Clinical trial NCT02744092
Conditions: Cancer Venous Thromboembolism Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Blood Clot
Keywords: Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Dabigatran (Pradaxa) Warfarin (Coumadin) Low molecular weight heparin (LMWH)
Sponsor: Alliance Foundation Trials, LLC.
Start date: 2016-12-13; Completion date: 2021-02-22
Enrollment: 811 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overarching objective of the study is to determine the effectiveness of LMWH/ warfarin vs. DOAC anticoagulation for preventing recurrent VTE in cancer patients. The intervention strategy is Direct Oral AntiCoagulants (DOAC) therapy with edoxaban, apixaban, rivaroxaban, or dabigatran. The comparator is low molecular weight heparin (LMWH) alone or with warfarin. The information gained will empower cancer patients and physicians to make more informed choices about anticoagulation strategies to manage VTE.

Detailed description:
Venous blood clots affect nearly a million Americans each year. Venous clots in the legs are called deep venous thrombosis (DVT) and are dangerous because they travel to the lungs where they cause blockages known as pulmonary emboli (PE). DVT and PE are called venous thromboemboli (VTE). Cancer is a risk factor with nearly 200,000 VTEs in cancer patients each year. The purpose of VTE treatment is to prevent the initial clot from spreading and to prevent new clots from forming. This is accomplished by thinning the blood, or anticoagulation. Without anticoagulation, VTEs recur and are often fatal.

Recently, the FDA has approved 4 new Direct Oral AntiCoagulants (DOACs) for preventing VTE recurrence. Few cancer patients were included in the efficacy trials, and practice guidelines fall silent on whether switching to DOAC therapy is advisable. To fill this knowledge gap, the Alliance Foundation Trials LLC, a research network of academic and community practices across the US, is conducting a pragmatic randomized effectiveness trial.

The overarching objective of the study is to determine the effectiveness of LMWH/ warfarin vs. DOAC anticoagulation for preventing recurrent VTE in cancer patients. The investigators will conduct a trial of 811 cancer patients followed for 6 months. The intervention strategy is DOAC therapy with edoxaban, apixaban, rivaroxaban, or dabigatran. The comparator is LMWH alone or with warfarin. Within each arm, patients can choose the agent they prefer based on side effects, drug interactions, and practical issues such as co-pays. The trial compares these two strategies in terms of treatment: 1) benefits based on VTE recurrence; 2) harms based on bleeding rates; 3) burdens based on patients' reports of their experiences; and 4) mortality rates.

The investigators hypothesize that the benefits, harms and burdens of DOAC treatment will be non-inferior to, or better than, usual care with LMWH/ warfarin among cancer patients. The information gained will empower cancer patients and physicians to make more informed choices about anticoagulation strategies to manage VTE.

Arms: arm 1: Randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). There are four FDA-approved DOAC drugs that may be used for this study: Rivaroxaban, Apixaban, Edoxaban, or Dabigatran. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. arm 2: Randomized Arm 2 will get anticoagulation therapy with low molecular weight heparin (LMWH) with or without a transition to warfarin. There are three FDA-approved LMWH drugs that may be used for this study: Dalteparin, Enoxaparin, or Fondaparinux. The treatment (including dosage form, dosage, frequency and duration) should be administered in accordance with the drug's FDA package insert, and all modifications are at the discretion of the treating investigator. arm 3: If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized).

Preference cohort: Non-randomized Arm 1 will get anticoagulation therapy with a Direct Oral AntiCoagulant (DOAC). arm 4: If an eligible participant is offered randomization and declines randomization, then a limited number of participants (up to N=190) will be allowed to enroll in the Preference Cohort. In this case, the treating physician and patient choose Arm 1 or Arm 2 (non-randomized).

Preference cohort: Non-randomized Arm 2 will get anticoagulation therapy with Low Molecular Weight Heparin (LMWH) with or without a transition to warfarin.
Interventions: intervention 1: Rivaroxaban intervention 2: Apixaban intervention 3: Edoxaban intervention 4: Dabigatran intervention 5: Warfarin intervention 6: Dalteparin intervention 7: Enoxaparin intervention 8: Fondaparinux
Intervention descriptions: intervention 1: Anticoagulation therapy. intervention 2: Anticoagulation therapy. intervention 3: Anticoagulation therapy. intervention 4: Anticoagulation therapy. intervention 5: Anticoagulation therapy. intervention 6: Anticoagulation therapy. intervention 7: Anticoagulation therapy. intervention 8: Anticoagulation therapy.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: Direct Oral Anticoagulants (DOACs) versus LMWH +/- Warfarin for VTE in Cancer: A 
Randomized Effectiveness Trial (CANVAS Trial) 
Protocol Short Title: CANVAS: Cancer-related VTE Anticoagulation Strategies 
NCT #: NCT02744092 
Updated: January 20, 2021
Supplement 1 
Table of Contents 
CANVAS TRIAL (AFT-28) PROTOCOL ............................................................................................... 2 
CANVAS TRIAL (AFT-28) STATISTICAL ANALYSIS PLAN......................................................... 69 


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ALLIANCE FOUNDATION TRIALS, LLC (AFT) 
 
PROTOCOL NUMBER 
AFT-28  
 
Direct Oral Anticoagulants (DOACs) versus LMWH +/- Warfarin for VTE in Cancer:  
A Randomized Effectiveness Trial (CANVAS Trial) 
 
CANVAS: Cancer-related VTE Anticoagulation Strategies 
 
Protocol Version: #7 
Protocol Version Date: January 20, 2021 
 
ClinicalTrials.gov Identifier: NCT02744092 
 
 
Study Chair 
Jean Connors MD 
Brigham and Women's Hospital  
75 Francis Street 
Boston, MA 02215 
Tel: 617-525-9337   
jconnors@bwh.harvard.edu 
 
 
Study Co-Chair 
Deborah Schrag MD MPH 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
Tel: 617-582-8301   
deb_schrag@dfci.harvard.edu 
 
 
 
 
AFT-28 Project Manager 
 
Central Study Coordinator 
617-732-8727 
CANVAS@AllianceFoundationTrials.org 
 
 
617-632-4490 
CANVAS_Coordinator@dfci.harvard.edu 
 
 
 
 
This study does not involve any investigational new drugs/agents/devices (no INDs). 
 
Drugs used in the study are all commercially available: 


Warfarin (Coumadin®) 
Dalteparin (Fragmin®) 
Enoxaparin (Lovenox®) 
Fondaparinux (Arixtra®) 
Rivaroxaban (Xarelto®) 
Apixaban (Eliquis®) 
Edoxaban (Savaysa®) 
Dabigatran (Pradaxa®) 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title:  
Direct Oral Anticoagulants (DOACs) versus LMWH +/- Warfarin for 
VTE in Cancer: A Randomized Effectiveness Trial (CANVAS Trial) 
 
 
Protocol Number:  
 
AFT-28 
 
 
Protocol Version/ Date:  
January 20, 2021 
 
 
Sponsor Name:  
 
Alliance Foundation Trials, LLC 
 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the described 
trial in compliance with all stipulations of the protocol, all applicable regulations, ICH Good Clinical 
Practice (GCP) and Declaration of Helsinki. 
 
 
 
 
 
 
------------------------------------------------- 
 
 
 
-------------------------------------- 
First Name, Last Name  
 
 
 
 
 
Date, Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CANVAS Trial (AFT-28) Resources  
 
Contact with QUESTIONS: 
Primary contact for questions about:  
• 
Patient eligibility 
• 
Drug administration 
• 
Protocol treatment 
• 
Dose modifications 
 
Study Chair Deb Schrag MD 
617-582-8301, Deb_schrag@dfci.harvard.edu* 
 
Study Chair Jean Connors MD 
617-525-9337, jconnors@bwh.harvard.edu* 
 
*CC: CANVAS_Coordinator@dfci.harvard.edu 
  
Primary contact for questions about: 
• 
Site activation 
• 
Protocol document 
• 
Consent form 
• 
Regulatory issues 
• 
Site Zone (online Electronic Master File) 
• 
Site reimbursement  
AFT-28 Project Manager 
CANVAS@AllianceFoundationTrials.org 
Primary contact for questions about: 
• 
Patient enrollment 
• 
Patient questionnaire administration 
• 
REDCap (online electronic data capture 
application) 
• 
Forms completion (CRFs) 
• 
Adverse event reporting  
• 
Submission of study data 
Central Study Coordinator 
617-632-4490 
CANVAS_Coordinator@dfci.harvard.edu 
 
SYSTEMS USED for this study: 
Site Zone is where you will:  
• 
Upload and submit the required documents 
for site activation for this study. 
• 
Find the most up-to-date study documents, 
such as protocol, model informed consent 
form, tip sheets, etc. 
https://sitezone.mywingspan.com/sitezone/#/trials 
For Site Zone help: 
TechSupport@AllianceFoundationTrials.org 
Site Protocol Training: 
• 
Watch the virtual training videos. 
 
The protocol training for study staff can be found here 
(15-minute video): 
https://vimeo.com/310853060/83ed78f342  
The protocol training for physicians can be found here 
(9-minute video): 
https://vimeo.com/310855828/43624a2713  
REDCap used to: 
• 
Enroll/randomize patients.  
• 
Enter all study data/case report forms 
(CRFs). 
• 
Report reportable adverse events. 
https://redcap.partners.org 
For REDCap help: 
Central Study Coordinator, 617-632-4490 
CANVAS_Coordinator@dfci.harvard.edu 


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CANVAS Trial (AFT-28) Synopsis 
 
Study Title 
Direct Oral Anticoagulants (DOACs) versus LMWH +/- 
Warfarin for VTE in Cancer: A Randomized Effectiveness Trial 
(CANVAS Trial) 
Study Number 
AFT-28 
Sponsor 
Alliance Foundation Trials, LLC (AFT) 
Funding 
This trial is supported through a Patient-Centered Outcomes 
Research Institute (PCORI) Award (CER-1503-29805). 
Study Type/Phase 
Randomized Effectiveness Trial 
Clinical Indication 
VTE (venous thromboembolism) associated with cancer  
ClinicalTrials.gov Identifier 
NCT02744092 
IND Number 
None, no IND 
Number of Trial Patients 
811 study-wide (Note: This is the final N.)  
Estimated Duration of Trial 
3.5 years  
Acronyms used througout the 
protocol 
AFT - Alliance Foundation Trials, LLC 
VTE - Venous Thromboembolism 
DVT - Deep Vein Thrombosis  
PE - Pulmonary Embolism  
LMWH - Low Molecular Weight Heparin  
DOAC - Direct Oral Anticoagulants  
Rationale 
Cancer patients are at risk for VTE (venous thromboembolism). 
Anticoagulation therapy is necessary to prevent recurrent VTE. 
Current practice patterns are a hybrid use of LMWH+/-warfarin.  
Recently, the FDA has approved 4 Direct Oral Anticoagulants 
(DOACs) for VTE based on efficacy trials showing non-
inferiority to warfarin.  Given the myriad exclusion criteria 
present in efficacy trials, the effectiveness of DOACs in cancer 
is unknown. 
Objectives 
Objective 1: To compare the effectiveness of anticoagulation 
with a DOAC (intervention) with LMWH/warfarin (comparator) 
for preventing VTE recurrence in patients with cancer.  
Objective 2: To compare the harms of DOAC vs. 
LMWH/warfarin therapy for cancer patients with VTE based on 
the cumulative rate of major bleeding at 6 months.  
Objective 3: To compare the impact of DOAC vs. 
LMWH/warfarin therapy on the experience and burden of 
anticoagulation therapy for cancer patients with VTE.  
Objective 4: To compare the impact of DOAC vs. 
LMWH/warfarin therapy on mortality in cancer patients with 
VTE.  


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Trial Design 
The study design is a randomized effectiveness study to evaluate 
the effectiveness of DOAC therapy compared to usual care with 
LMWH/warfarin. Participants who decline randomization will be 
offered the opportunity to participate in the preference cohort.** 
This is a hybrid design that consists of both a randomized cohort 
and a preference cohort.** Eligible patients who accept 
randomization will be enrolled in the study (the randomized 
cohort), and they will be randomly assigned to either the DOAC 
therapy group (Arm 1) or the usual care group (Arm 2).** Those 
patients who decline randomization but choose treatment on one 
of the two study arms (Arm 1 or Arm 2) will be enrolled to the 
study (the preference cohort).**  See the “Statistical 
Considerations” section of this protocol for complete details. 
 
**The randomized cohort closed to new enrollment in April, 
2020.  Based on the results of monthly data monitoring 
performed June 2017, the preference cohort is CLOSED to 
new enrollment following the closing rule specified in the 
protocol.** 
 
Eligibilty Criteria 
Can be found here: 4.0 Patient Selection / Eligibility Criteria 
Protocol Treatment 
Arm 1: Intervention arm, DOAC 
Arm 2: Usual care, LMWH/warfarin 
 
This effectiveness study will not provide any drugs because all 
drugs are commercially available, FDA-approved, and are being 
prescribed on-label.  Drugs should be billed to the patient's 
insurance company or to the patient as your site does for any 
other standard medication.  Drugs should be prescribed to the 
patient as your site does for any other standard medication. 


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Schema 
 
 
 
 
 
Enroll Eligible 
Arm 1 – Intervention Arm,  
DOAC 
 
Treating physician & patient  
choose between: 
 
• Rivaroxaban (Xarelto) 
• Apixaban (Eliquis) 
• Edoxaban (Savaysa) 
• Dabigatran (Pradaxa) 
Arm 2 – Usual Care Arm, 
LMWH/warfarin 
 
Treating physician & patient  
choose between: 
 
• Warfarin (Coumadin) 
• Dalteparin (Fragmin) 
• Enoxaparin (Lovenox) 
• Fondaparinux (Arixtra) 
Randomize 


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AFT-28 Protocol Table of Contents 
CANVAS TRIAL (AFT-28) RESOURCES .............................................................................................. 5 
CANVAS TRIAL (AFT-28) SYNOPSIS ................................................................................................... 6 
SCHEMA ..................................................................................................................................................... 8 
1.0  
BACKGROUND ............................................................................................................................ 11 
2.0 
OBJECTIVES ................................................................................................................................ 15 
3.0 
STUDY DESIGN ........................................................................................................................... 16 
3.1 
Description of study and schema ................................................................................................................. 16 
3.2 
Study Completion ........................................................................................................................................ 16 
4.0 
PATIENT SELECTION / ELIGIBILITY CRITERIA .............................................................. 17 
4.1 
Inclusion Criteria ......................................................................................................................................... 17 
4.2 
Exclusion Criteria ........................................................................................................................................ 17 
4.3 
Definitions and answers to FAQs with regard to the eligibility criteria ............................................... 18 
5.0 
SITE ACTIVATION ..................................................................................................................... 19 
6.0 
PATIENT ENROLLMENT AND RANDOMIZATION PROCEDURES ............................... 21 
6.1 
Stratification Factors and Treatment Assignments ...................................................................................... 23 
7.0 
SCHEDULE OF ASSESSMENTS ............................................................................................... 24 
8.0 
STUDY PROCEDURES ............................................................................................................... 26 
8.1 
Screen, approach, and obtain informed consent ..................................................................................... 26 
8.2 
Eligibility Checklist/Enrollment Form .................................................................................................... 27 
8.3 
Treatment Arm .......................................................................................................................................... 27 
8.4 
Baseline Study Questionnaire ................................................................................................................... 27 
8.5  
Treatment Status Update Form .................................................................................................................... 28 
8.6 
Follow-up Study Questionnaires .............................................................................................................. 28 
8.7 
Medical Record Abstraction ..................................................................................................................... 30 
8.8 
Change in Enrollment Status/Off-Study Form ....................................................................................... 30 
8.9 
Managing ineligible patients and registered patients who never receive protocol intervention ......... 31 
8.10  Notice regarding proprietary content embedded in the patient questionnaires ............................................ 31 
9.0 
DATA COLLECTION AND SUBMISSION .............................................................................. 33 
9.1 
Summary of data collection and submission: .......................................................................................... 33 
9.2 
Data Submission using REDCap ................................................................................................................. 34 
10.0 
DRUG INFORMATION ............................................................................................................... 35 
10.1 
General Considerations ................................................................................................................................ 35 
10.2 
Drug Information ...................................................................................................................................... 35 
11.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 36 
11.1  Overview of treatment plan ...................................................................................................................... 36 
11.2  Protocol Treatment ...................................................................................................................................... 37 
11.3 
Selecting an Anticoagulant .......................................................................................................................... 37 
11.3.1 Practice Guidelines ................................................................................................................. 37 
11.3.2  
FDA Package Inserts ....................................................................................................... 39 
11.4 
Protocol treatment administration - Dosing ................................................................................................. 40 
11.5  Dose Modifications ...................................................................................................................................... 43 
11.6  Ancillary therapy, concomitant medications, and supportive care .............................................................. 43 
11.7 
Extraordinary Medical Circumstances ......................................................................................................... 44 
12.0  ADVERSE EVENTS ..................................................................................................................... 45 
12.1  Overview ..................................................................................................................................................... 45 


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12.2  Routine adverse event reporting .................................................................................................................. 45 
12.3  Expedited Adverse Event Reporting (AFT-28) ........................................................................................... 45 
12.4  Expected Adverse Reactions ....................................................................................................................... 46 
12.5 
FDA MedWatch .......................................................................................................................................... 47 
12.6 
New or Recurrent VTEs on Study ............................................................................................................... 47 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 49 
13.1 Summary of the study design and rationale .................................................................................................... 49 
13.2 Accrual ............................................................................................................................................................ 50 
13.3 Statistical Considerations for Primary Endpoint – Please see Appendix 18.0 for more details in the SAP. ... 52 
13.3 
Statistical Considerations for Secondary Endpoints .................................................................................... 55 
13.3.6 Other/Persistence with treatment Endpoints ................................................................................................ 57 
13.3.7 Safety endpoint evaluation .......................................................................................................................... 57 
Safety endpoints: ................................................................................................................................ 57 
• 
Major bleeding (primary protocol safety endpoint) ......................................................... 57 
• 
Clinically significant non-major bleeding ........................................................................ 57 
• 
Any bleeding (major bleeding and clinically significant non-major bleeding and nuisance 
bleeding) 57 
• 
Other Serious Adverse Events (SAE) ................................................................................ 57 
13.5 Heterogeneity of Treatment Effects ................................................................................................................ 57 
13.5.1.1 Pre-specified subgroup 1: Patients with Highly Thrombogenic Tumors ............................. 57 
13.5.1.2. Pre-specified subgroup 2: Indwelling Central Venous Catheters ....................................... 58 
13.5.1.3. Pre-specified subgroup 3: Thrombocytopenia .................................................................... 58 
13.5.1.4. Other preplanned subgroups ............................................................................................... 58 
13.6 Toxicity ........................................................................................................................................................... 58 
13.7 Other statistical considerations ....................................................................................................................... 59 
13.8. Software ......................................................................................................................................................... 59 
13.8 Gender and Ethnicity ...................................................................................................................................... 60 
13.9 Study Monitoring ............................................................................................................................................ 60 
13.10 Endpoint Adjudication .................................................................................................................................. 60 
13.11 Site Audits..................................................................................................................................................... 61 
14.0  BUDGET ........................................................................................................................................ 62 
14.1 
Funding ........................................................................................................................................................ 62 
14.2 
Site and per case reimbursement ................................................................................................................. 62 
14.3  Drug costs .................................................................................................................................................... 62 
15.0 
REFERENCES .............................................................................................................................. 63 
16.0 
APPENDIX: NOTICE REGARDING PROPRIETARY CONTENT EMBEDDED IN THE 
STUDY QUESTIONNAIRES .................................................................................................................. 66 
17.0 PATIENT-FACING STUDY MATERIALS .................................................................................. 68 
• 
Model Informed Consent Form – ENGLISH .............................................................................................. 68 
• 
Model Informed Consent Form – SPANISH ............................................................................................... 68 
• 
Baseline Questionnaire (available in 6 formats; content identical in all 6 formats) .................................... 68 
• 
Baseline Study Questionnaire – for administration via paper - ENGLISH ................................................. 68 
• 
Baseline Study Questionnaire – for administration via secure weblink - ENGLISH .................................. 68 
• 
Baseline Study Questionnaire – for administration via phone - ENGLISH................................................. 68 
• 
Baseline Study Questionnaire – for administration via paper - SPANISH .................................................. 68 
• 
Baseline Study Questionnaire – for administration via secure weblink - SPANISH ................................... 68 
• 
Baseline Study Questionnaire – for administration via phone - SPANISH ................................................. 68 
• 
Follow-up Questionnaire (available in 6 formats; content identical in all 6 formats).................................. 68 
• 
Follow-up Study Questionnaire – for administration via paper - ENGLISH .............................................. 68 
• 
Follow-up Study Questionnaire – for administration via secure weblink - ENGLISH ............................... 68 
• 
Follow-up Study Questionnaire – for administration via phone - ENGLISH .............................................. 68 


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• 
Follow-up Study Questionnaire – for administration via paper - SPANISH ............................................... 68 
• 
Follow-up Study Questionnaire – for administration via secure weblink - SPANISH ................................ 68 
• 
Follow-up Study Questionnaire – for administration via phone - SPANISH .............................................. 68 
• 
Patient Medication Diary – ENGLISH ........................................................................................................ 68 
• 
Patient Medication Diary – SPANISH ........................................................................................................ 68 
• 
Drug Diary Letter – ENGLISH ................................................................................................................... 68 
• 
Drug Diary Letter – SPANISH .................................................................................................................... 68 
• 
Informational Flyer – ENGLISH ................................................................................................................. 68 
• 
Informational Flyer – SPANISH ................................................................................................................. 68 
• 
Informational Video – ENGLISH (not available in Spanish at this time) ................................................... 68 
18.0 
AFT-28 STATISTICAL ANALYSIS PLAN ............................................................................... 69 
1. INTRODUCTION ................................................................................................................................. 74 
2. STUDY OVERVIEW ............................................................................................................................ 74 
2.1. Objectives ........................................................................................................................................................ 74 
2.2. Study Design .................................................................................................................................................... 74 
2.3. Eligibility ......................................................................................................................................................... 75 
2.4. Randomization and stratification criteria ......................................................................................................... 75 
2.5. Sample size justification .................................................................................................................................. 76 
3. ANALYSIS METHODS AND PRESENTATION ............................................................................. 76 
3.1. General principles ............................................................................................................................................ 76 
3.2. Definition of analysis populations ................................................................................................................... 77 
3.3. Disposition of study subjects ........................................................................................................................... 78 
3.4. Baseline demographic and disease characteristics ........................................................................................... 78 
3.5. Primary endpoint evaluation ............................................................................................................................ 79 
3.5.1. Primary endpoint ...................................................................................................................... 79 
3.5.2. Analysis for the primary endpoint ............................................................................................ 79 
3.6. Secondary endpoint evaluation ........................................................................................................................ 81 
3.6.1. Secondary endpoints ................................................................................................................ 81 
3.6.2. Analyses for secondary endpoints ............................................................................................ 82 
3.7. Other/Persistence with treatment endpoints ..................................................................................................... 83 
3.8. Safety endpoint evaluation ............................................................................................................................... 83 
3.8.1. Safety endpoints........................................................................................................................ 83 
3.8.2. Analyses for safety endpoints ................................................................................................... 83 
3.9. Subgroup Analyses .......................................................................................................................................... 84 
3.9.1. Pre-specified subgroup 1: Patients with Highly Thrombogenic Tumors ................................. 84 
3.9.2. Pre-specified subgroup 2: Indwelling Central Venous Catheters ............................................ 84 
3.9.3. Pre-specified subgroup 3: Thrombocytopenia ......................................................................... 84 
3.9.4. Other preplanned subgroups .................................................................................................... 84 
3.10. Software ......................................................................................................................................................... 85 
REFERENCES ......................................................................................................................................... 85 
 
 
1.0  
BACKGROUND 
 
Venous Thromboemboli (VTE) are common, often lethal and a major public health threat A deep 
venous thrombosis (DVT) is a blood clot in a large vein, usually in the leg or pelvis. Patients often note 
swelling, pain or redness in one leg. Sometimes a DVT detaches from its site of formation and mobilizes 
in the blood stream. If the clot travels through the heart to the lungs, it can suddenly block an artery 
supplying the lungs. This event is called a pulmonary embolism (PE). PE symptoms include shortness of 


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breath, chest pain, and rapid heart rate. Each year in the US, an estimated 600,000–900,000 people 
develop VTE, and more than 100,000 die, many suddenly.1-4 Because people who survive a first VTE are 
at extremely high risk for another episode, a main treatment goal is to prevent a second event. 
 
