoracic Society. Optimum duration of 
anticoagulation 
for 
deep‐vein 
thrombosis 
and 
pulmonary 
embolism. 
Lancet 
1992;340(8824):873‐876. 
 
Rivaroxaban: https://www.xarelto-us.com/shared/product/xarelto/prescribing-
information.pdf (May 15, 2017) 
 
Rodger MA, Kahn SR, Wells PS et al. Identifying unprovoked thromboembolism patients 
at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 
2008;179(5):417‐426. 
 
Schulman S, Rhedin AS, Lindmarker P et al. A comparison of six weeks with six months 
of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration 
of Anticoagulation Trial Study Group. N 
Engl J Med 1995;332:1661‐1665. 
 
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non‐surgical patients. J Thromb Haemost 
2005;3(4):692‐694. 
 
Schulman S, Kearon C, Kakkar AK et al. Extended Use of Dabigatran, Warfarin, or 
Placebo in Venous Thromboembolism. N Engl J Med 2013;368(8):709‐718. 
 
Spyropoulos AC, Douketis, JD.  “How I treat anticoagulated patients undergoing an 
elective procedure or surgery” Blood, 2012; 120: 2954-62. 
Thorpe KE, Zwarenstein M, Oxman AD et al. A pragmatic‐explanatory continuum 
indicator 
summary 
(PRECIS): 
a 
tool 
to 
help 
trial 
designers. 
CMAJ 
2009;180(10):E47‐E57. 
 
Thrombosis Canada: 
(http://thrombosiscanada.ca/?page_id=502&calc=perioperativeAnticoagulantAlgorithm 
 
Vilchez JA, Gallego P, Lip GY. Safety of new oral anticoagulant drugs: a perspective. 
Ther Adv Drug Saf 2014;5(1):8‐20. 
 


 
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White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:I4-I8. 
PMID: 12814979 
 
White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous 
thromboembolism. Thromb Res 2009;123 Suppl 4:S11‐S17. 
 

ICF_004.pdf: 
COVET ICF version 08AUG2018 
Page 1 of 9 
 
Comparison of Oral anticoagulants for extended Venous 
Informed Consent Form 
 
NCT03196349 
8Aug2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


COVET ICF version 08AUG2018 
Page 2 of 9 
 
 
 
 
______________________________________________________________________ 
 
Consent to Participate in a Research Study 
 
Title of Study: Comparison of Oral anticoagulants for extended Venous 
Thromboembolism (COVET) 
Investigator: [name of site PI, contact information for PI and study team:] 
 
WHAT ARE SOME GENERAL THINGS TO KNOW ABOUT RESEARCH 
STUDIES? 
You are being asked to take part in this research study because you have venous 
thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary 
embolism (PE). Research studies include only those people who choose to take part. 
Your participation is voluntary. Please read this consent form carefully and take your 
time when making your decision about whether to participate. When your study doctor or 
a study staff member talks with you about this consent form, ask that person to explain 
any words or information that you do not clearly understand.  We encourage you to talk 
with your family and friends before you decide to take part in this research study.  The 
nature of the study, risks, inconveniences, discomforts, and other important information 
about the study are described in this document. 
 
Please tell the study doctor or a study staff member if you are taking part in another 
research study. 
 
WHO WILL PROVIDE FUNDING? 
Dr. Thomas Ortel of Duke University is the sponsor of the trial. The Patient-Centered 
Outcomes Research Institute (PCORI) is funding this trial.  The funds from PCORI are 
paying [Site PI] and the doctor’s research staff to do this study.   
 
WHO WILL BE MY STUDY DOCTOR? 
If you decide to take part in the study, [Site PI] will be your study doctor. The study 
doctor may be in contact with your regular doctor while you are in the study and 
afterwards, if needed. 
 
WHY IS THIS STUDY BEING DONE? 
 
Venous thromboembolism (VTE) is a medical problem involving blood clots forming in 
the veins.  When a clot forms in in a deep vein (usually in the leg) it is called a deep vein 
thrombosis (DVT).  When a clot breaks loose and travels to the lungs it is called a 
pulmonary embolism (PE).  VTE is a common, potentially fatal, yet treatable condition, 


COVET ICF version 08AUG2018 
Page 3 of 9 
and is the third leading cause of mortality by cardiovascular disease.  You are being 
invited to participate in this study because you have been diagnosed with VTE and have 
received initial treatment with a blood thinner (anticoagulant). 
 