 
Multiple pathophysiologic mechanisms put cancer patients at excess risk for VTE A cancer 
diagnosis is one of the strongest predisposing risks for VTE.  VTE is sometimes the first manifestation 
of cancer. The excess VTE risk in cancer stems from three interrelated pathogenic mechanisms: 1) 
hypercoagulability; 2) stasis or slow blood flow; and 3) vascular injury to blood vessel walls. Tumor 
features such as histology (adenocarcinoma), site (pancreatic, kidney, uterus) and extent of disease 
increase risk. Certain chemotherapy agents, hormonal therapy, the use of indwelling catheters, surgery, 
hospitalization and immobility all increase risk and contribute to the high frequency of VTE in cancer 
patients. 
 
VTE is a frequent distressing complication of cancer and is associated with high mortality Two 
population-based case control studies demonstrate that cancer increases the risk for VTE by 4 to 7 times 
and is the second leading cause of death in oncology patients.5, 6 Approximately 20% of all VTEs occur 
in cancer patients. A recent study showed that 12.5% of chemotherapy recipients in ambulatory practice 
developed a VTE within 12 months.7 The rate varied from 8% to 19% depending on cancer type. In 
contrast, the VTE rate was only 1.4% for age and gender matched cancer-free controls from these 
practices.8 Cancer patients with VTE have more advanced disease, worse performance status and higher 
risk of death. Although much of the excess is due to cancer itself, a significant proportion is due to 
recurrent VTE.1 
 
Anticoagulation therapy is necessary to prevent recurrent VTE Cancer patients face very high risks 
of recurrent VTE particularly if they have high tumor burden or are receiving chemotherapy.9 
Therefore, absent a major contraindication such as ongoing/active bleeding, very low platelet count, 
and/or large brain metastases, anticoagulation is indicated for cancer patients following VTE. This is 
true whether the VTE is symptomatic or an incidental finding detected on an imaging study. Practice 
guidelines recommend that advanced cancer patients continue anticoagulant therapy long-term since 
the risk of VTE persists indefinitely. 
 
Warfarin is the mainstay of anticoagulation treatment to prevent VTE but requires close 
monitoring Warfarin is an oral medication often known by its brand name, Coumadin. It prevents the 
formation of blood clots and their migration. The FDA approved it in 1954 when found to prevent blood 
clots, and its use remains ubiquitous. Despite its effectiveness, treatment with warfarin has major 
shortcomings. Its therapeutic window is narrow. Too little warfarin fails to protect against VTE. Too 
much leads to an excess risk of bleeding. There is great variability in its metabolism, and it interacts 
with some foods and many medications. Therefore, close monitoring is required. This entails blood 
testing, often weekly, to ensure that the international normalized ratio (INR) is within therapeutic range. 
Warfarin therapy is especially challenging for cancer patients for two reasons. First, cancer patients take 
many medications which can either accelerate or impede warfarin metabolism. Second, warfarin has to 
be reversed prior to surgical procedures. This takes about 5 days and requires multiple blood draws. 
 
Low Molecular Weight Heparins (LMWHs) Are the Guideline Sanctioned Approach for Treating 
VTE in Cancer For many years, the management of VTE consisted of several days of inpatient treatment 
with intravenous heparin followed by transition to oral warfarin. Because of unfractionated heparin’s short 
half-life and metabolism, it required close monitoring and intravenous treatment. In the1990s, the 
LMWHs (e.g., dalteparin (Fragmin) and enoxaparin (Lovenox)) were developed.10-13 They require 
subcutaneous injection but no blood monitoring. In 2003, the CLOT study demonstrated that in patients 
with malignancy and VTE, dalteparin was more effective than warfarin at reducing VTE recurrence 
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preferred regimen.7, 15-17   A Cochrane review of anticoagulation to prevent recurrent VTE in cancer found 
that recurrent VTE hazard was 0.47 (95% CI 0.32-0.71) for LMWH vs. warfarin with no major 
differences in bleeding, survival or other complications.14 
 
Anticoagulation therapy with either LMWH or warfarin is complex and often burdensome 
Notwithstanding its superior efficacy to warfarin and guideline endorsements, adherence to LMWH 
therapy is challenging because it requires daily injections. Patients encounter problems preparing 
syringes, injecting needles and with bruising. In order to undergo surgical procedures including biopsy, 
endoscopy, or catheterization, warfarin must be stopped a week in advance. To prevent VTE during this 
period, oncologists prescribe “a LMWH bridge” since LMWH has shorter half-life.  After procedures 
are complete, warfarin can be restarted and LMWH discontinued when warfarin again reaches 
therapeutic levels, typically after 5 days. Analyses of practice patterns suggest that among cancer 
patients with VTE: about a third choose LMWH, a third warfarin, and a third opt for LMWH but 
transition to warfarin within several months when injections become too burdensome.  Current 
oncology practice is thus best described as a hybrid strategy. 
 
Direct Oral AntiCoagulants (DOACs) have recently been FDA approved to treat/prevent VTE 
DOACs (Table 1) are a major, recent therapeutic advance for management of VTEs. They are oral but 
unlike warfarin, do not require intensive monitoring to stay within therapeutic range. Four DOACS 
have recently been FDA approved.18-22 Factor Xa activates prothrombin to thrombin and triggers the 
coagulation cascade to form clot. Thrombin cleaves fibrinogen to fibrin, forming the structure of the 
clot. Apixaban, edoxaban, and rivaroxaban, directly inhibit Xa. Dabiagatran directly inhibits 
thrombin. The DOACs were first approved to prevent stroke and embolism in atrial fibrillation and 
after orthopedic surgery. Each agent has been evaluated in large efficacy trials and shown to be at least 
as efficacious as warfarin at preventing recurrent VTE and at least as safe in terms of the risk of 
bleeding.18, 20, 22-24 
 
Table 1 
Comparison of DOACs Recently Approved by the FDA 
Direct Oral 
Anticoagulants 
(DOACs) 
Dabiagatran21 
(Pradaxa) 
Rivaroxaban20 
(Xarelto) 
Apixaban18 
(Eliquis) 
Edoxaban19 
(Savaysa) 
FDA approval date for 
VTE 
April 7, 2014 
Nov 2, 2012 
Aug 21, 2014 
Jan 8, 2015 
Target factor 
II (thrombin) 
Xa 
Xa 
Xa 
Renal clearance 
80 % 
33 % 
25 % 
35 % 
Renal dose modification 
Don’t use 
Not if CrCl<30ml/min 
None 
30mg if CrCl<50 
Hepatic metabolism 
Minimal 
Yes, CYP3A4 
Yes, CYP3A4 
Minimal 
Liver failure 
modification 
None 
Don’t use 
Don’t use 
None 
Bleeding risk vs. 
warfarin 
same 
same/better 
better 
better 
 
Efficacy trials have evaluated benefits/harms of DOACs for VTE in carefully selected patient 
groups Table 2 summarizes the large efficacy RCTs comparing the DOACs to a vitamin K 
antagonist (VKA) (e.g., warfarin). Each demonstrates that VTE recurrence, bleeding and death 
rates from anticoagulation with a DOAC are non-inferior to rates with VKA. They led the FDA to 
approve the DOACs for VTE treatment. Table 2 underscores how few cancer patients were 
included in these pivotal trials. A recent meta-analysis showed similar findings for cancer 
subgroups. For example, the OR for VTE was 0.56 (95% CI 0.27-1.14) for DOAC vs. VKA 
therapy.25 Notably, these trials excluded patients with short life expectancy and significant 


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comorbidities, and in some trials, patients were excluded if they were eligible for treatment with 
LMWH. As a result of this evidence gap, it is not surprising that practice guidelines from the 
National Comprehensive Cancer Network26, the American Society of Clinical Oncology7, 27, The 
European Society of Medical Oncology,16  The American Society of Hematology and the 
American Thoracic Society15 advocate neither for nor against DOAC use in cancer. These 
guidelines all emphasize the need for effectiveness studies and do not definitely recommend for or 
against use of DOACs versus LMWH/VKA therapy.28-30  
 
Table 2: Recent Large RCTs of DOACs vs. Warfarin Have Included Very Few Cancer Patients 
Overall Outcomes: Intervention vs. Control 
RCT Name 
Intervention 
Control 
N 
Cancer N 
(%) 
VTE/VTE 
death 
Bleeding/ 
Bleeding death 
Any death 
Amplify18 
Apixaban 
VKA 
5395 
169 (3%) 
1.5 vs. 1.9% 
4.3 vs. 9.7% 
1.5 vs. 1.9% 
Einstein-DVT22 
Rivaroxaban 
VKA 
3449 
207 (6%) 
2.1 vs. 3.0% 
8.1 vs. 8.1% 
2.2 vs. 2.9% 
Einstein-PE20 
Rivaroxaban 
VKA 
4832 
223 (4%) 
2.1 vs. 1.8% 
10.3 vs 11.4% 
2.4 vs. 2.1% 
HOKUSAI19 
Edoxaban 
VKA 
8240 
208 (2%) 
3.2 vs. 3.5% 
8.5 vs.10.3% 
3.2 vs 3.1% 
RE-COVER I21 
Dabigatran 
VKA 
2539 
121 (5%) 
2.4 vs. 2.1% 
1.6 vs. 1.9% 
1.6 vs. 1.7% 
RE-COVER II31 
Dabigatran 
VKA 
2589 
100 (4%) 
2.3 vs. 2.2% 
1.2 vs. 1.7% 
2.0 vs. 1.9% 
*AMPLIFY and RE-COVER I & II outcomes are event rates at 6 months; the other study outcomes 
reflect rates at 12 months 
 
With this background, the rationale for this study is compelling because: 
• 
VTEs occur commonly in cancer patients, can be fatal, and require anticoagulation to prevent 
recurrence. 
• 
Warfarin has long been the mainstay of VTE treatment but requires careful blood monitoring. 
• 
LMWHs are an alternative but require subcutaneous injection and thus are onerous for patients. 
• 
LMWH prevents recurrent VTE in cancer better than warfarin in some studies but isn’t clearly 
better in terms of safety or survival. 
• 
Longstanding usual practice is a hybrid of LMWH/warfarin with many patients transitioning back 
and forth between the two. Typically, patients start on a LMWH and transition to warfarin; 
however, some stay on LMWH for the long term and may transition to warfarin at a later date 
particularly if chronic self-administration of subcutaneous injections becomes arduous. 
• 
FDA has approved 4 DOACs for VTE based on efficacy trials showing non-inferiority to 
warfarin. These trials have included very few cancer patients leaving an evidence gap. 
• 
Given the myriad exclusion criteria present in efficacy trials, the effectiveness of DOACs in 
cancer is unknown. 
 
 
 


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2.0 
OBJECTIVES  
 
Cancer patients are frequently diagnosed with VTE and need to choose an anticoagulation strategy. 
Although there are now multiple options, patients and their doctors lack information that clearly balances 
benefits/harms and burdens so as to inform these choices. To fill this gap, the proposed study has the 
following goals: 
 
Objective 1: To compare the effectiveness of anticoagulation with a DOAC (intervention) with 
LMWH/warfarin (comparator) for preventing VTE recurrence in patients with cancer. 
Hypothesis: The benefit of secondary prophylactic anticoagulation with a DOAC is not worse 
than the benefit from treatment with LMWH/warfarin based on cumulative VTE recurrence 
reported by patients or their clinicians at 6 months. 
 
Objective 2: To compare the harms of DOAC vs. LMWH/warfarin therapy for cancer patients with VTE 
based on the cumulative rate of major bleeding at 6 months. 
Hypothesis: The harms from DOAC therapy are not worse than the harms from LMWH/warfarin 
therapy based on the cumulative rates of major bleeding reported by patients or clinicians at 6 
months. 
 
Objective 3: To compare the impact of DOAC vs. LMWH/warfarin therapy on the experience and burden 
of anticoagulation therapy for cancer patients with VTE. 
Hypothesis 3a: DOAC and LMWH/warfarin therapy are associated with similar overall HRQOL 
(health-related quality of life) at 3 and 6 months. 
Hypothesis 3b: DOAC therapy is superior to LMWH/warfarin based on the Anti-Clot Therapy 
Scale at 3 and 6 months. 
 
Objective 4: To compare the impact of DOAC vs. LMWH/warfarin therapy on mortality in cancer 
patients with VTE  
Hypothesis: The risks of all cause and cause-specific mortality for cancer patients treated with 
DOAC therapy are not worse than the risks for those treated with LMWH/warfarin based on 
survival at 6 months. 
 
 
 
 
 
 
 
 


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3.0 
STUDY DESIGN 
 
3.1 
Description of study and schema 
The study design is a prospective unblinded two-group randomized effectiveness study to 
evaluate the effectiveness of DOAC therapy compared to the usual care with LMWH/warfarin. 
The study has a hybrid design in that in addition to the randomized cohort, it also includes a 
preference cohort.** Eligible patients who accept randomization will be enrolled in the study (the 
randomized cohort), and they will be randomly assigned to either the DOAC therapy group 
(Arm 1) or the usual care group (Arm 2).** Those patients who decline randomization but choose 
treatment on one of the two study arms (Arm 1 or Arm 2) will be enrolled to the study (the 
preference cohort).**  See protocol section 13.0 Statistical Considerations and 18.0 
Statistical Analysis Plan for complete details. 
 
The study intervention, DOAC therapy, has established efficacy, but its real world effectiveness 
in cancer patients is unknown. The study outcomes are measurable and meaningful to patients 
and their families. Knowledge from this study will help patients and their clinicians make better 
informed decisions about anticoagulation therapy. To understand the impact of individuals who 
choose not to be randomized, the study will also track outcomes for patients who consent to 
report outcomes, but decline randomization.** This hybrid design as well as a well-specified plan 
for capturing important patient and treatment factors will enable better understanding of the 
relative risks/harms for individuals with specific features.  
 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The preference 
cohort is CLOSED to new enrollment. 
 
The protocol schema can be found above. 
 
 
3.2 Study Completion  
The anticipated study completion date (the date by which the last data point for final data analysis 
is received) is November 15th, 2020. This presumes that no patients are enrolled after May 1st and 
that 6 month follow up data is complete as of November 1st. Two extra weeks have been added in 
case it should be necessary to track late assessments. Please note: the official study completion 
date will be dependent on the date of the last enrolled patient.  
  
 
 


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4.0 
PATIENT SELECTION / ELIGIBILITY CRITERIA 
4.1 
Inclusion Criteria  
4.1.1 
Diagnosis of an advanced solid tumor, lymphoma, chronic lymphocytic 
leukemia (CLL), or myeloma (no time restrictions or limitations) –OR– 
diagnosis of early stage solid tumor cancer, lymphoma, chronic lymphocytic 
leukemia (CLL), or myeloma < 12 months prior to study enrollment. 
 
4.1.2 
Diagnosis of VTE < 30 days prior to study enrollment for which potential 
benefits of anticoagulation therapy to prevent recurrence of VTE are felt by the 
treating physician to exceed the potential harms. Diagnosis may be made based 
on physical exam or imaging studies. Participants with both symptomatic and 
asymptomatic VTEs are eligible. 
Any anticoagulation drug/strategy may be used to treat the index VTE; 
protocol treatment will begin < 14 days after enrollment. 
 
4.1.3 
Treating physician intends to put participant on anticoagulation therapy for at 
least three months.  
 
4.1.4  Age ≥ 18 years. 
 
4.1.5 
Platelet count is > 50,000/mm3  (< 7 days prior to enrollment). 
 
4.1.6  CrCl (Creatinine Clearance) is > 15 ml/min (<7 days prior to enrollment). 
 
 
4.2 
Exclusion Criteria 
 
 
4.2.1 
Diagnosis of acute leukemia.  
 
4.2.2 
Has ever received or is scheduled to receive an Allogeneic Hematopoietic Stem 
Cell Transplantation (alloHSCT). 
• 
Patients who have ever received an Autologous Hematopoietic Stem Cell 
Transplantation (autoHSCT) are eligible. 
 
• 
Patients who are scheduled to receive an Autologous Hematopoietic Stem Cell 
Transplantation (autoHSCT) are not eligible. 
 
4.2.3 
Ongoing, clinically significant bleeding (CTCAE grade 3 or 4). 
 
4.2.4 
Ongoing therapy with a P-gp inhibitor (e.g., nelfinavir, indinavir, or saquinavir-
protease inhibitors for HIV) as these drugs interact with the factor Xa inhibitors. 
 
4.2.5 
Need for ongoing therapy with: certain antifungals (itraconazole, ketaconazole, 
voriconazole); rifampin; or certain antiseizure medications (phenytoin, 
carbamazepine, phenobarbital) at the time of enrollment.  
 
4.2.6 
Subjects with any other contraindications to anticoagulation or conditions that as 
judged by the treating clinician would place the subject at increased risk of harm 
if s/he participated in the study. 


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4.2.7 
Pregnant or nursing.  
 
4.3 
Definitions and answers to FAQs with regard to the eligibility criteria  
 
General: 
• 
Non-English speaking participants are eligible for participation in this study.  Sites must follow 
their local SOPs for consenting non-English speaking participants.  Translated materials are 
currently available in Spanish. 
 
Criterion 4.1.1:  
• 
“Advanced” cancer means stage IV, metastatic, and/or recurrent cancer.   
• 
If diagnosed with advanced cancer, then date of cancer diagnosis can be any date (no time 
restrictions or limitations).   
• 
“Early stage” cancer means any cancer EXCEPT one that is stage IV, metastatic, and/or 
recurrent.  
• 
If diagnosed with early stage cancer, then the diagnosis date must be < 12 months prior to the 
date on which the patient is enrolled on this trial. 
• 
Patients with multiple malignancies are eligible as long as other criteria are met. 
• 
DCIS (ductal carcinoma in situ) and MDS (myelodysplastic syndromes) are not eligible. 
• 
Primary CNS (central nervous system) tumors, primary brain tumors, and/or brain metastases are 
eligible. 
 
Criterion 4.1.2:  
• 
Patients with a history of prior VTE and prior anticoagulation are allowed. 
• 
“VTE” means PE,DVT, and/or portal vein thrombosis (any or all are acceptable).  
• 
VTE stands for Venous Thromboembolism.  A VTE is a blood clot that breaks loose and 
travels in the blood.  DVTs and PEs are types of VTEs. 
• 
PE stands for Pulmonary Embolism.  A PE is a sudden blockage in a lung artery (often caused 
by a DVT that breaks loose and travels through the bloodstream to the lung).  
• 
DVT stands for Deep Vein Thrombosis.  A DVT is a blood clot that forms in a vein deep in the 
body, often in the leg or pelvis.  
• 
The following types of VTE are also eligible: any line associated clot, calf vein, splanchnic, and 
sub-segmental PE are eligible.  It is recommended that sites not enroll superficial vein 
thrombosis unless there is intention to treat with full dose anticoagulation for at least 3 months. 
• 
The VTE diagnosis that makes a patient eligible for this study will be referred to as the “index 
VTE” throughout this protocol.   
• 
“Recurrent VTE” is defined as the emergence of venous thrombosis of a site that was either 
previously uninvolved or had interval documentation of incident DVT or PE resolution. 
• 
The participant may receive ANY initial anticoagulation therapy for their index VTE.  
Protocol treatment will begin < 14 days after study enrollment/randomization.   
• 
“…for which potential benefits of anticoagulation therapy to prevent recurrence of VTE are felt 
by the treating physician to exceed the potential harms” – this judgment will be made by the 
treating physician in each patient’s case.  All anticoagulation strategies used in the course of the 
study should be used in accordance with FDA-labeling and clinical judgment. 
• 
Patients being treated prophylactically with anticoagulants are eligible. 
• 
Patients being treated with anticoagulants at a sub-therapeutic level (i.e., intermediate intensity or 
intermediate dosing) are eligible. 
• 
Patients who have been on standard (i.e., full) intensity anticoagulation and get a new clot are not 
eligible. 


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Criterion 4.2.3: 
NCI CTCAE v4.0 Bleeding (Hemorrhage) Grades:  
0=None 
1=Mild; intervention not indicated 
2= Moderate symptoms; medical intervention or minor cauterization indicated  
3= Transfusion, radiologic, endoscopic, or elective operative intervention indicated  
4= Life-threatening consequences; urgent intervention indicated 
[5=Death] 
 
Criterion 4.2.5: 
• 
Participants may be receiving fluconazole at the time of study enrollment. 
 
Criterion 4.2.6: 
• 
Contraindications include, but are not limited to: ongoing/active bleeding, very low platelet 
count, large brain metastases, etc.), or any condition that as judged by the treating physician 
would place the subject at increased risk of harm if s/he participated in the study.  Weblinks to the 
FDA drug labels for the anticoagulation drugs used in this study can be found in the protocol. 
 