Up to 5% of the population will experience VTE in their lifetime and the majority of 
these events will not be brought on by any specific event.  VTE is primarily a disease of 
the elderly with incidence rates increasing with age for both men and women. The 
standard therapy for all patients with VTE is anticoagulation for 3-6 months; the most 
common oral anticoagulants used are vitamin K antagonists (for example, warfarin) and 
the direct oral anticoagulants (for example, apixaban and rivaroxaban). For patients who 
sustain VTE that is not associated with any specific event (for example, after surgery, 
following long plane flights), referred as an ‘unprovoked’ VTE, current guidelines 
recommend continuing anticoagulation indefinitely after the initial treatment period.  
Your doctor or healthcare provider has determined that you would benefit from long-term 
anticoagulation because of your risk for recurrent VTE.  The purpose of the COVET 
study is to determine whether the direct oral anticoagulants apixaban and rivaroxaban are 
safer than warfarin (fewer bleeding complications) and still as effective as warfarin (no 
increase in recurrent blood clots). 
All three of the anticoagulant agents included in this study (rivaroxaban, apixaban, and 
warfarin) are FDA approved and have been shown to be effective in the prevention of 
recurrent VTE.  There have been no studies that have compared these three blood 
thinners for the purpose of preventing recurrent blood clots long-term. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
A total of 3000 people to be evaluated at approximately 60 institutions in the US and 
Canada will be enrolled in this study.   
 
WHAT IS INVOLVED IN THE STUDY? 
If you agree to be in this study, you will be asked to sign this consent form. You will have 
the following assessments to make sure that you are eligible: 
 
 Medical history (to assess your eligibility to participate in the study) 
 A review of medication(s) you have taken and are currently taking to treat your 
DVT/PE. 
 
If eligible, you will be randomly assigned (like drawing straws) to either receive warfarin 
(target INR of 2-3), apixaban (2.5mg twice daily) or rivaroxaban (10mg daily).  
Participants should start on the assigned study drug within one week of randomization.  
Participants on once daily medications will have flexibility in determining the daily 
dosing timing.  You will receive a prescription for the medication you are assigned to.   
All these medications are currently approved for treatment of the venous 
thromboembolism and pulmonary embolism. 
The following test and procedures will be performed for this study: 
 


COVET ICF version 08AUG2018 
Page 4 of 9 
 At the Screening/Randomization visit (Visit 1) 
o Review and sign the Informed Consent Document  
o Measure your height and weight 
o Review your Medical History  
o Review the medication(s) you have taken in the past and are currently 
taking to treat your DVT/PE 
o Complete the Anti-coagulant Treatment Scale (ACTS) patient 
satisfaction questionnaire that will ask you questions about your 
satisfaction with your anticoagulant treatment.  
o Complete the health questionnaire (EQ-5D-5L) that will ask you 
questions about mobility and usual activities after diagnosis of VTE.  
 
 
 At the Follow-up phone Visits (Month 1, Month 6 and Month 12) 
o You will be contacted by the Duke Clinical Research Institute (DCRI) 
Call Center to talk with you about the following: 
 A review of medication(s) you have taken and are currently 
taking since the previous visit 
 Review of information on specific events you may have 
experienced. 
 Ask you questions from the Anti-coagulant Treatment Scale 
(ACTS) patient satisfaction questionnaire that will ask you 
questions about your satisfaction with your anticoagulant 
treatment.  
 Ask you questions from the Health questionnaire (EQ-5D-5L) 
regarding your mobility, usual activities, etc.  
 
HOW LONG WILL I BE IN THIS STUDY? 
Your participation in the study is anticipated to be 12 months from your 
screening/randomization visit.    
 
You can choose to stop participating at any time without penalty or loss of any benefits to 
which you are entitled. However, if you decide to stop participating in the study, we 
encourage you to talk with your doctor first.   
 
WHAT ARE THE RISKS OF THE STUDY? 
 
As a result of your participation in this study, you are at risk for the following side 
effects. You should discuss these with the study doctor, and you may choose to talk with 
your regular health care provider, too.   
 
Apixaban may cause some, all, or none of the side-effects listed below. 
 Bleeding is the most relevant adverse event.  
 Major or severe bleeding may occur and, regardless of location of the 
bleeding, may lead to disabling, life threatening or even fatal outcomes. 
 


COVET ICF version 08AUG2018 
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Rivaroxaban may cause some, all, or none of the side-effects listed below. 
 Bleeding is the most relevant adverse event.  
 Major or severe bleeding may occur and, regardless of location of the 
bleeding, may lead to disabling, life threatening or even fatal outcomes. 
  