5.0 
SITE ACTIVATION 
In order to open this study at your site, please complete the following steps: 
 Step 1: Notify Alliance Foundation Trials (AFT) that your site is interested in opening 
the CANVAS Trial (AFT-28) by emailing CANVAS@AllianceFoundationTrials.org.   
 Step 2: AFT will email you a Site Information Sheet (SIS) for you to complete. 
 Step 3: Send the completed Site Information Sheet to 
CANVAS@AllianceFoundationTrials.org.   
 Step 4: Once AFT receives your site’s completed Site Information Sheet, AFT will send 
you a start-up package that will include information on the following: 
 Protocol and Protocol Signature page 
 ICF template (Model Informed Consent Form) 
 FDA Form 1572 template  
 REDCap user agreement 
 Information about how to: 
 You will receive an invitation from Wingspan to access the system.  Log 
into and use your Site Zone account (This is the “electronic Trial 
Management File” application where you will upload and submit the 
required documents for site activation for this study.  This is also where 


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you’ll find the most up-to-date study documents, such as protocol, model 
informed consent form, tip sheets, etc.) 
 Watch the Virtual Protocol Training (This is where study staff will 
watch the protocol training online video; no in-person SIV required by 
sponsor.) 
 Log into and use your REDCap account (This is where you will 
enroll/randomize patients and enter all study data/case report forms.) 
 Step 5: Obtain IRB Approval. This can be done in one of two ways:  
 Option 1: Use the Alliance Foundation Trials (AFT) Central IRB as your site’s 
IRB of record for this study [AFT will be using Quorum as the CIRB vendor for 
this study] --OR-- 
 Option 2: Submit this protocol to your site’s institutional IRB 
 If you modify the required language found in the Model Informed 
Consent Form (Model ICF), you must submit a tracked-changes version 
of your local Informed Consent Form to 
CANVAS@AllianceFoundationTrials.org for review and approval 
prior to IRB submission.   
 If you do NOT modify the required language found in the Model 
Informed Consent Form (Model ICF), you still need to submit it to 
CANVAS@AllianceFoundationTrials.org for review and approval 
prior to IRB submission.  
 Please note: the Model Informed Consent Form (Model ICF) does not 
allow Legally Authorized Representatives to sign consent on behalf of a 
participant.  In order to participate, a participant must be able to sign on 
his/her own behalf.  
 Please note: the Model Informed Consent Form (Model ICF) is now 
available in Spanish.  Additional information for your site regarding the 
Spanish-language ICF: 
• 
Your site may use the Model ICF in Spanish; however, if your 
site requires additional translation of any language found in your 
local ICF, AFT is not able to provide your site with any 
additional funds to pay for the translation of your local ICF.   
• 
If your site has an established procedure whereby Spanish-
language participants can be consented via the use of a Spanish-
language short form plus an English-language long form plus 
involvement of an interpreter, then this method is acceptable.  
Any fees associated with the use of an interpreter will be at your 


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site’s expense.  Your site is not mandated to use the Spanish-
language long-form ICF. 
 Step 6: Complete the required study training: 
To complete the required protocol training, each individual listed on the Delegation 
of Authority Log must:  
 Watch the Protocol Training online video available here:  
• 
The training for study staff can be found here (15-minute video): 
https://vimeo.com/310853060/83ed78f342  
 
• 
The training for physicians can be found here (9-minute video): 
https://vimeo.com/310855828/43624a2713  
 Step 7: Upload all of the following forms and documents into your Site Zone account: 
 IRB approval memo  
 IRB approved informed consent form 
 Protocol Signature page signed by the Site PI 
 Delegation of Authority log 
 Completed and Signed FDA Form 1572 (from Site PI only; site sub-investigators 
who will be consenting and treating patients on this trial should be listed on the 
Site PI’s FDA Form1572) 
 Human subject research training for the PI  
 The following are required for your site Principal Investigator  
 CV (curriculum vitae) signed and dated within 3 years 
 Step 8: Once all requirements above have been met, your site will receive a Site 
Activation Memo. Your site cannot consent and enroll patients into the CANVAS (AFT-
28) study without this memo. 
 
 
6.0 
PATIENT ENROLLMENT AND RANDOMIZATION PROCEDURES 
In order to enroll and randomize a participant, site staff should complete the following steps: 
 Ensure all eligibility criteria have been met within the protocol stated timeframes (the 
Eligibility Checklist/Enrollment Form can be found here: 
https://redcap.partners.org/redcap/).  
 Ensure patient has signed an appropriate informed consent form (ICF) and HIPAA 
authorization form. (At some sites, the ICF and HIPAA authorization are two separate 
documents each requiring participant signature.  At other sites, the HIPAA 
authorization is contained within the ICF, so only the ICF requires participant 
signature). 


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Sites will enroll participants to this study using REDCap.  To enroll a participant, follow these steps: 
 Log into https://redcap.partners.org/redcap/. 
➢ If you have problem with or questions about REDCap, please contact the Central 
Study Coordinator at 617-632-4490 or 
CANVAS_Coordinator@dfci.harvard.edu. 
 Click on the “My Projects” tab. 
 Click the project link titled: “CANVAS Trial (AFT-28).” 
 In the menu on the left-hand side of the screen, click on “Add / Edit Records”. 
 In the middle of the page, click on “Add new record”. 
 Fill out the Eligibility Checklist/Enrollment Form. 
 Toward the end of the Eligibility Checklist/Enrollment Form, click the button that 
says “Randomize”. 
 Immediately after clicking “Randomize”, a box will pop up that tells you to which 
arm the participant was randomized. 
 Click “Save Record” at the bottom of the Eligibility Checklist/Enrollment Form. 
 Immediately after saving the record, be sure to notify the participant’s Treating 
Physician of: 
a) The participant’s unique study ID number 
b) The study arm to which the participant has been randomized  
** If you need expedited assistance during normal business hours (M-F, 8a-4p EST), please 
contact the Central Study Coordinator at 617-632-4490 or 
CANVAS_Coordinator@dfci.harvard.edu. 
 
 


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6.1 
Stratification Factors and Treatment Assignments 
 
6.1.1 
Stratification Factors – None 
 
6.1.2 
Treatment Assignments 
 
Participants will be randomized 1:1 to either 
• 
ARM 1 – Intervention Arm, DOAC (choice of rivaroxaban, apixaban, 
edoxaban, or dabigatran) 
• 
ARM 2 – Usual Care Arm, LMWH/warfarin (choice of LMWH with or 
without a transition to warfarin) 
 
If an eligible participant is offered randomization and declines randomization**, then a 
limited number of participants (up to N=190) will be allowed to enroll in the Preference 
Cohort.  In this case, the treating physician and patient will choose protocol treatment on 
Arm 1 or Arm 2 (non-randomized).** 
 
 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The 
preference cohort is CLOSED to new enrollment. 
 
See Treatment Plan/Intervention section for details regarding protocol treatment. 


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7.0 
SCHEDULE OF ASSESSMENTS  
 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of cancer 
patients on this trial.  
 
 
Prior to 
Enrollment 
(< 7 days prior 
to enrollment) 
Baseline 
(After participant 
signs informed 
consent but 
before protocol 
treatment begins) 
2-weeks after 
enrollment  
(+/- 2 weeks) 
3-months after 
enrollment  
(+/- 1 month) 
6-months after 
enrollment  
(+/- 1 month) 
Tests & 
Observations  
- 
Tests & observations are not required per protocol; conduct test & 
observations (e.g., history, physical, etc.) as needed to provide appropriate, 
standard care. 
Routine adverse 
event reporting 
- 
 Routine adverse event reporting is not required per protocol; conduct 
adverse event assessments as needed to provide appropriate, standard care.   
Expedited serious 
adverse event 
(SAE) 
reporting, see 
Adverse 
Events 
Section 
- 
For this study, SAE requiring expedited reporting is defined as: 
ALL adverse events that meet the following criteria MUST be reported via 
the Expedited SAE Reporting Form at https://redcap.partners.org: 
1) All deaths on study require expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
2) Any grade 3, 4, or 5 bleeding or hemorrhaging event. 
3) Any AEs that result in blood transfusion(s). 
4) Any thromboembolic event (e.g., VTE, DVT, PE, blood clot, 
thrombosis, or embolism). 
5) Edema, dyspnea, stroke, and/or respiratory failure must be reported 
IF AND ONLY IF related to a thromboembolic event (e.g., VTE, 
DVT, PE, blood clot, thrombosis, or embolism). 
6) All other events do NOT need to be reported as expedited SAEs. 
 
Laboratory 
Studies+ 
 Platelet count 
>50,000 per 
mm3 
 CrCl > 15 
ml/min as 
calculated by 
the Cockcroft-
Gault method 
 Measure 
albumin (not an 
eligibility 
criteria, but 
should be 
recorded) 
 Lab studies are not required per protocol; conduct lab studies as needed to 
provide appropriate, standard care (e.g., if a participant receives warfarin, 
conduct routine blood monitoring per standard-of-care). 
 Making note of the following types of lab studies in the participant’s medical 
record is recommended but not required: hepatic, renal, platelet counts, CBC 
[complete blood count], red cell count, etc. 
Table continued on the next page 
 
 


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Table continued from the previous page  
 
Prior to 
Enrollment 
(< 7 days prior 
to enrollment) 
Baseline 
(After participant 
signs informed 
consent but 
before protocol 
treatment begins) 
2-weeks after 
enrollment  
(+/- 2 weeks) 
3-months after 
enrollment  
(+/- 1 month) 
6-months after 
enrollment  
(+/- 1 month) 
Case Report 
Forms (CRFs) to 
be completed by 
sites 
- 
Eligibility 
Checklist/ 
Enrollment Form 
Treatment Status 
Update Form 
- 
Medical Record 
Abstraction Form 
CRFs to be 
completed by 
sites OR by 
Central Study 
Coordinator 
- 
Change in Enrollment Status/Off-Study Form (as needed) 
Participant 
Questionnaires 
(see patient-
facing study 
materials ) 
- 
Baseline Study 
Questionnaire 
administered by 
Enrolling Site 
- 
Follow-up Study 
Questionnaire 
administered by 
Central Study 
Coordinator 
Follow-up Study 
Questionnaire 
administered by 
Central Study 
Coordinator 
Patient 
Medication 
Diary^ 
- 
REQUIRED: Participants will keep a monthly patient medication diary while 
on study.  The patient medication diary can be printed directly from the 
protocol appendix and given to the participant (each participant should receive 
6 copies of the diary, one for each month s/he is on study).  The medication 
diary should be returned to the Central Study Coordinator each month.^ 
+ In this pragmatic trial, labs and clinical endpoints collected under routine clinical care will be used for 
eligibility and trial execution.   
 
^ Because this is a pragmatic effectiveness trial whereby the protocol does not mandate monthly study 
visits, extra effort is needed to ensure we successfully collect medication diaries from participants.   There 
are many ways a mediation diary can be collected: 
• 
The patient can return the his/her monthly medication diary directly to the Central Study 
Coordinator each month.  Depending on the patient’s preference, each month s/he may: 
o Email a copy of (or picture of) their diary to CANVAS_Coordinator@dfci.harvard.edu 
o Call their diary into 617-632-4490 
o Mail their diary to CANVAS TRIAL, 450 Brookline Avenue, D-1014, Boston, MA 
02215 
o Fax their diary to 617-394-2801, ATTENTION: CANVAS Coordinator 
o Hand their diary to a member of the study staff at your clinic; the staff member at your 
site can then send the diary to the CANVAS Coordinator via email, phone call, mail, or 
fax. You site may also upload this data directly into REDCap, 
• 
Your site staff must proactively ask participants for their medication diaries following this 
procedure: 
o Contact participant up to three times for drug diaries via in person, phone, email, or 
postal mail.   
o If a participant gives you his/her drug diary, you can send it to the CANVAS Coordinator 
via email, phone call, mail, or fax. 
o If a drug diary is more than three months late after your site staff has made its three 
attempts to contact participants, then the CANVAS Coordinator may contact 
participants for their medication diaries up to three times via any of the following: email, 


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phone call, and/or mail.   If the CANVAS Coordinator is unsuccessful at getting diaries 
from participants after three attempts, then the form will be considered missing.   
Note:  Your site staff are responsible for notifying the CANVAS Coordinator that you 
exhausted your attempts to contact the participant. 
o Patients may report drug diary data orally to sites or central study coordinator, which can 
then be recorded by study staff on a paper diary which may then serve as source 
documentation.  
 
Note about missing forms: 
• 
If any of the following forms are missing for a participant, then this would constitute a major 
protocol violation:  
o Eligibility Checklist/Enrollment Form 
o Treatment Status Update Form 
o Medical Record Abstraction Form 
o Change in Enrollment Status/Off-Study Form (as needed) 
o Expedited Serious Adverse Event (SAE) Reporting Form (as/if needed) 
• 
Protocol violations must be filed after a form is missing for greater than 30 days after the data 
entry window has closed (please refer to Section 7.0 for schedule of assessments). 
 
• 
If any of the following forms are missing for a participant despite best efforts by Central Study 
Coordinator and Site Staff to collect from participant, then this does not constitute a major or 
minor protocol violation:  
o Baseline Study Questionnaire 
o Follow-up Study Questionnaire - 3 months 
o Follow-up Study Questionnaire - 6 months 
o Medication Diary - Month 1 of 6 
o Medication Diary - Month 2 of 6 
o Medication Diary - Month 3 of 6 
o Medication Diary - Month 4 of 6 
o Medication Diary - Month 5 of 6 
o Medication Diary - Month 6 of 6 
 
Note about questionnaires and drug diaries: 
• 
Study questionnaires and patient-reported drug diaries continue through the 6th month no matter 
how long the subject actually received protocol-directed anticoagulation.  
• 
Site study staff should complete the Medical Record Abstraction Form at the end of the 6th 
month no matter how long the subject actually received protocol-directed anticoagulation. 
• 
Because this is a pragmatic effectiveness trial whereby the protocol does not mandate regular 
study visits, drug accountability will be captured via the patient-reported drug 
diaries/questionnaires and the site’s 6-month medical record abstraction. 
 
 
8.0 
STUDY PROCEDURES 
 
 
This section describes the study procedures and data collection procedures for this study.  
 
8.1 
Screen, approach, and obtain informed consent 
 
When a cancer patient is diagnosed with a VTE, s/he should be screened for eligibility. If the 
patient is determined to be eligible, then the site clinician should approach the patients within 30 


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days of the index VTE diagnosis, explain the study, and ask the patient if s/he would like to 
participate. Consent should be obtained by following Health and Human Services (HHS) 
guidelines (http://www.hhs.gov/ohrp/policy/consent/) as well as site-specific policies for 
obtaining informed consent for research. If the patient agrees to participate, the consenting 
physician and the patient will both sign the informed consent form. The original copy of the 
signed informed consent form should be kept in the participant’s study file at the site, and a copy 
should be given to the participant for his/her records.  Informed consent may be obtained in 
inpatient or outpatient care settings. Patients may be invited to participate by phone but in-person 
signed informed consent is a prerequisite to enrollment and randomization. 
 
8.2 
Eligibility Checklist/Enrollment Form 
 
If the participant signs the informed consent document, the study staff at the site should fill out 
the Eligibility Checklist/Enrollment Form and submit it via REDCap (https://redcap.partners.org), 
as described in 9.2 Data Submission using REDCap.   
 
8.3 
Treatment Arm 
 
Participants will be randomized 1:1 to either 
• 
ARM 1 – Intervention Arm, DOAC (choice of rivaroxaban, apixaban, edoxaban, or 
dabigatran) 
• 
ARM 2 – Usual Care Arm, LMWH/warfarin (choice of LMWH with or without a 
transition to warfarin) 
 
If an eligible participant is offered randomization and declines randomization, then a limited 
number of participants (up to N=190) will be allowed to enroll in the Preference Cohort.  In this 
case, the treating physician and patient will choose protocol treatment on Arm 1 or Arm 2 (non-
randomized).** 
 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The preference 
cohort is CLOSED to new enrollment. 
 
See Treatment Plan/Intervention section for details regarding protocol treatment. 
 
For ALL study participants (regardless of treatment arm or cohort), the study procedures 
described in this section of this protocol are applicable and identical. 
 
8.4 
Baseline Study Questionnaire 
 
The Baseline Study Questionnaire will collect: patient-reported ECOG performance status, SF-
12 HR-QOL (the Optum SF-12 Health Survey uses 12 questions to measure functional health and 
well-being from the patient’s point of view), information about the index VTE, cancer type/status, 
co-morbidities, influence of insurance coverage on decision to be participate, and demographics.   
 
It is the enrolling site staff’s responsibility to administer the Baseline Study Questionnaire 
to the participant. 
 
Timing: The Baseline Study Questionnaire must be administered after the participant has signed 
informed consent but before protocol treatment begins.   
NOTE: The Baseline Study Questionnaire can be administered before or after the 
participant has been enrolled/ randomized as long as it is administered after the 


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participant has signed informed consent and before protocol treatment begins. It is 
operationally easiest to administer the Baseline Study Questionnaire immediately after 
the participant signs informed consent.   
 
 
To administer the questionnaire:  
 Print the questionnaire directly from Appendix: Baseline Study Questionnaire – for 
administration via paper 
 Have the participant fill out the paper questionnaire 
 Enter the participant’s responses into REDCap (https://redcap.partners.org) 
 Keep the original questionnaire in the participant’s study file at your site  
It is acceptable for a surrogate to complete the questionnaire on behalf of the patient.  The 
surrogate can be a friend, family member, caregiver, or other appropriate person.  The surrogate 
is NOT a research participant and should complete the questionnaire on behalf of the patient.  No 
information about the surrogate will be collected.   
 
If for any reason, the enrolling site staff is unable to administer the Baseline Study Questionnaire, 
they must notify the Central Study Coordinator immediately so that the Central Study 
Coordinator may attempt to administer the Baseline Study Questionnaire via phone, secure 
weblink, or postal mail.  The Central Study Coordinator can be reached at: 617-632-4490 and/or 
CANVAS_Coordinator@dfci.harvard.edu. 
 
See 9.2 Data Submission using REDCap for instructions on how to enter and submit the data via 
REDCap. 
 
8.5  
Treatment Status Update Form 
 
2-weeks after the participant has been enrolled, the site staff should submit the Treatment Status 
Update Form via https://redcap.partners.org.  The Treatment Status Update Form will ask sites to 
report: (1) whether or not the participant is receiving treatment in accordance with the treatment 
arm to which s/he was assigned (see next paragraph for more information); (2) if yes, which 
anticoagulation drug is the participant receiving; (3) if no, why not (e.g., due to insurance non-
coverage, patient refusal, transfer of care, receive no anticoagulation therapy, other); (4) if no, 
which anticoagulation drug is the participant receiving, if any.  
 
If participant is not receiving treatment in accordance with the treatment arm to which s/he was 
assigned, that is NOT a protocol violation.  Please keep this patient ON STUDY. 
• 
Arm 1: Switching between DOACs is allowed 
• 
Arm 2: Switching between LMWH/warfarin is allowed 
• 
Anticoagulation “breaks” and “gaps” are not protocol violations  
• 
Arm 1: Switching to LMWH is discouraged but is not a protocol violation.  
• 
Arm 2: Switching to DOAC is discouraged but is not a protocol violation 
• 
Record abstraction and medication diaries will ascertain these rates 
 
 
8.6 
Follow-up Study Questionnaires 
 
The Follow-up Study Questionnaire (administered at 3-months post-enrollment and again at 6-
months post enrollment) will collect: patient-reported ECOG performance status, SF-12 HR-
QOL, anticoagulation therapy information including dose and adherence, ACTS anticoagulation 


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therapy burden (the Anti-Clot Treatment Scale (ACTS) is a 15-item patient-reported instrument 
of satisfaction with anticoagulant treatment), VTE recurrence, and bleeding. 
 
It is the Central Study Coordinator’s responsibility to administer the Follow-up Study 
Questionnaires to the participant. 
 
Timing: The Follow-up Study Questionnaire will be administered once at 3-months (+/- 1 
month) after enrollment and once at 6-months (+/- 1 month) after enrollment.   
• 
If a participant has withdrawn consent to participate in the patient questionnaire 
component of this study, then do not administer any additional Follow-up Study 
Questionnaires.  
 
The Central Study Coordinator will contact the participant via phone, internet, and/or postal 
mail depending on participant preferences.   
 
• 
To administer the questionnaire via SECURE WEBLINK: The Central Study 
Coordinator will email the secure, individualized questionnaire link to the participant.  
The participant will enter his/her responses directly into REDCap using the link provided. 
• 
To administer the questionnaire via PHONE: The Central Study Coordinator will follow 
the phone script found in Appendix: Follow-up Study Questionnaire – for administration 
via phone”.  The Central Study Coordinator will enter the participant’s responses into 
REDCap. 
• 
To administer the questionnaire via POSTAL MAIL: The Central Study Coordinator will 
print and mail the paper version of the Follow-up Study Questionnaire along with a 
prepaid return envelope to the participant’s mailing address. The Central Study 
Coordinator will enter the participant’s responses into REDCap, and keep the original 
paper copy in the participant’s central study file. 
 
 
It is acceptable for a surrogate to complete the questionnaire on behalf of the patient.  The 
surrogate can be a friend, family member, caregiver, or other appropriate person.  The surrogate 
is NOT a research participant and should complete the questionnaire on behalf of the patient.  No 
information about the surrogate will be collected.  Each Follow-up Study Questionnaire may be 
completed by the patient himself/herself, by the same surrogate who completed a previous 
questionnaire on the participant’s behalf, or by a different surrogate.  The questionnaire will elicit 
whether the patient completed responses directly or via a surrogate. 
 
A participant will be contacted by the Central Study Coordinator up to 4 times in an attempt to 
complete each Follow-up Study Questionnaire.  If a participant has not responded after 4 
attempts, then the Central Study Coordinator will ask the enrolling site’s staff to attempt contact.  
If the enrolling site’s staff is unable to make contact after 4 attempts, then the questionnaire will 
be marked as missing, and the participant will not be contacted regarding that questionnaire 
again. 
 
Instructions to site: 
If the Central Study Coordinator is unable to contact an enrolled participant being treated at your 
site, the Central Study Coordinator will notify you by phone and email and ask for your 
assistance in contacting the participant.  If the participant has an upcoming clinic visit, the Central 
Study Coordinator may ask you to administer the Follow-up Study Questionnaire in-person.  
Your assistance is greatly appreciated! 
 


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After the participant/surrogate completes each Follow-up Study Questionnaire, the Central Study 
Coordinator will email or mail him/her (depending on the respondent’s preferences) a $25.00 
Amazon.com gift card. 
 