Warfarin may cause some, all, or none of the side-effects listed below. 
 Bleeding is the most relevant adverse event.  
 Major or severe bleeding may occur and, regardless of location of the 
bleeding, may lead to disabling, life threatening or even fatal outcomes. 
 
In addition, you may experience unforeseeable risks and inconveniences associated with 
the use of the study drugs warfarin, apixaban and rivaroxaban. There is the potential risk 
of loss of confidentiality.  Every effort will be made to keep your information 
confidential, however, this cannot be guaranteed.   
 
Other Study Procedure Risks:  
In addition, there may be uncommon or previously unknown problems that might occur.  
You should report any problems you have to the study team. 
 
Reproductive Risks:  
Taking study anticoagulant while pregnant may expose a fetus to significant risks. If you 
are of child-bearing potential and sexually active, you must agree to use appropriate 
contraception for as long as you are taking the study drug. Medically acceptable 
contraceptives include: 
 
 surgical sterilization (such as a tubal ligation or hysterectomy) 
 approved hormonal contraceptives (such as birth control pills, patches, 
implants or injections) 
 barrier methods (such as a condom or diaphragm) used with a spermicide, 
or 
 an intrauterine device (IUD).  
 
Contraceptive measures such as Plan B™, sold for emergency use after unprotected sex, 
are not acceptable methods for routine use.  If you become pregnant during this study or if 
you have unprotected sex, you must inform your study physician immediately. 
 
If you becomes pregnant during the course of the study and elect to carry the pregnancy 
to term, the following actions should be taken: 
1. Notify your study doctor immediately. 
2. Study doctor will discontinue your anticoagulant medication. 
3. Study doctor will decide what (if any) ongoing anticoagulation therapy to be 
prescribed (off study).  
4. You may continue with the follow-up telephone calls only.  
 


COVET ICF version 08AUG2018 
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ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may not be direct medical benefit to you.   
We hope that the information learned from this study will benefit other people with your 
condition in the future.   
 
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY? 
You do not have to participate in this study. You can get treatment or care for your illness 
even if you are not in a research study.  
 
Please talk to your doctor about these options before you decide to take part in this study. 
 
WHAT PERSONAL HEALTH INFORMATION ARE YOU ASKING 
PERMISSION TO GET FROM MY MEDICAL RECORD?  
  
 
If you sign this consent form, you are giving your permission for the following people or 
groups to give the researchers certain information about you:   
 
 Any health care providers, professionals or agencies who have provided your 
health services or treatment, such as physicians, clinics, hospitals, home health 
agencies, diagnostics centers, laboratories, treatment or surgical centers, or 
government health agencies 
 Any agencies that provide payment for health care, such as insurers, or 
government agencies 
 The Duke Clinical Research Institute and any third party vendors that are working 
with the sponsor during the course of the project. 
 
 
This information may be shared with, used by, or seen by collaborating researchers, the 
sponsor of the research study, the sponsor’s representatives, and government agencies 
(like the FDA) if needed to oversee the research study. Anybody who receives your 
information from us could share it with others without your permission and would not be 
protected by US Federal Privacy Rules. We can use or share your information if we do so 
in a way such that nobody can tell it is your information.  
 
If you want to participate in this study, you have to sign this authorization to allow access 
to your medical records. If you choose to not sign it, you are still able to receive your 
medical treatment not related to the study. If you do sign it, you can change your mind 
later by writing a letter that states you are taking back your permission. Mail the letter to 
[Address] or you can send us an email at [List email address]. Stopping your 
authorization will prevent sharing of information in the future, but will not affect any 
information that has already been shared.   
 
Research information collected about you might be put in your medical record.  
 
The permission you give us to access your medical record will last until the end of the 
study. You will be given a copy of this authorization. 


COVET ICF version 08AUG2018 
Page 7 of 9 
 
If the results of this study are made public, information that identifies you will not be used.  
 
 
HOW WILL MY PRIVACY BE PROTECTED? 
Except when required by law, and as outlined in this consent, you will not be identified 
by name, Social Security number, address, telephone number, or any other direct personal 
identifier in study records disclosed outside of your hospital. You will be assigned a 
unique code number so that any study data or samples sent outside of your hospital will 
only contain your unique study code.  The key to the code will be kept at the hospital 
where you took part in the study. As part of the study, results of your study-related tests 
will be reported to the data coordinating center, Duke Clinical Research Institute (DCRI).  
We ask that you provide your name and phone number so that DCRI may contact you 
during the follow-up period. We will also ask for the name and phone number of a family 
member that can answer health questions about you if we are unable to reach you. 
A copy of this consent form will go into your medical record.  
Representatives from DCRI will ask Dr. [add PI name] and his staff to send copies of 
parts of your record to DCRI to monitor the study. Monitoring means that DCRI staff 
may review study records to ensure that your information was entered correctly. A copy 
of this signed consent document, along with copies of your laboratory reports and records 
of important medical events that occur while you are in the study will be sent to DCRI 
via a secured electronic system. Trained personnel at the site will ensure that your name 
is removed from all medical record documents (but not your consent form) before they 
are sent and that you are identified only by your unique study code number on the 
documents that are sent. These documents will remain secured through DCRI’s password 
protected electronic file system.  
 