 
 
8.7 
Medical Record Abstraction  
 
At six months after enrollment (or at the time of the participant’s death, whichever occurs first), 
the site will conduct and submit the Medical Record Abstraction Form via REDCap.  The 
information needed to fill out the Medical Record Abstraction Form can be found in the 
participant’s medical record. 
 
The Medical Record Abstraction Form will collect the following types of information: 
• 
Demographics (age at diagnosis, current age, gender, race, ethnicity, marital status) 
• 
Clinician-reported ECOG performance status 
• 
Height, weight, BMI (body mass index) 
• 
Tobacco history (current use/former use/never use and pack year history) 
• 
Comorbidities using the Katz scale 
• 
VTE type, location, presentation, history 
• 
Tumor site, histology, and metastatic sites of disease 
• 
Presence of brain metastases 
• 
Lab Values (hepatic, renal, platelet counts, CBC [complete blood count], red cell count)  
• 
Other treatment types (hormone, chemo, surgery, radiation) 
• 
Bleeding, recurrent VTE, survival 
• 
Anticoagulation therapy selection, doses, modifications 
• 
Medication history during time on study. 
 
8.8 
Change in Enrollment Status/Off-Study Form 
 
Whenever there is a change in a participant’s enrollment status, the Change in Enrollment 
Status/Off-Study Form should be completed and submitted via REDCap 
(https://redcap.partners.org) within 1 week of the change.  A Change in Enrollment Status/Off-
Study Form can be submitted by the site or by the Central Study Coordinator. 
 
Reasons a participant might have a change in enrollment status or go off-study include: 
1. STUDY COMPLETE: Participant is being taken off study because s/he has reached the 
end of the 6-month study period. 
2. ACTIVE PARTICIPANT WITHDRAWAL: Study participant actively withdrew consent 
for one or more components of the study, including: 
a. protocol treatment, and/or 
b. participant questionnaires, and/or 
c. participant medication diaries, and/or 
d. access to his/her medical record for Medical Record Abstraction. 
HOW TO PROCEED: Unless the participant explicitly (and preferably in writing) 
withdraws consent to access his/her medical record, site study staff SHOULD 
complete the Medical Record Abstraction Form 6-months after the participant was 
enrolled. 
3. CLINICIAN WITHDRAWAL: Clinician took participant off protocol treatment. Please 
note that after taking a subject off protocol treatment, study questionnaires and patient-


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reported drug diaries continue through the 6th month. Site study staff should complete the 
Medical Record Abstraction Form at the end of the 6th month no matter how long the 
subject actually received protocol-directed anticoagulation.  
4. LOST TO FOLLOW-UP: Study participant is lost to follow-up. The site staff should still 
complete the Medical Record Abstraction Form 6-months after the participant was 
enrolled. 
5. DEATH: If a study participant dies, the site staff should complete the Medical Record 
Abstraction Form, then complete a change of enrollment/off-study form in REDCap If 
the central study coordinator is informed of a participant’s death in real time during a 
touch for a Follow-Up Study Questionnaire, a surrogate may complete the survey. 
Surrogates may not be contacted directly for Follow-Up Study Questionnaires. 
6. FOUND TO BE INELIGIBILE: Participant was enrolled on the trial but was later found 
to be ineligible. Select one: 
a. Yes, protocol treatment will continue [treating physician, study chair, and 
executive officer agree there are no safety concerns if the patient continues 
protocol treatment]. 
b. No, protocol treatment will not continue [in this case, study questionnaires and 
patient-reported drug diaries continue through the 6th month. Site study staff 
should complete the Medical Record Abstraction Form at the end of the 6th 
month no matter how long the subject actually received protocol-directed 
anticoagulation]. 
7. OTHER: Please specify. 
 
8.9 
Managing ineligible patients and registered patients who never receive protocol 
intervention 
 
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may continue protocol treatment, provided the treating physician, study chair, and executive 
officer agree there are no safety concerns if the patient continues protocol treatment. Notification 
of the local IRB and/or Central IRB may be necessary per local/central IRB policies. 
 
Study participants who are registered to the trial but never receive study intervention (for a reason 
other than because they were deemed ineligible) should still complete all follow-up requirements: 
the Medical Record Abstraction (done by the site) and the 3 participant study questionnaires (at 
baseline, 3-months, and 6-months) and the patient-reported drug diaries.  Data will be analyzed 
using the intention to treat cohortin sensitivity analyses 
 
8.10  
Notice regarding proprietary content embedded in the patient questionnaires 
 
Two validated, proprietary instruments are embedded in the patient questionnaires for this study: 
 
1. SF-12 - The Optum™ SF-12v2® Health Survey uses 12 questions to measure functional 
health and well-being from the patient’s point of view.  The SF-12 shall be and remain at 
all times the property of Optum. 
 
2. ACTS - The Anti-Clot Treatment Scale (ACTS) is a 15-item patient-reported instrument 
of satisfaction with anticoagulant treatment. It includes a 12-item ACTS Burdens scale 
and a 3-item ACTS Benefits scale.  The ACTS shall be and remain at all times the 
property of Bayer Pharma AG, as licensed by Mapi Research Trust.32   


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a. ACTS Author: Stefan Cano and Donaa Lamping with a research grant provided 
by Bayer Pharma AG 
b. ACTS Owner: Bayer Pharma AG 
c. ACTS Copyright notice: ACTS © Bayer AG, 2006. All Rights Reserved. 
d. ACTS References: 32 The Anti-Clot Treatment Scale (ACTS) in clinical trials: 
cross-cultural validation in venous thromboembolism patients. Heath Qual Life 
Outcomes. 2012 Sep 26; 10:120. 
 
AFT-approved and activated sites may use and administer the Survey Materials at their site, only 
on behalf of AFT, only during the Study term, and only for the Approved Purpose (as outlined in 
this protocol).  Sites may not use the Survey Materials for any other purpose, including but not 
limited to reproducing, copying, modifying, or distributing the licensed survey content without 
the owner’s consent.  See Appendix for more information.   
 


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9.0 
DATA COLLECTION AND SUBMISSION 
 
9.1 
Summary of data collection and submission: 
 
 
 
Data collected from site 
 
 
Data collected from participant 
Timing 
Case Report 
Form (CRF) 
How to collect & 
submit data 
Name of 
Assessment 
How to collect & 
submit data 
At time of 
enrollment  
(after patient signs 
informed consent but 
before protocol 
treatment begins) 
Eligibility 
Checklist/ 
Enrollment 
Form  
➢Submit 
electronically via 
REDCap, detailed 
instructions in section 
9.2 
Baseline 
Study 
Questionnaire  
➢Administered by 
enrolling site staff  
➢Filled out by the 
participant and/or their 
surrogate 
➢Responses entered into 
REDCap by site staff  
2-weeks post 
enrollment 
Treatment Status 
Update Form 
➢Submit 
electronically via 
REDCap 
- 
- 
3-months post 
enrollment 
- 
- 
Follow-up 
Study 
Questionnaire 
 
➢Administered by the 
Central Study Coordinator  
➢Filled out by the 
participant and/or their 
surrogate (respondent 
given $25 gift card upon 
completion) 
➢Responses entered into 
REDCap by Central Study 
Coordinator 
6-months post 
enrollment 
Medical Record 
Abstraction 
Form 
➢ Medical record 
abstraction (i.e., chart 
review) conducted by 
site staff 
➢Entered into 
REDCap by site staff 
Follow-up 
Study 
Questionnaire 
 
➢Administered by the 
Central Study Coordinator  
➢Filled out by the 
participant and/or their 
surrogate (respondent 
given $25 gift card upon 
completion) 
➢Responses entered into 
REDCap by Central Study 
Coordinator 
Ongoing, as needed 
(from enrollment 
through off-study) 
Expedited 
Adverse Event 
Reporting 
 
 
 
Change in 
Enrollment 
Status/Off-Study 
Form 
➢Entered into 
REDCap by site staff 
when a reportable 
event occurs, see 
section 12 for details 
 
➢Entered into 
REDCap by site staff 
or Central Study 
Coordinator whenever 
a change in participant 
status occurs, see 
section 8.8 for 
details 
- 
- 


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9.2 
Data Submission using REDCap 
 
Sites will use REDCap to: (a) enroll and randomize participants, (b) submit case report forms 
(CRFs), and (c) conduct Expedited Adverse Event Reporting for this study.   
 
To enroll and randomized participants via REDCap, see the instructions found in Section 6.0. 
 
To enter and submit case report forms and to conduct Expedited Adverse Event Reporting via 
REDCap, follow these steps: 
 Log into https://redcap.partners.org. 
➢ If you have problem with or questions about REDCap, please contact the Central 
Study Coordinator at 617-632-4490 or 
CANVAS_Coordinator@dfci.harvard.edu. 
 Click on the “My Projects” tab. 
 Click the project link titled: “AFT-28: CANVAS Trial.” 
 In the menu on the left-hand side of the screen, click on “Add / Edit Records” 
 From the dropdown menu, select the Study ID Number for the participant of interest. 
 In the menu on the left-hand side of the screen, click on the name of the CRF you would 
like to edit. 
 When done entering data, scroll down and click “Save Record” at the bottom of the form. 


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10.0 
DRUG INFORMATION 
 
10.1 
General Considerations 
 
All drugs used in this study are commercially available, FDA-approved, and are being prescribed 
on-label.  This study does not involve any investigational new drugs/agents/devices (no INDs). 
 
This study will NOT provide any drugs because all drugs used in this study are commercially 
available, FDA-approved, and are being prescribed on-label.  Drugs should be prescribed per 
standard practice at your site and billed to the patient's insurance company or the patient as your 
sites does for any other standard medication. 
 
If a patient is assigned to a treatment and unable to receive that treatment as a result of insurance 
coverage issues, this should be recorded. 
 
10.2 
Drug Information 
 
FDA Package Inserts: 
Generic name 
 
Brand name 
Drug class 
Link to FDA Package Insert^ 
• 
How supplied & storage: Section 16 of 
package insert 
• 
Administration: Section 2 
• 
Drug interactions: Section 7 
• 
Pharmacokinetics: Section 12.3 
• 
Adverse reactions: Section 6 
 
ARM 1 – Intervention Arm, DOAC 
Rivaroxaban 
Xarelto® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/022406s023lbl.pdf  
Apixaban 
 
Eliquis® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2018/202155s020lbl.pdf  
Edoxaban 
Savaysa® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/206316s012lbl.pdf  
Dabigatran 
Pradaxa® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2018/022512s035lbl.pdf  
ARM 2 – Usual Care Arm, LMWH/warfarin 
Dalteparin 
Fragmin® 
LMWH 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/020287s069lbl.pdf 
 
Enoxaparin 
Lovenox® 
LMWH 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/020164s110lbl.pdf  
Fondaparinux 
Arixtra® 
Indirect Xa 
inhibitor 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/021345s035lbl.pdf  
Warfarin 
Coumadin® 
Vitamin K 
antagonist 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/009218s118lbl.pdf  
^Links to FDA Package Inserts are included here for easy reference; however, if the FDA Package 
Insert/Safety Labeling changes, you are required to use the most up-to-date FDA Package Insert/Safety 
Label. 
 


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11.0 
TREATMENT PLAN/INTERVENTION 
 
11.1  
Overview of treatment plan 
 
 
 
 
 
 
 
 
 
 
 
 
1. Diagnosis of index VTE 
2. Treat index VTE (any anticoagulation drug/strategy may be used to treat the index VTE; this is 
not part of the study) 
3. Study enrollment and randomization (must occur within 30 days of the index VTE 
diagnosis). 
4. Switch from therapy to treat the index VTE (not part of study) to anticoagulation therapy 
intended to prevent recurrent VTE (i.e., protocol treatment).  Begin protocol treatment < 14 
days after enrollment. 
➢ If participant consented to randomization, treat according to the arm to which the 
participant was randomized, either: Randomized Arm 1 or Randomized Arm 2. 
➢ If participant did not consent to randomization, treat according to the arm that the 
participant and his/her treating physician chose, either: Non-Randomized Arm 1 or 
Non-Randomized Arm 2** 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The 
preference cohort is CLOSED to new enrollment. 
5. Six months after the participant is enrolled, protocol treatment ends; After protocol treatment 
period ends, continue or discontinue anticoagulation therapy according to individual 
institutional guidelines and the best clinical judgment of the responsible physician. Record 
the decision. 
 
 
 
Regardless of protocol treatment arm and/or anticoagulation drug(s) used, treat the patient 
according to individual institutional guidelines, the best clinical judgment of the responsible 
physician, and in consultation with national treatment guidelines and the drug’s package insert. 
Administer Protocol Treatment 
Treat index VTE 
Index VTE 
Diagnosis 
Enroll/Randomize 
(< 30 days after 
index VTE 
diagnosis) 
Off-Study 
(6-months after 
study enrollment) 
Off-study; physician and 
patient decide whether to 
continue or discontinue 
anticoagulation therapy 
Begin Protocol Treatment 
(< 14 days after enrollment) 


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11.2  
Protocol Treatment 
 
Protocol treatment should commence < 14 days after date of enrollment. 
 
Protocol Treatment Arms: 
 
Participants will be randomized 1:1 to either 
• 
ARM 1 – Intervention Arm, DOAC (choice of rivaroxaban, apixaban, edoxaban, or 
dabigatran) 
• 
ARM 2 – Usual Care Arm, LMWH/warfarin (choice of LMWH with or without a 
transition to warfarin) 
 
If an eligible participant is offered randomization and declines randomization, then a limited 
number of participants (up to N=190) will be allowed to enroll in the Preference Cohort.  In this 
case, the treating physician and patient will choose protocol treatment on Arm 1 or Arm 2 (non-
randomized).** 
 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The preference 
cohort is CLOSED to new enrollment. 
 
10.2.1 ARM 1 – Intervention Arm, DOAC 
For all participants in ARM 1 – Intervention Arm, DOAC, the treating physician and 
participant should choose anticoagulation therapy with Rivaroxaban (Xarelto), Apixaban 
(Eliquis), Edoxaban (Savaysa), or Dabigatran (Pradaxa). 
 
10.2.2 ARM 2 – Usual Care Arm, LMWH/warfarin: 
For all participants in ARM 2 – Usual Care Arm, LMWH/warfarin, the treating 
physician and participant should choose anticoagulation therapy with Warfarin 
(Coumadin); Dalteparin (Fragmin); Enoxaparin (Lovenox); or Fondaparinux (Arixtra). 
 
11.3 
Selecting an Anticoagulant 
 
11.3.1 Practice Guidelines  
When selecting an appropriate anticoagulant for the participant, please refer to standard 
practice guidelines, some of which are provided here for easy reference: 
 
➢ National Comprehensive Cancer Network (NCCN) Guidelines: Cancer-
Associated Venous Thromboembolic Disease15 
Available at: https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf 
 
➢ American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines 16 
Available at: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278055/pdf/112295.pdf  
 
 


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➢ European Society for Medical Oncology Clinical Practice Guidelines 
17 
Available at: 
http://annonc.oxfordjournals.org/content/22/suppl_6/vi85.full.pdf+html  
 
➢ American Thoracic Society (ATS) - Statements, Guidelines & Reports 
Available at: https://www.thoracic.org/statements/  
 
➢ The American Society of Hematology (ASH) - ASH Clinical Practice 
Guidelines  
Available at: http://www.hematology.org/Clinicians/Guidelines-
Quality/Guidelines.aspx  
 
➢ American Society of Clinical Oncology (ASCO) Guidelines, Tools, & 
Resources 33 
Available at: https://www.asco.org/practice-guidelines/quality-
guidelines/guidelines  
 
33Available at: http://jco.ascopubs.org/content/33/6/654.full.pdf+html  
 
➢ Up to DateTM and ClinicalKeyTM are for-profit content developers to which 
many clinicians subscribe. 
 
 
 


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11.3.2  FDA Package Inserts  
 
When selecting an appropriate anticoagulant for the participant, please also refer to the 
drug(s) FDA Package Inserts, provided here for easy reference: 
 
Generic name 
 
Brand name 
Drug class 
Link to FDA Package Insert^ 
• 
How supplied & storage: Section 16 of 
package insert 
• 
Administration: Section 2 
• 
Drug interactions: Section 7 
• 
Pharmacokinetics: Section 12.3 
• 
Adverse reactions: Section 6 
 
ARM 1 – Intervention Arm, DOAC 
Rivaroxaban 
Xarelto® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/022406s023lbl.pdf  
Apixaban 
 
Eliquis® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2018/202155s020lbl.pdf 
Edoxaban 
Savaysa® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/206316s012lbl.pdf  
Dabigatran 
Pradaxa® 
DOAC 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2018/022512s035lbl.pdf   
ARM 2 – Usual Care Arm, LMWH/warfarin 
Dalteparin 
Fragmin® 
LMWH 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/020287s069lbl.pdf 
 
Enoxaparin 
Lovenox® 
LMWH 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/020164s110lbl.pdf  
Fondaparinux 
Arixtra® 
Indirect Xa 
inhibitor 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/021345s035lbl.pdf 
Warfarin 
Coumadin® 
Vitamin K 
antagonist 
https://www.accessdata.fda.gov/drugsatfda_docs/labe
l/2017/009218s118lbl.pdf 
^Links to FDA Package Inserts are included here for easy reference; however, if the FDA Package 
Insert/Safety Labeling changes, you are required to use the most up-to-date FDA Package Insert/Safety 
Label. 
 


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11.4 
Protocol treatment administration - Dosing 
 
For complete dosing information, please review the FDA package inserts.  The dosing 
information (pulled directly from the FDA package inserts) for each of the LMWH, warfarin, or 
DOAC drugs is provided here for quick reference. Review recommendations for converting to or 
from other oral or parenteral anticoagulants. Temporarily discontinue before invasive or surgical 
procedures when possible, then restart when feasible. Interruptions in anticoagulation do NOT 
constitute protocol violations. Treatment actually administered and breaks in treatment should be 
recorded on the Medical Record Abstraction Form. Monitoring for patients on anticoagulation 
therapy should be as per local management protocols. Patients on warfarin receiving 
chemotherapy should have their INR checked once per week. Patients with stable INR not 
receiving chemotherapy may have their INR checked every other week. All patients irrespective 
of anticoagulation strategy should be instructed to call their physicians with new bleeding or 
evidence of recurrent VTE.  
 
Dosing Summary Table  
Drug 
 
Dosing Summary^ (for complete dosing information, please review standard practice 
guidelines and FDA package insert) 
ARM 1 – Intervention Arm, DOAC 
Rivaroxaban 
Treatment of DVT:  
• 
Initial treatment of VTE is 15 mg bid x 21 days. If patient has completed 21 days of other 
anticoagulant treatment then use 20 mg qd. If treatment with other anticoagulant has started, 
use rivaroxaban at 15 mg bid to complete 21 days then transition to 20 mg qd. 
• 
Orally, take 15 mg and 20 mg tablets with food; take 10 mg tablets with or without food. 
• 
Avoid if creatinine clearance (CrCl) ≤ 30 mL/min 
• 
Dose modify or avoid in hepatic failure 
• 
If a dose is not taken at the scheduled time, administer the dose as soon as possible on the 
same day. 
Apixaban 
 
• 
Initial treatment of VTE dose is 10 mg bid x 7 days, then transition to 5 mg bid. If patient has 
completed 7 days of treatment with another anticoagulant, then use 5 mg bid; otherwise, use 
10 mg bid to complete 7 days of anticoagulant treatment before switching to 5 mg bid. 
• 
In patients with at least 2 of the following characteristics: age >=80 years, body weight <=60 
kg, or serum creatinine >=1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily.  
[For patients who require a decreased dose of Apixaban the suggested dosing is seven 
days of 5 mg bid followed by 2.5 mg bid for duration of treatment.] 
• 
Dose modify or avoid in hepatic failure 
• 
If a dose is not taken at the scheduled time, the dose should be taken as soon as possible on 
the same day [the missed dose should be skipped if it cannot be taken at least 6 hours before 
the next scheduled dose] and twice daily administration should be resumed.  The dose should 
not be doubled to make up for a missed dose. 
Edoxaban 
Treatment of DVT and PE: 
• 
Requires 5 days of treatment with a parenteral agent before initiating edoxaban for VTE 
treatment 
• 
The recommended dose is 60 mg once daily 
• 
The recommended dose is 30 mg once daily for patients with CrCL 15 to 50 mL/min or body 
weight less than or equal to 60 kg or who use certain P-gp inhibitors 
• 
No dose modification for hepatic failure 
• 
If a dose is missed, the dose should be taken as soon as possible on the same day.  Dosing 
should resume the next day according to the normal dosing schedule.  The dose should not be 
doubled to make up for a missed dose. 


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Table continued from the previous page 
Drug 
 
Dosing Summary^  
(for complete dosing information, please review the FDA package insert) 
Dabigatran 
• 
Requires 5 days of treatment with a parenteral agent before initiating dabiagtran for VTE treatment  
• 
For patients with CrCl >30 mL/min: 150 mg orally, twice daily  
• 
For patients with CrCl 15-30 mL/min: 75 mg orally, twice daily  
• 
No dose modification for hepatic failure 
• 
Instruct patients not to chew, break, or open capsules  
• 
If a dose is not taken at the scheduled time, the dose should be taken as soon as possible on the same 
day.  The missed dose should be skipped if it cannot be taken at least 6 hours before the next 
scheduled dose.  The dose should not be doubled to make up for a missed dose. 
ARM 2 – Usual Care Arm, LMWH/warfarin 
Dalteparin 
Treatment of VTE in patients with cancer:  
• 
Month 1: 200 IU/kg subcutaneous once daily 
• 
Months 2 - 6: 150 IU/kg subcutaneous once daily 
• 
For missed doses: patients should inject the missed dose as soon as they remember. However, if it is 
almost time* for the next dose, skip the missed dose and continue regular dosing schedule.  Patients 
should not inject a double dose to make up for a missed one. 
Enoxaparin 
Treatment of DVT: 
 
• 
1 mg/kg sc bid (preferred) 
• 
Alternative dosing 1.5 mg/kg sc qd is acceptable 
• 
For missed doses: patients should inject the missed dose as soon as they remember. However, if it is 
almost time* for the next dose, skip the missed dose and continue regular dosing schedule.  Patients 
should not inject a double dose to make up for a missed one. 
Fondaparinux 
Treatment of deep vein thrombosis (DVT):  
• 
Weight < 50 kg 5 mg sc qd 
• 
Weight 50-100kg 7.5 mg sc qd 
• 
Weight > 100 kg 10 mg sc qd  
• 
For missed doses: if participants miss a dose, they should take their dose as soon as they remember.  
They should not take 2 doses at the same time. 
Warfarin 
• 
Individualize dosing regimen for each patient, and adjust based on INR response.  
• 
Review conversion instructions from other anticoagulants. 
• 
The anticoagulant effect of warfarin persists beyond 24 hours.  If a patient misses a dose of warfarin 
at the intended time of day, the patient should take the dose as soon as possible on the same day.  
The patient should not double the dose the next day to make up for a missed dose.  
sc = subcutaneous; qd = daily; bid = twice daily 
^The CANVAS protocol does not mandate doses so clinicians should prescribe a dose that they feel is in 
the best interest of the patient. Dose modifications are not protocol violations.  Study chair Jean Connors 
is available to discuss individual patient level dosing if needed. 
*Regarding “almost time for the next dose:” The package inserts/full prescribing information does not 
provide any more detail on this issue.  Decisions regarding “almost time for the next dose” are at the 
treating clinician’s discretion.  In general: 
• 
If a patient is prescribed an injection once per day, then: if a patient misses a dose at the 
intended time of day, they should take the dose as soon as possible on the same day.  The patient 
should not double the dose the next day to make up for the missed dose. 
• 
If a patient is prescribed an injection twice per day (i.e., once every 12-hours), then: if a patient 
misses a dose at the intended time of day, the patient should take the dose as soon as possible 
unless his/her next schedule dose time is in ≤6 hours.  If his/her next scheduled dose time is in ≤6 
hours, then skip the missed dose and resume with the next scheduled dose. 


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11.4.1 Additional dosing considerations – ARM 1 - Intervention Arm, DOAC: 
The DOACs have different initial dosing strategies that should be understood. Dosing is 
based on the time after diagnosis of the index VTE. All patients should be treated with 
full intensity at time of index VTE diagnosis unless significant contraindications exist. 
• 
Dabigatran and edoxaban: at least 5 days of a parenteral agent which can be 
any of the LMWH agents or intravenous heparin are required for initial treatment 
followed by a switch to dabigatran or edoxaban.  
• 
Rivaroxaban: the dose of 15 mg BID is used for the first 21 days after VTE 
diagnosis, followed by change in dose to 20 mg once daily. If participants have 
had 21 days or more of LMWH therapy prior to enrollment/initiation they may 
initiate rivaroxaban at the 20 mg qd dose. If participants have had fewer than 21 
days of LMWH at initiation they should receive treatment at the initial (acute 
dose) to complete 21 days total before switching to 20 mg qd. 
• 
Apixaban: 10 mg bid is used for the first week of treatment after VTE diagnosis 
followed by 5 mg BID. If participants have had 7 days of LMWH therapy prior 
to randomization they may initiate apixaban at the 5mg bid dose, if treatment has 
not been for 7 days then use 10 mg bid to complete 7 days before switching to 5 
mg bid. 
sc = subcutaneous; qd = daily; bid = twice daily 
 
 
 
 
Decisions regarding vomited doses are at the treating clinician’s discretion.  In general, if 
a patient can see the undigested pill in their vomit, then the vomited dose can be treated 
like a missed dose.  If the patient vomits more than 1 hour after taking the dose, then the 
dose should not be made up.  
 
Table: Renal Insufficiency Dose: Initial and Chronic Treatment of VTE  
The table details initial dosing and chronic dosing suggestions in the setting of normal and abnormal renal 
function. Please refer to package inserts and local guidelines for details. Deviations and rounding do not 
constitute protocol violations. 
ARM 1 – Intervention Arm, DOAC 
CrCl 
mL/min 
Rivaroxaban 
Apixaban 
Edoxaban* 
Dabigatran* 
Normal 
Renal 
Function 
> 50  
Initial: 15 mg bid x 
3 weeks 
Chronic: 3 week, 20 
mg qd  
Initial: 10 mg bid x 
1 week 
Chronic: 5 mg bid  
Initial: LMWH x 5 
days 
Chronic: 60 mg qd  
Initial: LMWH x 5 
days 
Chronic: 150 mg bid  
30-49  
Initial: 15 mg bid x 
3 weeks 
Chronic: 20 mg qd 
Initial: 10 mg bid x 
1 week 
Chronic: 5 mg bid 
Initial: LMWH x 5 
days 
Chronic: 30 mg qd  
Initial: LMWH x 5 
days 
Chronic: 150 mg bid 
< 30 
Avoid  
Initial: 10 mg bid x 
1 week 
Chronic: 5 mg bid 
Initial: LMWH x 5 
days 
Chronic: 30 mg qd  
Initial: LMWH x 5 
days 
Chronic: 75 mg bid  
< 15  
Avoid  
Initial:10 mg bid x 1 
week  
Chronic: 5 mg bid 
Not recommended  
Initial: LMWH x 5 
days 
Chronic: 75mg bid 
sc = subcutaneous; qd = daily; bid = twice daily 
*Edoxaban and Dabigatran require initial treatment with parenteral agent for 5 days. 


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11.4.2 Additional dosing considerations – ARM 2 – Usual Care Arm, 
LMWH/warfarin: 
 
• 
Individualize warfarin dosing regimen for each patient, and adjust based on INR 
response.  
• 
Monitoring: per local warfarin management protocols but no less frequently than 
every 2 weeks 
• 
Review conversion instructions from other anticoagulants. 
• 
Rounding is acceptable in accordance with pre-filled syringes/vial sizes 
• 
Switching between LMWHs is acceptable 
• 
Switching between LMWH and warfarin is acceptable 
 
11.5  
Dose Modifications 
 
 
Dose modifications are allowed, and are not considered protocol violations. 
• 
Skipped or omitted doses are not protocol violations.   
• 
Drug discontinuation is not a protocol violation. 
• 
Delayed or postponed doses are not protocol violations. 
• 
Dose reductions are not protocol violations and should be done at the discretion of the 
treating clinician. 
• 
Re-escalation of doses is not a protocol violation and should be done at the discretion of 
the treating clinician. 
 
At 3 and 6 months, participants will report their use of treatment, the number of days with no 
anticoagulant therapy, and the number of days with each type of anticoagulant therapy. 
Study CRAs will also abstract this information from medical records at 6 months. 
 
11.6  
Ancillary therapy, concomitant medications, and supportive care 
 
Use of ancillary/concomitant therapy is allowed and should be done according to individual 
institutional guidelines, and the best clinical judgment of the responsible physician.  Supportive 
care measures are allowed during trial participation (i.e., antiemetics, antidiarrheals, steroids, 
others).  Supportive care should be administered at the discretion of the treating clinician.  Use of 
ancillary/concomitant therapy is not a protocol violation.  Use of aspirin and NSAIDS is also at 
the discretion of the treating physician based on risk/benefits. 
 
Patients should receive all supportive and usual standard care while on this study.  This 
includes blood product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  When administering anticoagulation therapy, ancillary therapy, 
concomitant medications, and/or supportive care, the treating clinician(s) must take into 
account drug interactions as per standard good clinical practice.  For complete drug 
interaction information, please review the FDA package inserts.  The drug interaction information 
for each of the LMWH, warfarin, or DOAC drugs (pulled directly from the FDA package inserts) 
is provided here for quick reference.  
When making dose modifications, the guiding principal should be: Regardless of treatment arm 
and/or anticoagulation drug(s) used, treat the patient according to individual institutional guidelines, 
the best clinical judgment of the responsible physician, and in consultation with the drug’s package 
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Drug Interactions Summary Table - Excerpted from FDA Package Inserts 
Drug 
 
Drug Interactions Summary 
(for complete drug interaction information, please review the FDA package insert) 
ARM 1 – Intervention Arm, DOAC 
Rivaroxaban 
• 
Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid 
concomitant use  
• 
Prophylaxis of DVT: Anticoagulants: Avoid concomitant use 
Apixaban 
 
• 
Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of 
apixaban: Reduce apixaban dose to 2.5 mg or avoid concomitant use.  
• 
Simultaneous use of strong inducers of CYP3A4 and P-gp reduces blood 
levels of apixaban: Avoid concomitant use. 
Edoxaban 
• 
Anticoagulants: Avoid concomitant use  
• 
Rifampin: Avoid concomitant use  
Dabigatran 
• 
P-gp inducers rifampin: Avoid coadministration with dabigatran  
• 
P-gp inhibitors dronedarone and systemic ketoconazole in patients with 
moderate renal impairment (CrCl 30-50 mL/min): Consider reducing 
dabigatran dose to 75 mg twice daily  
• 
P-gp inhibitors in patients with severe renal impairment (CrCl <30 
mL/min): dabigatran use not recommended  
ARM 2 – Usual Care Arm, LMWH/warfarin 
Dalteparin 
• 
Use Dalteparin with care in patients receiving oral anticoagulants, platelet 
inhibitors, and thrombolytic agents 
Enoxaparin 
• 
Discontinue agents which may enhance hemorrhage risk prior to initiation 
of enoxaparin or conduct close clinical and laboratory monitoring 
Fondaparinux 
• 
Discontinue agents that may enhance the risk of hemorrhage prior to 
initiation of therapy with Fondaparinux unless essential. If co-
administration is necessary, monitor patients closely for hemorrhage.  
Warfarin 
• 
Consult labeling of all concurrently used drugs for complete information 
about interactions with warfarin or increased risks for bleeding.  
• 
Inhibitors and inducers of CYP2C9, 1A2, or 3A4: May alter warfarin 
exposure. Monitor INR closely when any such drug is used with warfarin.  
• 
Drugs that increase bleeding risk: Closely monitor patients receiving any 
such drug (e.g., other anticoagulants, antiplatelet agents, nonsteroidal anti-
inflammatory drugs, serotonin reuptake inhibitors).  
• 
Antibiotics and antifungals: Closely monitor INR when initiating or 
stopping an antibiotic or antifungal course of therapy.  
• 
Botanical (herbal) products: Some may influence patient response to 
warfarin necessitating close INR monitoring.  
 
 
11.7 
Extraordinary Medical Circumstances 
 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient 
no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: 
• 
Document the reason(s) for discontinuation of therapy on study forms. 
• 
Follow the patient for protocol endpoints. 
 


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12.0  
ADVERSE EVENTS 
 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research. For this trial, adverse events must be described and graded using the terminology and grading 
categories defined in the NCI’s Common Terminology Criteria for Adverse Events (CTCAE), Version 5. 
The CTCAE is available at ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Attribution to protocol treatment for each adverse event must be determined by the investigator and 
reported on the required forms using the codes provided. 
 
12.1  
Overview 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  
 
• 
For this trial, routine “Solicited Adverse Event” reporting is not required.   
• 
For this trial, “Expedited Serious Adverse Event” reporting is required using the SAE 
Report Form in REDCap (https://redcap.partners.org). Adverse event reporting begins at 
enrollment should continue until 30 days after the last administration of on-study protocol 
treatment. 
 
12.2  
Routine adverse event reporting 
 
Because this study only involves on-label use of FDA-approved drugs, no routine “Solicited 
Adverse Event” reporting is required. Even though routine solicited adverse event reporting is 
not required for this trial, treat the patient according to individual institutional guidelines, the best 
clinical judgment of the responsible physician, and in consultation with the drug’s package insert 
and standard practice guidelines. 
 
On the Medical Record Abstraction Form which will be completed at 6-months post enrollment 
(or at the time of the participant’s death, whichever occurs first), the following will be ascertained 
via retrospective chart review: 
➢ Information about bleeding events that occurred during the 6-month study period. 
➢ Information about recurrent VTEs that occurred during the 6-month study period. 
➢ Information about any other adverse reactions during the 6-month study period. 
 
12.3  
Expedited Adverse Event Reporting (AFT-28) 
 
Investigators are required to report serious adverse events as defined in the table below. The 
descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5 will be utilized for AE reporting.  The CTCAE is located at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All events determined to be “reportable” in an expedited manner must be reported using REDCap 
(https://redcap.partners.org).  NOTE: CTEP-AERS is not being used for this trial. 
 
Investigators should also report all events determined to be “reportable” in an expedited manner 
to their local IRB per institutional policy. 
 


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REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS  
 
For this study, SAE requiring expedited reporting is defined as: 
ALL adverse events that meet the following criteria MUST be reported via the Expedited SAE 
Reporting Form at https://redcap.partners.org: 
1) All deaths on study require expedited reporting regardless of causality.  Attribution to 
treatment or other cause should be provided. 
2) Any grade 3, 4, or 5 bleeding or hemorrhaging event. 
3) Any AEs that result in blood transfusion(s). 
4) Any thromboembolic event (e.g., VTE, DVT, PE, blood clot, thrombosis, or embolism). 
5) Edema, dyspnea, stroke, and/or respiratory failure must be reported IF AND ONLY IF 
related to a thromboembolic event (e.g., VTE, DVT, PE, blood clot, thrombosis, or 
embolism). 
6) All other events do NOT need to be reported as expedited SAEs. 
 
If an AE meets the definition of SAE requiring expeditated reporting as defined above, the AE 
must initially be reported via the Expedited SAE Reporting Form at https://redcap.partners.org  ≤ 
24 hours of learning of the AE, followed by a complete expedited report via the Expedited SAE 
Reporting Form at https://redcap.partners.org  ≤ 5 calendar days of the initial 24-hour report. 
 
Serious adverse events that occur more than 30 days after the last administration of study protocol 
treatment and have an attribution of possible, probable, or definite require reporting as follows: 
• 
If an AE meets the definition of SAE requiring expeditated reporting as defined above, 
the AE must initially be reported via the Expedited SAE Reporting Form at 
https://redcap.partners.org  ≤ 24 hours of learning of the AE, followed by a complete 
expedited report via the Expedited SAE Reporting Form at https://redcap.partners.org  ≤ 
5 calendar days of the initial 24-hour report. 
 
Treatment expected adverse events include those listed in Section 12.4 Expected Adverse 
Reactions and in the package insert. 
 
 
 
12.4  
Expected Adverse Reactions 
 
For complete adverse reaction information, please review the FDA package inserts.  The adverse 
reaction information for each of the LMWH, warfarin, or DOAC drugs (pulled directly from the 
FDA package inserts) is provided here for quick reference.  
 
Expected Adverse Reaction Summary Table 
Drug 
 
Expected Adverse Reaction Summary 
(for complete adverse reaction information, please review the FDA package insert) 
ARM 1 – Intervention Arm, DOAC 
Rivaroxaban 
The most common adverse reaction (>5%) was bleeding. 
Apixaban 
Most common adverse reactions (>1%) are related to bleeding. 
Edoxaban 
Treatment of DVT and PE: The most common adverse reactions (≥ 1%) are 
bleeding, rash, abnormal liver function tests and anemia. 


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Dabigatran 
Most common adverse reactions (>15%) are gastritis-like symptoms and 
bleeding 
ARM 2 – Usual Care Arm, LMWH/warfarin 
Dalteparin 
Most common adverse reaction is hematoma at the injection site. 
Enoxaparin 
Most common adverse reactions (>1%) were bleeding, anemia, 
thrombocytopenia, elevation of serum aminotransferase, diarrhea, and 
nausea. 
Fondaparinux 
The most common adverse reactions are bleeding complications. Mild local 
irritation (injection site bleeding, rash, and pruritus) may occur following 
subcutaneous injection. Anemia, insomnia, increased wound drainage, 
hypokalemia, dizziness, hypotension, confusion, bullous eruption, hematoma, 
post-operative hemorrhage, and purpura may occur. 
Warfarin 
Most common adverse reactions are fatal and nonfatal hemorrhage from any 
tissue or organ. 
 
12.5 
FDA MedWatch 
 
MedWatch is the FDA’s Safety Information and Adverse Event Reporting Program.  MedWatch 
is the FDA gateway for clinically important safety information and reporting serious problems 
with human medical products.   
 
MedWatch reporting is not required per protocol; however, if you would like to report 
SUSPECTED ADVERSE REACTIONS, you may contact FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch at your discretion. 
 
12.6 
New or Recurrent VTEs on Study 
 
If a patient experiences a new or recurrent VTE while on study, sites should follow these steps: 
 
• 
First and foremost, please make anticoagulation treatment decisions that are in the best 
interest of the patient.  Sites are NOT required to stick with the anticoagulant to which 
the patient was assigned per protocol.  Sites can switch anti-clot drugs (to an anti-clot 
drug from Arm 1, Arm 2, or neither arm), dose modify drugs, or discontinue drugs.  
Select the strategy that is best for the patient in view of the totality of their care. 
 
o For patients on treatment with a DOAC:  From a standard of care approach, if 
your patient was assigned to treatment with a DOAC and they develop a new 
VTE while taking the DOAC without interruption, it is recommended that they 
switch to a parenteral agent/standard of care.  
 
o For patients taking warfarin:  If the patient is on warfarin, we suggest that they 
switch to a parenteral agent. If the patient develops a new VTE while taking full 
dose parenteral agent without interruption then we suggest escalating the dose to 
125% as is convention based on small study results34, 35 
 
 
• 
If the participant is taken off protocol treatment, please:  
o have a member of your study staff (CRA) log into REDCap and fill out a 
“Change in Enrollment Status/Off-Study Form.”   
▪ 
On the form, please select the 3rd response option which says: 


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“CLINICIAN WITHDRAWAL: Clinician took participant off protocol 
treatment. Please note that after taking a subject off protocol treatment, 
study questionnaires and patient-reported drug diaries continue through 
the 6th month. Site study staff should complete the Medical Record 
Abstraction Form at the end of the 6th month no matter how long the 
subject actually received protocol-directed anticoagulation.”  
➢ There are no study questionnaires or medical record tracking that 
extend beyond 6 months. 


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13.0 
STATISTICAL CONSIDERATIONS  
 
Note: This revised statistical considerations section reflects the result of monthly data monitoring 
for April, 2020.  As of April 28th, 2020, the study has enrolled a total of 808 patients. Please note, 
140 patients were enrolled to the preference cohort which closed in December 2017. The remaining 
patients are enrolled in the randomized cohort. Please see the finalized Statistical Analysis Plan 
(SAP) outlined in Appendix 18.0. Select references from this plan are included below.   
 
Study Design: Randomized Effectiveness Trial with Hybrid observational component 
Sample Size:  The planned total sample size is revised from 890 to 808 total patients (140 patients in 
the preference cohort and 668 in the randomized cohort) due to significant curtailment of the accrual 
rate caused by the COVID-19 pandemic. The study closed to new enrollment in April 2020. Anticipated 
final N is expected to be 811 patients.  
Accrual Time: Approximately 3 years  
Study Duration: Approximately 3.5 years 
 
Primary Endpoint:  
Cumulative VTE recurrence reported by patients or their clinicians at 6 months 
 
Secondary Endpoints: 
• 
Cumulative incidence of major bleeding reported by patients or clinicians at 6 months 
• 
Cumulative incidence of all bleeding events and bleeding according to its severity in the 
following categories:1) major bleeding, 2) clinically significant non-major and 3) nuisance  
• 
Cumulative incidence of death at 6 months  
• 
Overall HRQOL at 3 and 6 months 
• 
Overall score on the Anti-Clot Therapy Scale at 3 and 6 months 
 
Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting): anticipated 
November 2020 
 
13.1 Summary of the study design and rationale 
 
The study design is a randomized effectiveness study to evaluate the effectiveness of DOAC 
therapy compared to usual care with LMWH/warfarin. Participants who decline randomization 
will be offered the opportunity to participate in the preference cohort**. This is a hybrid design 
that consists of both a randomized cohort and a preference cohort. Eligible patients who accept 
randomization will be enrolled in the study (the randomized cohort), and they will be randomly 
assigned either the DOAC therapy group or the usual care group. Those patients who decline 
randomization but choose treatment on one of the two study arms will be invited to the study (the 
preference cohort**).  The rationale of employing the hybrid study design with the two cohorts 
is that both cohorts have own strength, and they complement each other. Specifically, the 
randomized controlled design is the most rigorous study design for comparing treatment 
alternatives. However, it may not capture the effectiveness under the real-world setting because 
the analysis population is limited to only those patients who accept randomization. On the other 
hand, the non-randomized study (i.e., the preference cohort**) assesses effectiveness more likely 
under real-world circumstances, while the internal validity (i.e., the comparability between the 
two treatment groups) has to rely on unverifiable assumptions. This hybrid study design will 
maximize the totality of evidence of comparative effectiveness between the DOAC and usual 
care.  All statistical analyses (details below) will be performed with the randomized cohort and 
the preference cohort separately, and they will be combined using a meta-analytic methodology 


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(details below).  The results from the randomized cohort will be considered as the primary results. 
 
**Based on the results of monthly data monitoring conducted in June 2017, the preference 
cohort is CLOSED to new enrollment, following the closing rule #2 specified in the protocol.  
The randomized cohort CLOSED to new enrollment in April, 2020. 
 
 
13.2 Accrual 
 
13.2.1 Total accrual  
 
The accrual rate is expected to be approximately 30 patients per month. Patients who 
accept randomization will be randomized equally to the two arms (randomized cohort). 
Patient who decline randomization but choose either of the two arms will be invited to 
enroll (preference cohort**). Since preliminary clinical experience suggests that the 
majority of patients will accept randomization, we expect that 80% of the 30 patients (i.e., 
24 patients per month) will accept randomization and the rest of the 20% (6 patients per 
month) will decline. Because the results of monthly data monitoring conducted in June 
2017 met a criterion for closing the accrual to the preference cohort (see 13.2.2), it was 
closed after 140 patients were enrolled to it. Approximately 810 patients (670 patients 
in the randomized cohort and 140 patients in the preference cohort) will be enrolled in the 
study. We planned to enroll a total of 890 patients (750 patients in the randomized 
cohort and 140 patients in the preference cohort) with 32 months of accrual period, 
considering that the accrual rate in the first few months of the study is generally slower 
than thereafter. However, due to significant curtailment of the accrual rate caused by the 
COVID-19 pandemic since March 2020, we have revised the planned total sample size to 
810 patients. (see 13.2.4 for details) 
 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The 
preference cohort is CLOSED to new enrollment. 
 
13.2.2 Monitoring of accrual and the stopping rule  
 
Note:  The conditions for “Preference Cohort Closing Rule #2” below have been met as 
of June 1st, 2017; the pre-set imbalance between arm selection in the preference cohort 
has been met. As such, the preference cohort is CLOSED to new enrollment. This 
section was intentionally left as it was, in order to clarify the closing rules specified 
in the original protocol. 
 
Although we expect that 80% of eligible patients will accept randomization, the true 
proportion is not known. In addition, there is no reliable information about which arm 
will be more likely chosen among the patients in the preference cohort. If almost all 
patients chose one of the two arms, the preference cohort would not provide reliable 
information regarding the treatment difference. Therefore, to avoid such a potential 
imbalance, we will continuously monitor the number of enrolled patients in each cohort 
and each arm. Following the rules below, we will terminate the enrollment of the 
preference cohort. 
 