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. 
 
WHAT ARE THE COSTS TO ME IF I PARTICIPATE IN THIS STUDY? 
You or your insurance provider will be responsible for all costs related to your medical 
care, including the cost of drugs used in this study.  The study will provide co-pay 
assistance for up to $60.00 per month if you are randomized to rivaroxaban or apixaban 
and $10.00 per month if you are randomized to warfarin to help with out-of-pocket costs 
you may incur. Reimbursement for routine lab work such as INRs required to monitor the 
warfarin is not provided by the study and should be billed to your health insurance 
company or other third party payor.  Your doctor or health care provider will help 
identify additional drug cost assistance programs.  Your doctor or health care provider 
will also review the expected out-of-pocket/copay costs for each of the study drugs with 
you.  If there is any expected out-of-pocket/copay cost for any of the three study drugs, 
either the full cost of the study drug, or a copy, that is not sufficiently off-set by the copay 


COVET ICF version 08AUG2018 
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provided through the study, and you are unable and/or unwilling to cover that cost, then 
you will not be eligible to participate in the study.   
 
WHAT ABOUT COMPENSATION? 
You will not be paid for participation in this study.  The co-payment assistance is not 
considered compensation for study participation.  Your participation in the study is 
voluntary. 
 
WHAT IF I AM INJURED?  
Immediate necessary medical care is available at [medical center] in the event that you 
are injured as a result of your participation in this research study. However, there is no 
commitment by Duke University, PCORI, or your study doctor to provide monetary 
compensation or free medical care to you in the event of a study-related injury.  Your 
health insurance company or other third party will be billed for the costs of this care.  If 
your insurance company or third party payer does not pay for these costs, you will be 
billed for them. 
 
For questions about the study or research-related injury, contact Dr. [ PI] at [phone 
number here with area code] during regular business hours or at [PI’s 24-hour number 
with area code] after hours and on weekends and holidays. 
 
WHAT IF I WANT TO STOP BEFORE MY PART IN THE STUDY IS 
COMPLETE? 
You can withdraw from this study at any time, without penalty.  The investigators also 
have the right to stop your participation at any time. This could be because you have had 
an unexpected reaction, or have failed to follow instructions, or because the entire study 
has been stopped. If you withdraw, no new information will be collected but we will use 
data that has already been collected.  
 
 
NEW FINDINGS 
If important new findings come up that might change your decision to be in this study, 
you will be given information about those findings as soon as possible. If you choose to 
stay in the study, you may be asked to sign a new version of the consent form. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have complaints, 
concerns or suggestions about the research, contact Dr. [PI] at [PI’s Number with Area 
Code] during regular business hours and at [PI’s 24-hour Number with Area Code] after 
hours or on a weekend or holiday. 
 
For questions about your rights as a research participant, contact [the IRB name and 
contact number] 
 


COVET ICF version 08AUG2018 
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STATEMENT OF CONSENT  
The purpose of this study, the procedures to be followed, the study’s risks and benefits 
have been explained to me.  I have been allowed to ask questions, and my questions have 
been answered to my satisfaction.  I have been told whom to contact if I have questions, 
to talk about problems, concerns, or suggestions related to the research, or to obtain 
information or offer input about the research.  I have read this consent form (or it has 
been read to me) and I agree to be in this study, with the understanding that I may 
withdraw at any time. I have been told that I will be given a copy of this consent form 
and that a copy of this form will become part of my medical record. 
 
I authorize the use and disclosure of health information from my medical record to the 
people or groups identified in this consent form for the purposes described in this document.  
 
I have read the information provided above.  I have asked all the questions I have at this 
time.  I voluntarily agree to participate in this research study. 
 
_____________________________________________________  
__________________ 
Signature of Research Subject 
 
 
Date 
 
_____________________________________________________ 
Printed Name of Research Subject 
 
_____________________________________________________  
__________________ 
Signature of Research Team Member Who Obtained Consent 
 
Date 
 
_____________________________________________________ 
Printed Name of Research Team Member Who Obtained Consent