Preference Cohort Closing Rule #1:  
All statistical analyses (details below) will be performed with the randomized cohort and 
the preference cohort separately, and they will be combined using a meta-analytic 


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methodology (details below).  The results from the randomized cohort will be considered 
the primary results. Therefore, to guarantee the statistical power for the analysis with the 
randomized cohort, we will cap the number of patients in a preference cohort to be 190. 
Once 190 patients are enrolled in the preference cohort, we will close the accrual to 
the preference cohort, keeping the enrollment of the randomized cohort open.  
 
Preference Cohort Closing Rule #2:**  
The rule #2 is set to avoid an extreme imbalance of the number of patients between the 
two arms in the preference cohort. The ideal situation in terms of statistical efficiency for 
the analysis is that the number of patients who choose the DOAC arm is the same as 
those choose the usual care arm (i.e., 50% vs. 50%), and deviation from this balance 
induces information loss for the analyses. Thus, we will close the accrual of the 
preference cohort if we observe a large imbalance in sample size between two groups, 
even if the number of the preference cohort has not reached the cap of the 190. 
Specifically, we require that, out of the 190 patients, at least 38 patients (i.e., 20% of 190) 
should be in each of the two arms. After 50 patients are enrolled in the preference cohort, 
we will continuously calculate the conditional probability that sample size of either arm 
in the preference cohort will end up to be less than 38. When this conditional probability 
becomes great than 50%, we will consider terminating the enrollment to the preference 
cohort. The stopping boundary corresponding to this rule is given in following Table. 
 
**The randomized cohort CLOSED to new enrollment in April, 2020.  The 
conditions for “Preference Cohort Closing Rule #2” have been met; the pre-set 
imbalance between arm selection in the preference cohort has been met. As such, 
the preference cohort is CLOSED to new enrollment. 
 
Table: Closing rule #2 
Total number of patients enrolled 
in the preference cohort 
Stopping boundary 
Observed sample size in the 
preference cohort 
Observed absolute difference in 
sample size between groups 
50 
10 vs. 40 
30 or larger 
60 
12 vs. 48 
36 or larger 
70 
14 vs. 56 
42 or larger 
80 
16 vs. 64 
48 or larger 
90 
18 vs. 72 
54 or larger 
100 
20 vs. 80 
60 or larger 
110 
22 vs. 88 
66 or larger 
120 
24 vs. 96 
72 or larger 
130 
26 vs. 104 
78 or larger 
140 
28 vs. 112 
84 or larger 
150 
30 vs. 120 
90 or larger 
 
 
13.2.3 Planned modifications of accrual to enrich enrollment for pre-specified 
subgroup analyses 
 
We plan to evaluate effectiveness in the following three key subgroups of cancer patients.   
 
Patients with: 


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1) Highly Thrombogenic Tumors 
2) Indwelling Central Venous Catheters 
3) Thrombocytopenia 
 
The accrual goals for the three subgroups are 300, 500 and 200 patients, respectively (see 
below for sample size and power considerations about these subgroups). We anticipate 
that each of the accrual goals will be automatically achieved by enrolling a total of 810 
patients in this study. However, it may not be the case. Therefore, as soon as the 700th 
patient is enrolled in the study, we will project the total number of patients that will be 
enrolled in each of the three subgroups. If enrollment is not on track for any of the three 
subgroups, we will consider modifying the eligibility criteria, so that the accrual goals of 
those subgroups can be achieved. In that case, the modified eligibility criteria will be 
active right after the 700th patient is enrolled.  
 
13.2.4 Modifications to the size of the final analytic cohort; Updated statistical 
proposal (Prepared by Hajime Uno PhD, Study Statistician in April 2020):  
 
As of April 28, 2020, the study has enrolled at total of 808 patients. Of the 808, 668 were enrolled in the 
randomized cohort. When we discontinue the patient enrollment now, the total sample size is expected 
to be around 810 depending on the exact date of formal closure. With this sample size, the power of non-
inferiority test already reaches 90% (See Table). For superiority, it is slightly below the 80% target power 
at 75%. The expected length of confidence interval (CI) for the difference in event rate is now 6.1% with 
808 patients, and it would have been 5.8% with the planned total sample size (N=890). This suggests that 
the gain in the precision may be marginal. Given the challenges to continued accrual in the setting of the 
COVID-19 pandemic and the recently reported results of the Caravaggio study we propose revision as 
follows. 
Table: Power calculation for the primary analysis 
Date 
N (Randomized 
Cohort) 
N (total) 
Length of CI 
for difference 
Power 
 
Non-inferiority 
Superiority 
Revised 
Statistical 
Analysis Plan 
668 
808 
6.1% 
0.900 
0.756 
Originally 
Planned Goal 
750 
890 
5.8% 
0.927 
0.797 
 
Enrollment to the CANVAS trial will therefore be suspended in April 2020 before reaching the 
original proposed 890 patient accrual mark. The final N will be reported upon study closure at all 
sites but it is expected to be around 810 depending on the exact date of formal closure 
 
 
13.3 Statistical Considerations for Primary Endpoint – Please see Appendix 18.0 for more 
details in the SAP. 
 
13.3.1 Primary Analysis 
 
The primary aim of this study is to compare the intervention and comparator arms with 
respect to their ability to prevent recurrent VTE. Because the intervention (DOAC 
therapy) is more easily administered than the comparator (usual care with LMWH 
warfarin), DOAC is expected to have higher adherence and therefore decreased incidence 
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described by Friedlen et al36. The primary analysis will test the noninferiority of the 
DOAC therapy with the primary analytic cohort (modified ITT population of the 
randomized cohort). If noninferiority is demonstrated, superiority of the DOAC therapy 
will be tested. 
 
Because VTE is often a proximate cause of death in cancer patients’ unexplained sudden 
demise, but diagnostic procedures are rarely performed (post-mortem scans, autopsies, 
etc.), we considered VTEs that were clinically significant as the primary outcome on the 
basis of an antemortem diagnosis. Separately, we looked at all-cause deaths because 
deaths from cancer and deaths from VTE are difficult and in many cases nearly 
impossible to distinguish.  This is the approach that has been taken in efficacy trials that 
have compared DOAC and LMWH therapies. We will estimate the cumulative incidence 
of recurrent VTE at 6 months using the standard competing risk analysis method,49 where 
death will be treated as a competing risk. We calculate the difference in the 6 month 
incidence rate between groups and corresponding 0.90 confidence interval (CI).  
 
 
1) Non-inferiority test of DOAC 
 
 
The hypothesis for testing the noninferiority of the DOAC strategy is that the 
difference in the primary endpoint at 6 months is no greater than a noninferiority 
margin of 3% for the intervention-comparator. This noninferiority margin was 
selected based on what is acceptable to patients based on patient-stakeholder 
input as well as on input provided by clinicians 
 
To confirm the noninferiority hypothesis, we will construct a two-sided 90% 
confidence interval (CI) for the difference in the cumulative incidence of the 
primary endpoint at 6 months (180 days). If the upper bound of the CI is less than 
3%, we will conclude that the DOAC management strategy is non-inferior to the 
LMWH/warfarin strategy for management of VTE in patients with cancer.  
 
2) Superiority test of DOAC 
 
If noninferiority of DOAC is demonstrated, a superiority test of DOAC will be 
performed using a one-sided 0.05 significance level and the same two-sided 
90% CI for the difference in the event rate of the primary endpoint at 6 months 
as used for the noninferiority test. When the upper bound of the CI is less than 
0, we will conclude that DOAC therapy is superior to LMWH/warfarin in 
terms of VTE prevention. Because we will perform the superiority test only 
after the noninferiority of DOAC is demonstrated, the overall type I error rate 
is maintained at the 0.05 level (one-sided) without splitting alpha.36 
 
13.3.2 Interim Analysis 
 
This study design incorporates several interim analyses and one final analysis for the 
comparison of the primary endpoint.  A 90% two-sided repeated confidence interval 
(RCI)37 for the difference in the cumulative incidence rate of VTE at 6 months (DOAC 
minus Usual Care) between two arms was estimated. We use the critical values based on 
the Lan-DeMets error spending function38 corresponding to the truncated version of 
O’Brien-Fleming boundaries.39 


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Prior to the final analysis, four interim analyses were conducted on September 7, 2018, 
March 22, 2019, September 9, 2019, and March 25, 2020. Given these interim analyses, 
the critical value for the final analysis will be 1.710, which corresponds to a one-sided 
0.0436 alpha. The confidence coefficient of the 90% two-sided RCI will be 91.28% for 
the final analysis.  
 
 
13.3.3 Secondary Analyses 
 
1) Analysis with other summary measures 
The absolute difference in 6-month event rate based on the cumulative 
incidence function (CIF) is the primary summary measure of the between-group 
difference. As a secondary analysis, we will calculate subhazard ratio using a 
Fine and Gray model40. We will construct 0.90 CIs for these measures.   
 
 
2) Alternative way to handle deaths 
In the primary analysis, we handle deaths as competing risks and estimate the 
recurrent VTE rates by the CIF approach. As a secondary analysis, we will handle 
deaths as censored observations and estimate the recurrent VTE event rates by the 
Kaplan-Meier method. We will calculate the hazard ratio and difference in the 
event rate at 6 months and corresponding 0.90 CIs.  
 
3) Sensitivity Analyses including data from the preference cohort 
This study allowed a limited number of participants to enroll in the preference 
cohort if an eligible participant declines randomization. The Preference 
Cohort Closing Rules were pre-specified in Section 13.2.2 in the study 
protocol to specify the maximum number of participants enrolled in the 
preference cohort and to avoid an extreme imbalance of the number of 
participants between two groups. The results of monthly data monitoring in 
June 2017 observed the pre-set imbalance criteria in between arm selection. 
The enrollment to the preference cohort was therefore closed in December 
2017, after 140 patients had enrolled in it. 
 
First, we will compare characteristics between the preference and randomized 
cohorts to assess potential heterogeneity between the two cohorts. Fisher’s 
exact test will be used for nominal categorical variables, and two-sample 
Wilcoxon tests will be used for ordered categorical or continuous variables.  
 
We will estimate the difference in VTE event rate at 6 months and its standard 
error from the preference cohort, using a propensity score approach to adjust 
for potential treatment selection.41 We will then combine the result with that 
from the randomized cohort, using a weighted average. An optimal weight 
(i.e., the reciprocals of the variance) will be used. The resulting estimate for 
the difference in VTE event rate and 90% CI can be considered an overall 
average treatment effect of DOAC across the full cohort. In no circumstance 
will analyses of the full cohort be presented as primary.  
 
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We will also conduct the same analyses for each of the following subtypes of 
VTE recurrence. 
1) Pulmonary embolism (PE) with or without deep vein thrombosis (DVT) 
2) DVT without PE 
 
5) Adjusted analyses 
We will perform adjusted analysis to estimate the adjusted treatment effect, 
using generalized linear mixed-effects models with the logit link. Censored 
observations will be handled by the inverse probability censoring weight 
technique. 42 The participating sites will be included as random-effects.43 
Those baseline characteristics variables (see 3.4) whose distributions are not 
balanced between two groups (p<0.05) in the randomization cohort will be 
included as fixed-effects in the models for adjustment.  
 
6) Sensitivity Analyses using the ITT and the per protocol populations. 
Sensitivity analyses will be performed with alternative cohort specification.  
We will repeat all the analyses using the ITT population and then using the 
per-protocol population.  
 
13.3 Statistical Considerations for Secondary Endpoints 
 
13.3.4 Secondary endpoints 
▪ 
Cumulative incidence of major bleeding reported by either patients or clinicians at 6 
months 
▪ 
Cumulative incidence of all bleeding events and bleeding according to its severity in 
the following categories:1) major bleeding, 2) clinically significant non-major and 3) 
nuisance  
▪ 
Cumulative incidence of death at 6 months  
▪ 
Overall HRQOL at 3 and 6 months 
▪ 
Overall score on the Anti-Clot Therapy Scale at 3 and 6 months 
 
 
13.3.5 Analyses for secondary endpoints  
1) Cumulative rates of major bleeding reported by patients or clinicians at 6 
months (NCI CTCAE Grade 3, 4, or 5) 
We will repeat the analogous analyses as performed for the primary endpoint 
(see 13.3.1). The primary analysis plan for major bleeding, fatal or non-fatal, is 
also based on the sequential evaluation of noninferiority and superiority. We 
will construct a two-sided 90% CI for the difference in the cumulative 
incidence rate for the composite outcomes of major bleeding and death. If the 
upper bound of the CI is less than 2.5%, we will conclude that DOAC is 
noninferior to LMWH/warfarin in terms of major bleeding.  The same 
secondary analyses as planned for the primary endpoint will be performed. In 
contrast to clotting, fatal bleeding events are usually clinically manifest and 
recorded and therefore can be distinguished. 
 
2) Cumulative incidence of all bleeding events reported by patients or 
clinicians at 6 months in the following categories: 1) major bleeding 
(Grade >=3), 2) clinically significant non-major (Grade 2); and,3) 
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Clinically significant non-major bleeding is defined as Grade 2 Nuisance 
bleeding is defined as Grade 1 according to the NCI CTCAE criteria. We will 
perform the same analysis as described above for major bleeding events. 
 
 
3) Mortality (Cumulative incidence of death at 6 months) 
Time from randomization to death from any cause is a secondary endpoint. 
The study is powered to confirm the primary hypothesis for recurrent VTE; we 
do not anticipate enough power to perform a confirmatory analysis for all-
cause mortality. We will instead focus on providing quantitative information 
for the between-group difference for this endpoint. We will describe the 
survival time distribution by treatment group using the Kaplan-Meier method. 
Also, we will compare the restricted mean survival times (RMST)44 between 
groups. The truncation time point for calculating the RMST will be 6 months, 
which will give us an estimate of 6-month lifetime expectancy for each group. 
We will estimate the difference in RMST and corresponding 90% CI. Hazard 
ratio and its 90% CI will also be calculated if the proportional hazards 
assumption is reasonable. The determination of the violation of the 
proportional hazards assumption will be based on a significant p-value (<0.05) 
for the Grambsch and Therneau test. 45 
 
 
4) The Patient-Centered Experience of Anticoagulation QOL and Burdens 
 
a. Health Related Quality of Life (SF-12) at 3 and 6 months 
For SF-12, the primary analysis variable is the difference in the SF-12 mean 
change score from baseline. We will consider 2-point differences as clinically 
meaningful. We will use multiple imputations to handle missing 
observations.46 
 First, we will create 10 complete datasets, imputing missing values using 
chained equations, where we include measurements at baseline, 3 months, 
and 6 months. Second, we will estimate mean changes and the standard errors 
for each of the 10 complete sets. We will then use Rubin’s method to derive 
an estimate for the difference in the mean change score between two groups.  
Using the resulting estimate and the standard error, we will perform a Z-test 
to evaluate equality of SF-12 scores between groups. 
 
 
b. Anti-Clot Treatment Scale (ACTS) score at 3 and 6 months 
For ACTS score, the primary analysis variables are the ACTS Burdens 
total score and the ACTS Benefits total score. We will consider 2-point 
differences as clinically meaningful. To minimize potential bias due to 
missing observations, we will allow and include surrogate estimates for 
all 3 patient-reported outcome assessments. Next, we will use multiple 
imputation to handle missing observations. First, we will create 10 
complete datasets, imputing missing values using chained equations, 
where we include measurements at baseline, 3 months, and 6 months. 
Second, we will estimate mean changes and the standard errors for each 
of the 10 complete sets. Lastly, we will integrate the results using Rubin’s 
method. 
 


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13.3.6 Other/Persistence with treatment Endpoints 
▪ 
Performance status  
We will use the two-sample Wilcoxon test to evaluate between-group 
differences in  ECOG PS.  
▪ 
Cumulative rates of remaining on any anti-coagulation therapy at 3 and 6 months 
▪ 
Cumulative rates of remaining on the assigned (and/or selected in the case of the 
preference cohort) anti-coagulation therapy at 3 and 6 months. 
 
13.3.7 Safety endpoint evaluation 
 
                    Safety endpoints: 
• 
Major bleeding (primary protocol safety endpoint) 
• 
Clinically significant non-major bleeding 
• 
Any bleeding (major bleeding and clinically significant non-major bleeding and 
nuisance bleeding) 
• 
Other Serious Adverse Events (SAE) 
 
For this trial, “Expedited Serious Adverse Event” reporting is required using the SAE 
Report Form in REDCap. Adverse event reporting begins at enrollment and should 
continue until 30 days after the last administration of on-study protocol treatment. 
SAEs for other adverse events are reported via the following guidelines: 
- 
Grade 1 or 2 adverse events that resulted in hospitalization for 24 or more hours, 
or 
- 
Grade 3, 4, or 5 adverse events regardless of hospitalization 
 
The analysis plan for major bleeding and any bleeding are outlined in section 13.3.5. 
Incidence of all other SAEs will be summarized by cohort, arm, grade, and type of 
SAE.  Fisher’s exact test will be performed to compare the event rates. 
 
 
13.5 Heterogeneity of Treatment Effects  
 
13.5.1 Subgroup Analysis 
 
We will perform subgroup analyses to investigate the potential heterogeneity of 
treatment effects. For each subgroup, we will perform the same analyses described in 
the previous sections. The treatment effect by subgroup will be summarized by point 
estimates and corresponding 90% confidence intervals. We will create forest plots to 
display those results. This analysis will be performed with an exploratory purpose; we 
will not adjust for multiple comparisons.   
 
First, we will focus on the 3 key subgroups described below because these groups are 
common, and decision making in these contexts is challenging for oncologists and 
patients. These 3 subgroups represent populations of particular interest for clinical 
decision makers.   
 
13.5.1.1 Pre-specified subgroup 1: Patients with Highly Thrombogenic Tumors 
We anticipate that at least 300 patients with lung (NSCLC and small cell), 
pancreas, esophagogastric and ovarian cancers are represented in the study 
sample. These patients have an even higher risk of VTE than cancer patients in 


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general. Based on anticipated higher adherence rates to DOAC therapy and the 
likelihood of warfarin failures in the LMWH/warfarin arm, we anticipate a slight 
advantage for DOACs over the standard care arm. As planned for the full cohort 
analysis, we will only test for superiority in the subgroup if noninferiority is met. 
 
13.5.1.2. Pre-specified subgroup 2: Indwelling Central Venous Catheters 
We anticipate that a subgroup of approximately 500 study participants will have 
an indwelling central venous catheter in place at the time of enrollment. This 
recruitment should not be challenging given how commonplace use of these 
catheters has become in routine oncology practice. The rate of VTEs is expected 
to be slightly higher for patients with a central venous catheter due to the excess 
risk of upper extremity clots. 
 
13.5.1.3. Pre-specified subgroup 3: Thrombocytopenia  
We will consider the subgroup of participants with baseline platelet counts less 
than 150,000/microliter. Thrombocytopenic cancer patients face high risk of 
VTE but also face higher risks of bleeding. In this setting, the choice of 
anticoagulation strategy is challenging.  
 
13.5.1.4. Other preplanned subgroups  
We will perform the same analysis for the following subgroups with an 
exploratory purpose. 
• 
Sex (Male, Female) 
• 
Age (below 65, equal or greater than 65) 
• 
Participants with central nervous system (CNS) tumor involvement 
• 
Participants with liver metastases  
• 
Participants with albumin <3.5mg/dL 
• 
Participants treated with bevacizumab 
• 
Participants incidentally detected VTE on routine imaging studies 
(versus symptomatically detected VTE) 
• 
Participants with metastatic disease (versus completely resected disease 
or no radiographic evidence of tumor) 
• 
Participants with >80% days of persistence with anticoagulant therapy 
(vs. >50-80% vs. <=50%) by participant estimate 
• 
Participants with >80% days of persistence with anticoagulant therapy 
(vs. >50-80% vs. <=50%) by medical record abstraction/dose refills 
• 
Solid tumors versus hematologic malignancies 
 
 
We will perform subgroup analyses to investigate the potential 
heterogeneity of treatment effects. For each subgroup, we will perform 
the same analysis described in the previous sections. The treatment 
effect by subgroup will be summarized by point estimates and 
corresponding 90% confidence intervals. We will create forest plots to 
display those results. This analysis will be performed with an 
exploratory purpose; we will not adjust for multiple comparisons.   
 
13.6 Toxicity 
 


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Using the AFT mechanism, we will monitor reportable adverse events every month during the 
study. Every month, the study chair and the study statistician will determine if further review by 
the study team and the DMSB is necessary.  
In particular, we will monitor the adverse event rates of 1) thrombosis, 2) bleeding and 3) all-cause 
of mortality. If a statistically significant difference in any of these adverse events is observed at any 
time during the study, the DMSB will consider recommending the termination or modification of 
the study from safety perspective.  
Toxicity event rates will be compared between DOAC and LMWH/warfarin, using Fisher’s exact 
test. Please see section 13.5 for evaluation of bleeding risk and categorization of bleeding events.  
 
13.7 Other statistical considerations 
 
Regarding missing values, we will perform both complete case analyses and multiple imputation 
analyses to account for missing data.47 
 
 
13.8. Software 
The statistical analyses will be performed with R version 4.0.2, Stata version 16, and SAS version 
9.4. 
 
 
 
 
 
 


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13.8 Gender and Ethnicity 
 
Based on preliminary clinical experience, the anticipated accrual in subgroups defined by gender 
and race is: 
Category 
Gender 
 
Total 
Females 
Males 
 
Ethnic Categorya 
Hispanic or Latino  
69 
69  
138 
Not Hispanic or Latino  
335 
335 
670  
Ethnic Category: Total of all subjects 
404 
404 
808 
 
Racial Categoryb 
American Indian or Alaskan Native  
5 
5 
10 
Asian  
22 
22 
44 
Black or African American  
53 
53 
106 
Native Hawaiian or other Pacific Islander  
1 
1 
2 
White  
313 
313 
626 
Two or More Races 
10 
10 
20 
Racial Category: Total of all subjects 
404 
404 
808 
aHispanic or Latino (17%), Not Hispanic or Latino (83%) 
bAmerican Indian or Alaskan Native (1.2%), Asian (5.4%), African-American (13.2%), Native 
Hawaiian or other Pacific Islander (0.2%), White (77.4%), Two or more races (2.5%) 
Source: https://www.census.gov/quickfacts/table/PST045215/00 
 
13.9 Study Monitoring 
 
The study will be monitored by the AFT data safety and monitoring board (DSMB) to ensure 
objectivity and the safety of participants. The DSMB will meet twice each year either at a face-
to-face meeting or by teleconference.  At each meeting, the study will be reviewed for safety 
and progress toward completion. When appropriate, the DMSB will also review formal interim 
analyses of the outcome data. If necessary, the DSMB will recommend study closure or 
modifications. Any DMSB recommendations for changes to the study will be circulated to 
investigators in the form of addenda to this protocol document.  This study will adhere to 
standards for the conduct and reporting of RCTs described in the CONSORT statement.48 
 
13.10 Endpoint Adjudication  
 
All case report forms for patients with recurrent VTE and major bleeding episodes will be 
reviewed and categorized by physician adjudicators who are not knowledgeable of the 
patients’ treatment assignment. Discrepant interpretations between any two endpoint 
adjudicators will be evaluated by a third adjudicator who is also not knowledgeable as to the 
patients’ treatment assignments. Cases of discrepant interpretation of the primary endpoint will 
be discussed among the adjudicators until consensus is achieved. 
 


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13.11 Site Audits 
 
Audits visits will be conducted on-site as part of the AFT investigator site audit program, 
according AFT policies and procedures. Not all patients will be audited. A minimum of 1 patient or at 
least 10% of PCORI-funded AFT trial cases at the site will be audited. 
 
 
 


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14.0  
BUDGET 
 
14.1 
Funding 
 
This trial is supported through a Patient-Centered Outcomes Research Institute (PCORI) Award 
(CER-1503-29805). 
 
14.2 
Site and per case reimbursement 
 
Sites that open the CANVAS Trial (AFT-28) will receive the following site reimbursement rates: 
 
$2,000 one-time seed funds payable upon submission of site IRB approval of the study 
 
+$250 per case reimbursement payable upon submission of each Eligibility 
Checklist/Enrollment Form 
 
+$500 per case reimbursement payable upon submission of each Medical Record 
Abstraction Form (1 Medical Record Abstraction Form required per participant, usually 
completed and submitted 6-months post enrollment)  
 
Sites do not need to invoice AFT.  Payments will be sent automatically based on data entered into 
REDCap. 
 
14.3  
Drug costs 
 
This study will not provide any drugs because all drugs used in this study are FDA-approved and 
are being prescribed on-label.  Drugs should be billed to the patient's insurance company or the 
patient as your site does for any other standard medication. 
 
One practical aspect about the design of this study is that patients can be enrolled up to 30 days 
after the index VTE, and during that first 30 days, patient may be treated with any type of 
anticoagulant. This should give practitioners enough time to obtain prior authorizations for 
necessary insurance coverage, etc. During this period, participants can be started on LWMH and 
then transitioned to a DOAC when coverage has been obtained. 
 
 


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Alonso-Coello P, Montori VM, Sola I, et al. Values and preferences in oral anticoagulation in 
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Devereaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of physicians 
and patients on anticoagulation in patients with atrial fibrillation: observational study. Multicenter Study. 
BMJ (Clinical research ed). Nov 24 2001;323(7323):1218-22.  
30. 
Holbrook A, Labiris R, Goldsmith CH, Ota K, Harb S, Sebaldt RJ. Influence of decision aids on 
patient preferences for anticoagulant therapy: a randomized trial. Comparative Study 
Randomized Controlled Trial 
Research Support, Non-U.S. Gov't. CMAJ. May 22 2007;176(11):1583-7. doi:10.1503/cmaj.060837 


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Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with 
dabigatran 
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Feb 
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2014;129(7):764-72. 
doi:10.1161/CIRCULATIONAHA.113.004450 
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Cano SJ, Lamping DL, Bamber L, Smith S. The Anti-Clot Treatment Scale (ACTS) in clinical 
trials: cross-cultural validation in venous thromboembolism patients. Health and quality of life outcomes. 
2012;10:120. doi:10.1186/1477-7525-10-120 
33. 
Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in 
patients with cancer: american society of clinical oncology clinical practice guideline update 2014. Practice 
Guideline 
Research Support, Non-U.S. Gov't. J Clin Oncol. Feb 20 2015;33(6):654-6. doi:10.1200/JCO.2014.59.7351 
34. 
Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular 
weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in 
cancer patients. J Thromb Haemost. May 2009;7(5):760-5. doi:10.1111/j.1538-7836.2009.03326.x 
35. 
Ihaddadene R, Le Gal G, Delluc A, Carrier M. Dose escalation of low molecular weight heparin in 
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Jul 
2014;134(1):93-5. 
doi:10.1016/j.thromres.2014.04.028 
36. 
Freidlin B, Korn EL, George SL, Gray R. Randomized clinical trial design for assessing 
noninferiority when superiority is expected. J Clin Oncol. Nov 1 2007;25(31):5019-23. 
doi:10.1200/JCO.2007.11.8711 
37. 
Jennison C, Turnbull BW. Interim Analyses: the repeated confidence interval approach. J R Stat 
Soc Series B Stat Methodol. 1989;51 (3):305-334.  
38. 
Lan KKG, Demets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-663.  
39. 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. Sep 
1979;35(3):549-56.  
40. 
Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat 
Assoc. 1999;94(446):496-509.  
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D'Agostino Jr. RB. Propensity score methods for bias reduction in the comparison of a treatment 
to a non-randomized control group. Statistics in medicine. 1998;17(19):2265-2281.  
42. 
Uno H, Cai T, Tian L, Wei LJ. Evaluating prediction rules for t-year survivors with censored 
regression models. Journal of the American Statistical Association. 2007;102(478):527-537.  
43. 
Senn SJ, Lewis RJ. Treatment Effects in Multicenter Randomized Clinical Trials. JAMA. Mar 26 
2019;321(12):1211-1212. doi:10.1001/jama.2019.1480 
44. 
Uno H, Claggett B, Tian L, et al. Moving beyond the hazard ratio in quantifying the between-group 
difference in survival analysis. J Clin Oncol. Aug 1 2014;32(22):2380-5. doi:10.1200/JCO.2014.55.2208 
45. 
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted 
residuals. Biometrika 1994;81(3):515-526.  
46. 
Schafer JL. Multiple imputation: a primer. Statistical methods in medical research. Mar 
1999;8(1):3-15. doi:10.1177/096228029900800102 
47. 
Carpenter J KM. Multiple Imputation and its Application. Wiley, UK. 2013; CONSORT 
STATEMENT with extension to non-inferiority trials.  
49. 
Pintilie M. Competing risks: A practical perspective. Wiley, UK. 2006. 
50. 
Raksob G BH, Angchaisuksiri P, et al. . Edoxaban for long-term treatment of venous 
thromboembolism in cancer patients. oral abstract at 55th American Society of Hematology 
Annual Meeting and Exposition. 2013. 
51. 
Raskob G, Buller H, Prins M, Segers A, Shi M, Schwocho L, van Kranen R, Mercuri M. 
Edoxaban for the long-term treatment of venous thromboembolism: rationale and design of the 
Hokusai-venous thromboembolism study--methodological implications for clinical trials. Journal 
of thrombosis and haemostasis : JTH. Jul 2013;11(7):1287-1294. 
52. 
Sprynger M. [Hokusai-VTE: edoxaban versus warfarin for the treatment of symptomatic venous 
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53. 
Long Q, Little, R.J. Causal inference in hybrid intervention trials involving treatment choice. 
Journal of the American Statistical Association. 2008:474-484. 
54. 
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bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. 
Journal of thrombosis and haemostasis : JTH. Jan 2010;8(1):202-204. 
55. 
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. Journal of thrombosis and haemostasis : JTH. Apr 
2005;3(4):692-694. 
56. 
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57. 
Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. 
Medical care. Mar 1989;27(3 Suppl):S178-189. 
58. 
Tian L, Zhao L, Wei LJ. Predicting the restricted mean event time with the subject's baseline 
covariates in survival analysis. Biostatistics. Apr 2014;15(2):222-233. 
59. 
Cai T, Tian L, Wong PH, Wei LJ. Analysis of randomized comparative clinical trial data for 
personalized treatment selections. Biostatistics. Apr 2011;12(2):270-282. 
 
 
 
 
 
16.0 
Appendix: Notice regarding proprietary content embedded in the study questionnaires 
 


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17.0 PATIENT-FACING STUDY MATERIALS 
 
Not enclosed with this protocol.  
 
To obtain copies of the following materials, either: 
➢ Download them from SiteZone (https://sitezone.mywingspan.com/sitezone/#/trials), or  
➢ Email CANVAS@AllianceFoundationTrials.org to request copies. 
 
• 
Model Informed Consent Form – ENGLISH 
• 
Model Informed Consent Form – SPANISH 
• 
Baseline Questionnaire (available in 6 formats; content identical in all 6 formats) 
• 
Baseline Study Questionnaire – for administration via paper - ENGLISH 
• 
Baseline Study Questionnaire – for administration via secure weblink - ENGLISH 
• 
Baseline Study Questionnaire – for administration via phone - ENGLISH 
• 
Baseline Study Questionnaire – for administration via paper - SPANISH 
• 
Baseline Study Questionnaire – for administration via secure weblink - SPANISH 
• 
Baseline Study Questionnaire – for administration via phone - SPANISH 
• 
Follow-up Questionnaire (available in 6 formats; content identical in all 6 formats) 
• 
Follow-up Study Questionnaire – for administration via paper - ENGLISH 
• 
Follow-up Study Questionnaire – for administration via secure weblink - ENGLISH 
• 
Follow-up Study Questionnaire – for administration via phone - ENGLISH 
• 
Follow-up Study Questionnaire – for administration via paper - SPANISH 
• 
Follow-up Study Questionnaire – for administration via secure weblink - SPANISH 
• 
Follow-up Study Questionnaire – for administration via phone - SPANISH 
• 
Patient Medication Diary – ENGLISH 
• 
Patient Medication Diary – SPANISH 
• 
Drug Diary Letter – ENGLISH 
• 
Drug Diary Letter – SPANISH  
• 
Informational Flyer – ENGLISH 
• 
Informational Flyer – SPANISH 
• 
Informational Video – ENGLISH (not available in Spanish at this time) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18.0 
AFT-28 Statistical Analysis Plan  
 
ALLIANCE FOUNDATION TRIALS, LLC (AFT) 
 
PROTOCOL NUMBER 
AFT-28  
 
Direct Oral Anticoagulants (DOACs) versus LMWH +/- Warfarin for VTE in Cancer:  
A Randomized Effectiveness Trial (CANVAS Trial) 
 
CANVAS: Cancer-related VTE Anticoagulation Strategies 
 
Statistical Analysis Plan 
 
 Version: 2 
 
Date: January 25, 2021  
 
ClinicalTrials.gov Identifier: NCT02744092 
 
 
Study Chair 
Jean Connors MD 
Brigham and Women's Hospital  
75 Francis Street 
Boston, MA 02215 
Tel: 617-525-9337   
jconnors@bwh.harvard.edu 
 
 
Study Co-Chair 
Deborah Schrag MD MPH 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
Tel: 617-582-8301   
deb_schrag@dfci.harvard.edu 
 
 
Study Statistician 
Hajime Uno PhD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
Tel: 617-682-6893   
huno@ds.dfci.harvard.edu 


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SIGNATURE PAGE 
 
 
 
Protocol Title:  
Direct Oral Anticoagulants (DOACs) versus LMWH +/- Warfarin 
for VTE in Cancer: A Randomized Effectiveness Trial (CANVAS 
Trial) 
 
 
Protocol Number:  
 
AFT-28 
 
 
SAP Version:   
  
Version 2  
 
Date:  
 
 
January 25, 2021 
 
 
 
 
 
 
 
 
Jean Connors, MD 
Study Chair 
 
Date 
 
 
 
 
 
Deborah Schrag, MD, MPH 
Study Co-Chair 
 
 
 
 
Date 
Hajime Uno, PhD 
Study Statistician 
 
 
 
 
Date 
 
 
 
 
 
 
 
 


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RECORDS ON REVISIONS 
Version 
Date for creation or 
modification 
Person in charge 
Remarks 
Ver. 1 
December 15, 2020 
Hajime Uno 
Originally prepared 
Ver. 2 
January 25, 2021 
Hajime Uno 
Updated  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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AFT-28 Statistical Analysis Plan Table of Contents 
1. INTRODUCTION ................................................................................................................................. 74 
2. STUDY OVERVIEW ............................................................................................................................ 74 
2.1. Objectives ...................................................................................................................................................... 74 
2.2. Study Design ................................................................................................................................................. 74 
2.3. Eligibility ......................................................................................................................................................... 75 
2.4. Randomization and stratification criteria ................................................................................................... 75 
2.5. Sample size justification .............................................................................................................................. 76 
3. ANALYSIS METHODS AND PRESENTATION ............................................................................. 76 
3.1. General principles ........................................................................................................................................ 76 
3.2. Definition of analysis populations ............................................................................................................... 77 
3.3. Disposition of study subjects ...................................................................................................................... 78 
3.4. Baseline demographic and disease characteristics ................................................................................ 78 
3.5. Primary endpoint evaluation ....................................................................................................................... 79 
3.5.1. Primary endpoint................................................................................................................... 79 
3.5.2. Analysis for the primary endpoint ....................................................................................... 79 
3.5.2.1. Primary analysis ................................................................................................................................................ 79 
3.5.2.2. Planned Interim Analyses................................................................................................................................... 80 
3.5.2.3. Secondary analyses of the primary endpoint ...................................................................................................... 80 
3.6. Secondary endpoint evaluation .................................................................................................................. 81 
3.6.1. Secondary endpoints ........................................................................................................... 81 
3.6.2. Analyses for secondary endpoints ..................................................................................... 82 
3.7. Other/Adherence Endpoints ....................................................................................................................... 83 
3.8. Safety endpoint evaluation .......................................................................................................................... 83 
3.8.1. Safety endpoints ................................................................................................................... 83 
3.8.2. Analyses for safety endpoints ............................................................................................. 83 
3.9. Subgroup Analyses ...................................................................................................................................... 84 
3.9.1. Pre-specified subgroup 1: Patients with Highly Thrombogenic Tumors ...................... 84 
3.9.2. Pre-specified subgroup 2: Indwelling Central Venous Catheters ................................. 84 
3.9.3. Pre-specified subgroup 3: Thrombocytopenia ................................................................. 84 
3.9.4. Other preplanned subgroups .............................................................................................. 84 
3.10. Software ....................................................................................................................................................... 85 
REFERENCES ......................................................................................................................................... 85 
 
 
 


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Glossary of abbreviations 
AFT -- Alliance Foundation Trials, LLC 
CI -- Confidence Interval 
CNS -- Central Nervous System 
DOAC -- Direct Oral Anticoagulants 
DVT -- Deep Vein Thrombosis 
ITT – Intention-to-Treat  
LMWH -- Low Molecular Weight Heparin  
PE -- Pulmonary Embolism  
SD – Standard Deviation 
SE – Standard Error 
RCT – Repeated Confidence Interval 
VTE -- Venous Thromboembolism 
 
 
 


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1. Introduction 
 
This document describes the statistical analyses and data presentations for the randomized 
effectiveness of Direct Oral Anticoagulants (DOACs) versus LMWH +/- Warfarin for VTE in 
cancer. This statistical analysis plan is developed in reference to AFT-28 Protocol Version 7.0 
dated January, 20, 2021. 
2. Study overview 
 
2.1. Objectives 
The primary objective of the study is to compare the effectiveness of anticoagulation with a 
DOAC (intervention) with LMWH/warfarin (comparator) for preventing VTE recurrence in 
patients with cancer. The hypothesis is that the benefit of secondary prophylactic 
anticoagulation with a DOAC is not worse than the benefit from treatment with LMWH/warfarin 
based on cumulative VTE recurrence reported by patients or their clinicians at 6 months. 
The secondary objectives are:  
1) To compare the harms of DOAC vs. LMWH/warfarin therapy for cancer patients with VTE 
based on the cumulative rate of major bleeding at 6 months. 
• 
Hypothesis: The harms from DOAC therapy are not worse than the harms from 
LMWH/warfarin therapy based on the cumulative rates of major bleeding reported by 
patients or clinicians at 6 months. 
2) To compare the impact of DOAC vs. LMWH/warfarin therapy on the experience and 
burden of anticoagulation therapy for cancer patients with VTE. 
• 
Hypothesis A: DOAC and LMWH/warfarin therapy are associated with similar overall 
HRQOL (health-related quality of life) at 3 and 6 months. 
• 
Hypothesis B: DOAC therapy is superior to LMWH/warfarin based on the Anti-Clot 
Therapy Scale at 3 and 6 months. 
3) To compare the impact of DOAC vs. LMWH/warfarin therapy on mortality in cancer 
patients with VTE  
• 
Hypothesis: The risks of all-cause and cause-specific mortality for cancer patients treated 
with DOAC therapy are not worse than the risks for those treated with LMWH/warfarin 
based on survival at 6 months. 
 
2.2. Study Design 
The study design is a randomized effectiveness study to evaluate the effectiveness of DOAC 
therapy compared to usual care with LMWH/warfarin. Eligible patients who accept randomization 
will be enrolled in the study (the randomized cohort), and they will be randomly assigned either 
the DOAC therapy group or the usual care group at a 1:1 ratio. Those patients who decline 
randomization but choose treatment on one of the two study arms will be invited to the study (the 
preference cohort). The rationale of employing the hybrid study design with the two cohorts is 
that both cohorts have their own strengths, and they complement each other. Specifically, the 
randomized controlled design is the most rigorous study design for comparing treatment 
alternatives. However, it may not capture the effectiveness under the real-world setting because 
the analysis population is limited to only those patients who accept randomization. On the other 
hand, the non-randomized study (i.e., the preference cohort) assesses the effectiveness that 
more likely occurs under real-world circumstances, while the internal validity (i.e., the 
comparability between the two treatment groups) has to rely on unverifiable assumptions. This 
hybrid study design will maximize the totality of evidence of comparative effectiveness between 
the DOAC and usual care.  All statistical analyses (details below) will be performed with the 
randomized cohort and the preference cohort separately, and they will be combined using a 


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meta-analytic methodology (details below).  The results from the randomized cohort will be 
considered the primary results. 
 
2.3. Eligibility  
 
The protocol (Section 4.0) stated: 
• 
Inclusion criteria 
▪ Diagnosis of an advanced solid tumor, lymphoma, chronic lymphocytic leukemia 
(CLL), or myeloma (no time restrictions or limitations) –OR– diagnosis of early 
stage solid tumor cancer, lymphoma, chronic lymphocytic leukemia (CLL), or 
myeloma < 12 months prior to study enrollment. 
▪ Diagnosis of VTE < 30 days prior to study enrollment for which potential benefits 
of anticoagulation therapy to prevent recurrence of VTE were judged by the 
treating physician to exceed the potential harms. Diagnosis may be made based 
on physical exam or imaging studies. Participants with both symptomatic and 
asymptomatic VTEs are eligible. Any anticoagulation drug/strategy may be used 
to treat the index VTE; protocol treatment will begin < 14 days after enrollment. 
▪ Treating physician intends to put participant on anticoagulation therapy for at 
least three months.  
▪ Age ≥ 18 years. 
▪ Platelet count is > 50,000/mm3 (< 7 days prior to enrollment). 
▪ CrCl (Creatinine Clearance) is > 15 ml/min (<7 days prior to enrollment). 
 
• 
Exclusion criteria 
▪ 
Diagnosis of acute leukemia.  
▪ Has ever received or is scheduled to receive an Allogeneic Hematopoietic Stem 
Cell Transplantation (alloHSCT). 
▪ Patients who have ever received an Autologous Hematopoietic Stem Cell 
Transplantation (autoHSCT) are eligible. 
▪ Patients who are scheduled to receive an Autologous Hematopoietic Stem Cell 
Transplantation (autoHSCT) are not eligible. 
▪ 
Ongoing, clinically significant bleeding (CTCAE grade 3 or 4). 
▪ 
Ongoing therapy with a P-gp inhibitor (e.g., nelfinavir, indinavir, or saquinavir-protease 
inhibitors for HIV) as these drugs interact with the factor Xa inhibitors. 
▪ 
Need for ongoing therapy with: certain antifungals (itraconazole, ketaconazole, 
voriconazole); rifampin; or certain antiseizure medications (phenytoin, carbamazepine, 
phenobarbital) at the time of enrollment.  
▪ 
Subjects with any other contraindications to anticoagulation or conditions that as judged 
by the treating clinician would place the subject at increased risk of harm if s/he 
participated in the study. 
▪ 
Pregnant or nursing.  
 
 
2.4. Randomization and stratification criteria 
If an eligible participant was offered randomization and declined to be randomized, then a 
limited number of participants were allowed to enroll in the Preference Cohort, where the 
treating physician and patient chose protocol treatment on Arm 1 or Arm 2. 


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Participants who agreed to be randomized or participants who entered after the closure 
of the preference cohort were randomized 1:1 to either: 
Arm 1 – Intervention Arm, DOAC (choice of rivaroxaban, apixaban, edoxaban, or 
dabigatran) 
Arm 2 – Usual Care Arm, LMWH/warfarin (choice of LMWH with or without a 
transition to warfarin) 
 
2.5. Sample size justification 
 
The protocol (Section 13.2.4) stated that: 
• 
As of April 28, 2020, the study has enrolled a total of 808 patients. Of the 808, 668 were 
enrolled in the randomized cohort. When we discontinue the patient enrollment now, the total 
sample size is expected to be around 810 depending on the exact date of formal closure. With 
this sample size, the power of noninferiority test already reaches 90% (See Table). For 
superiority, it is slightly below the 80% target power at 75%. The expected length of 
confidence interval (CI) for the difference in event rate is now 6.1% with 808 patients, and it 
would have been 5.8% with the planned total sample size (N=890). This suggests that the 
gain in the precision may be marginal. Given the challenges to continued accrual in the setting 
of the COVID-19 pandemic and the recently reported results of the Caravaggio study we 
propose revision as follows. 
• 
 
Table: Power calculation for the primary analysis 
Date 
N 
(Randomized 
Cohort) 
N (total) 
Length of CI 
for 
difference 
Power 
 
Noninferiority 
Superiority 
Revised 
Statistical 
Analysis Plan 
668 
808 
6.1% 
0.900 
0.756 
Originally 
Planned Goal 
750 
890 
5.8% 
0.927 
0.797 
 
 
Note that the termination of the new enrollment to the CANVAS trial therefore was 
approved by the AFT DSMB in April 2020 before reaching the original proposed 890 
patient accrual mark. Upon formal study closure at all sites, the final total sample size 
was 811 (140 in the preference cohort, 671 in the randomized cohort).  
 
3. Analysis methods and presentation  
 
3.1. General principles 
Analysis will be performed on the preference cohort and the randomized cohort separately. 
Where appropriate, variables will be summarized descriptively (frequency counts and percents 
for categorical variables, and counts, means, standard deviations (SD), medians, minimums, 
maximums, etc., for continuous variables) for two treatment groups – DOACs and Control.  The 
primary analysis cohort is the randomized cohort. The secondary analysis cohort is the 
preference cohort. Using meta-analysis technique, the results from two cohorts will be 
combined.  


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We will construct 90% two-sided confidence intervals (CI) for the between-group comparisons 
for the analyses of VTE, bleeding, and mortality. A 90% two-sided CI corresponds to conducting 
a statistical test at a one-sided 5% significance level. For the other analyses, all confidence 
intervals, statistical tests, and resulting p-values will be reported as two-sided and assessed at 
the 5% significance level. If the computed lower confidence bound for proportion variables is 
less than –1, then the lower bound is defined as –1.  If the computed upper confidence bound 
for proportion variables is greater than 1, then the upper bound is defined as 1.  
 
3.2. Definition of analysis populations 
 
Intention-to-Treat (ITT) population 
The intention-to-treat population for the randomized cohort includes all randomized subjects. 
The corresponding population for the preference cohort consists of all patients who would not 
be randomized but participated in this study. The corresponding population for the full cohort 
consists of all randomized subjects and all subjects in the preference cohort. In the analyses 
with the ITT populaiton, we peformed the analyses by group, using the assinged treatment 
group indicator regardless of whether the subject recieved the assigned treatment or not.   
 
Modified Intention-to-Treat (ITT) population (Primary analyses) 
Based on the data review performed before conducting the final analysis, we found that quite a 
few subjects in this pragmatic trial did not receive treatment according to their assigned group. 
In the ITT population, those patients who received treatment in the group opposite to the one to 
which they were randomized would also be included in the analysis. Based on the concern that 
these subjects could cause a potential bias toward the noninferiority claim with the ITT analysis, 
we have defined a modified ITT population. In order to be conservative with regard to testing the 
non-inferiorty hypothesis, the primary analyses will rely on the modified ITT population. The 
modified ITT population includes all subjects who received a study drug according to their 
assigned treatment group and participated in this study. 
 
The modified ITT population for the randomized cohort includes all randomized subjects who 
received at least one dose of the anti-coagulation treatment strategy to which they were 
assigned. The preference modified ITT population includes all non-randomized subjects who 
received the anti-coagulation treatment which they preferred subsequet to informed consent to 
study participation. The full modified ITT population includes the sum of the two aformentioned 
categories (randomized cohort and preference cohort). 
 
 
Per-protocol population 
The per-protocol population includes those patients who received a study drug of the assigned 
treatment group and do not have any major protocol violations.  
 
The randomized per protocol population includes those subjects who received a study drug 
according to the randomized treatment assignement and do not have any major protocol 
violations. The preference per protocol population includes those subjects who were not 
randomzied and received a study drug according to the subject’s preference and do not have 
any major protocol violation. The full per protocol population is the sum of the two 
aformentioned categories. 
 
Safety population 


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The safety populations are identifical to the modified ITT populations. 
 
3.3. Disposition of study subjects 
Following the CONSORT guideline1 a CONSORT diagram will be generated to describe the 
patient population by cohort with descriptions of the numbers of participants in the preference 
and randomized cohorts displayed side by side. 
 
3.4. Baseline demographic and disease characteristics 
Baseline patient characteristics and disease characteristics listed below will be summarized 
using descriptive statistics by group. The two-sample Wilcoxon test will be used for between-
group comparisons of continuous variables and ordered categorical variables, and Fisher’s 
exact test will be used for nominal categorical variables.    
 
List of the variables: 
• 
Age at enrollment [year] 
• 
Age category (<65, >=65 year old) 
• 
Sex (Male/Female) 
• 
Race (Native American or Alaska Native/Asian/Black or African American/Native 
Hawaiian or other Pacific Islander/White/Unknown) 
• 
Ethnicity (Hispanic or Latino/Not Hispanic/Unknown) 
• 
Height [cm] 
• 
Weight [kg] 
• 
BMI 
• 
Education level (Grade school or less/high school or GED/Some vocational, business or 
trade school/some college/college/some graduate school/graduate or professional 
degree) 
• 
Whether out-of-pocket costs of anti-clotting drugs affect decision to participate in the 
study (not at all/a little/moderate/quite a bit/extremely) 
• 
Payment (Private insurance/Medicare/Medicaid/Military or Veterans Sponsored/Self Pay/ 
Other/Unknown) 
• 
ECOG performance status (0/1/2/3/4) 
• 
Smoking status (current/former/never) 
• 
Cancer ever metastasized (Yes/No) 
• 
HighlyThrombogenetic Tumors (Yes/No)  
• 
Indwelling Central Venous Catheters (Yes/No) 
• 
Thrombocytopenia (Yes/No) (<150,000/mm3) 
• 
Creatinine Clearance [ml/min] (Gender-specific Normal/abnormal) 
• 
Albumin [g/dL] (<3.5mg/dl vs. >=3.5mg/dl) 
• 
Self described global health status at baseline (excellent/very good/good/fair/poor) 
• 
Current cancer Type (solid cancer vs hematologic cancer) 
• 
Current cancer Subtype (Leukemia/Lymphomas/Blood Disorders, Breast, 
Gastrointestinal and Digestive, Gynecologic, Head and Neck, Neurological (Brain), 
Sarcoma, Skin/Melanoma, Thoracic (Chest/Lung), Genitourinary, Other) 
• 
AJCC cancer stage at diagnosis (0, I, II, III, IV, Not applicable) 
• 
Blood clot type (PE, DVT, Both, Unknown) 
• 
The part(s) of the body where the blood clot found 
o Lung (Yes/No) 
o Leg (Yes/No) 
o Arm (Yes/No) 


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o Other (Yes/No) 
• 
Site of index VTE diagnosis (inpatient hospital stay/outpatient appointment/emergency 
department/home/other) 
• 
Site of index VTE first treatment (inpatient hospital stay/outpatient 
appointment/emergency department/home/other) 
• 
First index VTE treatment prescribed 
(Warfarin/Dalteparin/Enoxaparin/Fondaparinux/Heparin/Other oral medication/Other 
injectable medication/Unknown) 
• 
Previous VTEs and the number of prior VTEs (No, 1, 2, 3+) 
• 
Bleeding at baseline (None, Mild, Moderate, Severe) 
 
3.5. Primary endpoint evaluation 
3.5.1. Primary endpoint 
The primary endpoint is cumulative VTE recurrence reported by either patients or their clinicians 
at 6 months. A recurrent VTE is synonymous with the cumulative incidence of any VTE 
irrespective of the anatomic site. Note that we will analyze the VTE recurrent event rate at 6 
months but the data we will use to assess this primary endpoint is not a dichotomous variable 
that indicates the presence/absence of cummulative VTE recurrent events at 6 months. The 
analysis variable we will use for the primary endpoint is time from enrollment to occurrence of a 
VTE recurrent event. We will estimate the VTE recurrent event at 6 months using a time-to-
event analysis with this analysis variable, where deaths are handled as competing risks and 
lost-to-followup patients are handled as censored observations (see Section 3.5.2.1 for details). 
This approach accounts for censored observations more appropriately than an analysis using a 
dichotmous variable, whereas it yields the same result if there are no censored observations. 
 
3.5.2. Analysis for the primary endpoint 
 
3.5.2.1. Primary analysis  
The primary aim of this study is to compare the intervention and comparator arms with respect 
to their ability to prevent recurrent VTE. Because the intervention (DOAC therapy) is more easily 
administered than the comparator (usual care with LMWH warfarin), DOAC is expected to have 
higher adherence and therefore decreased incidence of VTE. Accordingly, a noninferiority 
design with a superiority alternative is preferred, as described by Friedlen et al.2 The primary 
analysis will test the noninferiority of the DOAC therapy with the primary analytic cohort 
(modified ITT population of the randomized cohort). If noninferiority is demonstrated, superiority 
of the DOAC therapy will be tested. 
 
Because VTE is often a proximate cause of death in cancer patients’ unexplained sudden 
demise, but diagnostic procedures are rarely performed (post-mortem scans, autopsies, etc.), we 
considered VTEs that were clinically significant as the primary outcome on the basis of an 
antemortem diagnosis. Separately, we looked at all-cause deaths because deaths from cancer 
and deaths from VTE are difficult to distinguish. Cancer patients routinely die at home and it is 
not possible to determine whether the proximate cause of death was a VTE, progression of tumor 
or some other cause. Indeed, the cause of many deaths in cancer patients is multifactorial.  We 
will estimate the cumulative incidence of recurrent VTE at 6 months using standard competing 
risk analysis methods2, where death will be treated as a competing risk. We calculate the 
difference in the 6 months incidence rate between groups and the corresponding 0.90 confidence 
interval (CI).  
 
1) Noninferiority test of DOAC 


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The hypothesis for testing the noninferiority of the DOAC strategy is that the difference in 
the primary endpoint at 6 months is no greater than a noninferiority margin of 3% for the 
intervention-comparator. This noninferiority margin was selected based on what is 
acceptable to patients based on patient-stakeholder input as well as on input 
provided by clinicians 
 
To confirm the noninferiority hypothesis, we will construct a two-sided 90% confidence 
interval (CI) for the difference in the cumulative incidence of the primary endpoint at 6 
months (180 days). If the upper bound of the CI is less than 3%, we will conclude that the 
DOAC management strategy is non-inferior to the LMWH/warfarin strategy for 
management of VTE in patients with cancer.  
 
2) Superiority test of DOAC 
 
If noninferiority of DOAC is demonstrated, a superiority test of DOAC will be performed 
using a one-sided 0.05 significance level and the same two-sided 90% CI for the 
difference in the event rate of the primary endpoint at 6 months as used for the 
noninferiority test. When the upper bound of the CI is less than 0, we will conclude that 
DOAC therapy is superior to LMWH/warfarin in terms of VTE prevention. Because we 
will perform the superiority test only after the noninferiority of DOAC is demonstrated, 
the overall type I error rate is maintained at the 0.05 level (one-sided) without splitting 
alpha.3 
 
3.5.2.2. Planned Interim Analyses 
This study design incorporates several interim analyses and one final analysis for the 
comparison of the primary endpoint.  A 90% two-sided repeated confidence interval (RCI)4 for 
the difference in the cumulative incidence rate of VTE at 6 months (DOAC minus Usual Care) 
between two arms was estimated. We use the critical values based on the Lan-DeMets error 
spending function5 corresponding to the truncated version of O’Brien-Fleming boundaries.6  
 
Prior to the final analysis, four interim analyses were conducted on September 7, 2018, March 
22, 2019, September 9, 2019, and March 25, 2020. Given these interim analyses, the critical 
value for the final analysis will be 1.710, which corresponds to a one-sided 0.0436 alpha. The 
confidence coefficient of the 90% two-sided RCI will be 91.28% for the final analysis.  
 
3.5.2.3. Secondary analyses of the primary endpoint 
 
1) Analysis with other summary measures 
The absolute difference in 6-month event rate based on the cumulative incidence function 
(CIF) is the primary summary measure of the between-group difference. As a secondary 
analysis, we will calcuate a subhazard ratio using the Fine and Gray model.7 We will construct 
0.90 CIs for these measures.   
 
2) Alternative way to handle deaths 
In the primary analysis, we handle deaths as competing risks and estimate the recurrent VTE 
rates by the CIF approach. As a secondary analysis, we will handle deaths as censored 
observations and estimate the recurrent VTE event rates by the Kaplan-Meier method. We will 
calculate the hazard ratio and difference in the event rate at 6 months and corresponding 0.90 
CIs. 
 


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3) Sensitivity Analyses including data from the preference cohort 
This study allowed a limited number of participants to enroll in the preference cohort if an 
eligible participant declines randomization. The Preference Cohort Closing Rules were pre-
specified in Section 13.2.2 in the study protocol to specify the maximum number of 
participants enrolled in the preference cohort and to avoid an extreme imbalance of the 
number of participants between two groups. The results of monthly data monitoring in June 
2017 observed the pre-set imbalance criteria in between arm selection. The enrollment to the 
preference cohort was thereforeclosed in December 2017, after 140 patients had enrolled in 
it. 
 
First, we will compare characteristics between the preference and randomized cohorts to 
assess potential heterogeneity between the two cohorts. Fisher’s exact test will be used for 
nominal categorical variables, and two-sample Wilcoxon tests will be used for ordered 
categorical or continuous variables.  
 
We will estimate the difference in VTE event rate at 6 months and its standard error from the 
preference cohort, using a propensity score approach to adjust for potential treatment 
selection.8 We will then combine the result with that from the randomized cohort, using a 
weighted average. An optimal weight (i.e., the reciprocals of the variance) will be used. The 
resulting estimate for the difference in VTE event rate and 90% CI can be considered an 
overall average treatment effect of DOAC across the full cohort. In no circumstance will 
analyses of the full cohort be presented as primary.  
 
4) Analysis by type of VTE recurrence 
We will also conduct the same analyses for each of the following subtypes of VTE recurrence. 
1) Pulmonary embolism (PE) with or without deep vein thrombosis (DVT) 
2) DVT without PE 
 
5) Adjusted analyses 
We will perform adjusted analysis to estimate the adjusted treatment effect, using 
generalized linear mixed-effects models with the logit link. Censored observations will be 
handled by the inverse probability censoring weight technique. 9 The participating sites will 
be included as random-effects. 10 Those baseline characteristics variables (see 3.4) whose 
distributions are not balanced between two groups (p<0.05) in the randomization cohort will 
be included as fixed-effects in the models for adjustment.  
 
6) Sensitivity Analyses using the ITT and the per protocol populations. 
Sensitivity analyses will be performed with alternative cohort specification.  
We will repeat all the analyses using the ITT population and then using the per-protocol 
population.  
 
3.6. Secondary endpoint evaluation 
3.6.1. Secondary endpoints 
• 
Cumulative incidence of major bleeding reported by either patients or clinicians at 6 
months 
• 
Cumulative incidence of all bleeding events and bleeding according to its severity in the 
following categories:1) major bleeding, 2) clinically significant non-major and 3) nuisance  
• 
Cumulative incidence of death at 6 months  
• 
Overall HRQOL at 3 and 6 months 
• 
Overall score on the Anti-Clot Therapy Scale at 3 and 6 months 


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3.6.2. Analyses for secondary endpoints 
1) Cumulative rates of major bleeding reported by patients or clinicians at 6 months (grade 
3, 4, or 5) 
We will repeat the analogous analyses as performed for the primary endpoint (see 3.5.2). 
The primary analysis plan for major bleeding, fatal or non-fatal, is also based on the 
sequential evaluation of noninferiority and superiority. We will construct a two-sided 90% 
CI for the difference in the cumulative incidence rate for the composite outcomes of major 
bleeding and death. If the upper bound of the CI is less than 2.5%, we will conclude that 
DOAC is noninferior to LMWH/warfarin in terms of major bleeding.  The same secondary 
analyses as planned for the primary endpoint will be performed. In contrast to clotting, fatal 
bleeding events are usually clinically manifest and recorded and therefore can be 
distinguished. 
 
 
2) Cumulative incidence of all bleeding events reported by patients or clinicians at 6 
months in the following categories: 1) major bleeding (Grade >=3), 2) clinically significant 
non-major (Grade 2); and,3) nuisance bleeding (Grade 1)  
 
Clinically significant non-major bleeding is defined as Grade 2 Nuisance bleeding is 
defined as Grade 1 according to the NCI CTCAE criteria. We will perform the same 
analyses as described for major bleeding. 
 
 
3) Mortality 
Time from randomization to death from any cause is a secondary endpoint. The study is 
powered to confirm the primary hypothesis for recurrent VTE; we do not anticipate 
enough power to perform a confirmatory analysis for all-cause mortality. We will instead 
focus on providing quantitative information for the between-group difference for this 
endpoint. We will describe the survival time distribution by treatment group using the 
Kaplan-Meier method. Also, we will compare the restricted mean survival times 
(RMST)11 between groups. The truncation time point for calculating the RMST will be 6 
months, which will give us an estimate of 6-month lifetime expectancy for each group. 
We will estimate the difference in RMST and the corresponding 90% CI. The hazard 
ratio for death and its 90% CI will also be calculated if the proportional hazards 
assumption is reasonable. The determination of the violation of the proportional hazards 
assumption will be based on a significant p-value (<0.05) for the Grambsch and 
Therneau test.12 
 
 
4) The Patient-Centered Experience of Anticoagulation QOL and Burdens 
 
i) Health Related Quality of Life (SF-12) at 3 and 6 months 
For SF-12, the primary analysis variable is the difference in the SF-12 mean change 
score from baseline. We will consider 2-point differences as clinically meaningful. We will 
use multiple imputations to handle missing observations.13 First, we will create 10 
complete datasets, imputing missing values using chained equations, where we include 
measurements at baseline, 3 months, and 6 months. Second, we will estimate mean 
changes and the standard errors for each of the 10 complete sets. We will then use 
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between two groups.  Using the resulting estimate and the standard error, we will 
perform a Z-test to evaluate equality of SF-12 scores between groups. 
 
ii) Anti-Clot Treatment Scale (ACTS) score at 3 and 6 months 
For ACTS score, the primary analysis variables are the ACTS Burdens total score 
and the ACTS Benefits total score at month 6. We will consider 2-point differences as 
clinically meaningful. To minimize potential bias due to missing observations, we will 
allow and include surrogate estimates for all 3 patient-reported outcome 
assessments. Next, we will use multiple imputation to handle missing observations. 
First, we will create 10 complete datasets, imputing missing values using chained 
equations, where we include measurements at baseline, 3 months, and 6 months. 
Second, we will estimate mean changes and the standard errors for each of the 10 
complete sets. Lastly, we will integrate the results using Rubin’s method. 
 
3.7. Other/Persistence with treatment endpoints 
• 
Performance status 
We will use the two-sample Wilcoxon test to evaluate between-group differences in  
ECOG PS. 
• 
Cumulative rates of remaining on any anti-coagulation therapy at 3 and 6 months 
• 
Cumulative rates of remaining on the assigned (and/or selected in the case of the 
preference cohort) anti-coagulation therapy at 3 and 6 months. 
• 
 
 
3.8. Safety endpoint evaluation 
3.8.1. Safety endpoints 
• 
Major bleeding (primary protocol safety endpoint) 
• 
Clinically significant non-major bleeding 
• 
Any bleeding (major bleeding and clinically significant non-major bleeding and nuisance 
bleeding) 
• 
Other Serious Adverse Events 
 
For this trial, “Expedited Serious Adverse Event” reporting is required using the SAE 
Report Form in REDCap. Adverse event reporting begins at enrollment and should 
continue until 30 days after the last administration of on-study protocol treatment. SAEs 
for other endpoints are reported via the following guidelines: 
• 
Grade 1 or 2 adverse events that resulted in hospitalization for 24 or more hours, 
or 
• 
Grade 3, 4, or 5 adverse events regardless of hospitalization 
 
 
 
 
3.8.2. Analyses for safety endpoints 
The analysis plan for major bleeding and any bleeding are outlined in section 3.6.2. Incidence of 
all other SAEs will be summarized by cohort, arm, grade, and type of SAE.  Fisher’s exact test 
will be performed to compare the event rates.  
 


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3.9. Subgroup Analyses 
We will perform subgroup analyses to investigate the potential heterogeneity of treatment 
effects. For each subgroup, we will perform the same analyses described in the previous 
sections. The treatment effect by subgroup will be summarized by point estimates and 
corresponding 90% confidence intervals. We will create forest plots to display those results. 
This analysis will be performed with an exploratory purpose; we will not adjust for multiple 
comparisons.   
 
First, we will focus on the 3 key subgroups described below because these groups are common, 
and decision making in these contexts is challenging for oncologists and patients. These 3 
subgroups represent populations of particular interest for clinical decision makers.   
 
3.9.1. Pre-specified subgroup 1: Patients with Highly Thrombogenic 
Tumors 
We anticipate that at least 300 patients with lung (NSCLC and small cell), pancreas, 
esophagogastric and ovarian cancers are represented in the study sample. These patients have 
an even higher risk of VTE than cancer patients in general. Based on anticipated higher 
adherence rates to DOAC therapy and the likelihood of warfarin failures in the LMWH/warfarin 
arm, we anticipate a slight advantage for DOACs over the standard care arm. As planned for 
the full cohort analysis, we will only test for superiority in the subgroup if noninferiority is met. 
 
3.9.2. Pre-specified subgroup 2: Indwelling Central Venous Catheters 
We anticipate that a subgroup of approximately 500 study participants will have an indwelling 
central venous catheter in place at the time of enrollment. This recruitment should not be 
challenging given how commonplace use of these catheters has become in routine oncology 
practice. The rate of VTEs is expected to be slightly higher for patients with a central venous 
catheter due to the excess risk of upper extremity clots. 
 
3.9.3. Pre-specified subgroup 3: Thrombocytopenia  
We will consider the subgroup of participants with baseline platelet counts less than 
150,000/microliter. Thrombocytopenic cancer patients face high risk of VTE but also face higher 
risks of bleeding. In this setting, the choice of anticoagulation strategy is challenging.  
 
3.9.4. Other preplanned subgroups  
We will perform the same analysis for the following subgroups with an exploratory purpose. 
• 
Sex (Male, Female) 
• 
Age (below 65, equal or greater than 65) 
• 
Participants with central nervous system (CNS) tumor involvement 
• 
Participants with liver metastases  
• 
Participants with albumin <3.5mg/dL 
• 
Participants treated with bevacizumab 
• 
Participants incidentally detected VTE on routine imaging studies (versus 
symptomatically detected VTE) 
• 
Participants with metastatic disease (versus completely resected disease or no 
radiographic evidence of tumor) 
• 
Participants with >80% days of persistence with anticoagulant therapy (vs. >50-80% vs. 
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• 
Participants with >80% days of persistence with anticoagulant therapy (vs. >50-80% vs. 
<=50%) by medical record abstraction/dose refills 
• 
Solid tumors versus hematologic malignancies 
 
3.10. Software 
The statistical analyses will be performed with R version 4.0.2, Stata version 16, and SAS 
version 9.4. 
 
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• 
 
2. Pintilie M. Competing Risks: A Practical Perspective. UK: John Wiley & Sons; 2006. 
 
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• 
 
10. Senn SJ, Lewis RJ. Treatment Effects in Multicenter Randomized Clinical Trials. JAMA 
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11. Uno H, Claggett B, Tian L, et al. Moving beyond the hazard ratio in quantifying the between-
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