A Pilot Study Assessing the Feasibility of a Randomized Controlled Trial Investigating Primary Thromboprophylaxis With Rivaroxaban in Patients With Malignancy and Central Venous Catheters
Phase: PHASE3
Conditions: Upper Extremity Deep Vein Thrombosis, Central Venous Catheter Thrombosis, Cancer
Sponsor: Ottawa Hospital Research Institute

Confidentiality agreement 
This protocol contains confidential information belonging to Drs. Rick Ikesaka and Marc Carrier. Except 
as may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold 
such information in confidence and not to disclose it to others (except where required by applicable law) 
nor use it er nau orized purposes. In the event of actual or suspected breach of this obligation, Dr. 
Rick 1keaka Jr Ma c 1 rrier, The Ottawa Hospital should be promptly notified. 
be,a-
Date 
Protocol Title: A pilot study assessing the feasibility of a randomized controlled trial 
investigating primary thromboprophylaxis with rivaroxaban in patients with malignancy and 
central venous catheters: TRIM-Line 
Protocol #20180357 
Co-Principal Investigators 
Dr. Rick lkesaka 
St. Joseph's Healthcare Hamilton 
Charlton Campus 
50 Charlton Ave East 
Hamilton ON, L8N 4A6 
and 
Dr. Marc Carrier 
Ottawa Hospital — General Campus 
501 Smyth Road 
Ottawa, ON, K1H 8L6 
Coordinating Centre 
Ottawa Hospital Research Institute 
1053 Carling Ave, Ottawa, ON K1Y 4E9 
Funding Mechanism 
CanVECTOR Network 
Sponsor 
Ottawa Hospital Research Institute 
Protocol Version 
18September2019 Version 1.3 
NCT # 
03506815 
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Site Investigator Name (Printed) 
ator Name (Signature) 
bf2-e--Cà--,à.cotS 
SIGNATURE PAGE 
I have read and understand the protocol and I agree that it contains all the ethical, legal and scientific 
information necessary to conduct this study. I will conduct this study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. 
I will work according to the 
principles of Good Clinical Practice (GCP) as described in the Food and Drug Act, Division 5, Health 
Canada regulations, The Declaration of Helsinki (2004), and Good Clinical Practice (GCP) as described in the 
International Council on Harmonisation (ICH) document. Further, I will conduct the study in keeping with 
local regulatory requirements. 
I will provide copies of the protocol and access to all relevant information to study personnel under my 
supervision. I will discuss this material with them to ensure that they are fully informed about the drug 
and the study. 
Signature 
Date 
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Trial Personnel 
Investigators 
Rick Ikesaka 
St. Joseph's Healthcare Hamilton 
Room F301 Fontbonne Building 
Charlton Campus 
50 Charlton Ave East 
Hamilton ON, L8N 4A6 
Marc Carrier 
Sudeep Shivakumar 
Cynthia Wu 
The Ottawa Hospital, General Campus, Box 201a - 501 Smyth 
Road Ottawa ON K1N 8L6 CANADA 
Ph: 613-737-8899 ext 73034 
QEII Health Sciences Centre, VG-Site Bethune Building 
1276 South Park Street Room 432 Halifax Nova Scotia 
CANADA B3H 2Y9 
Ph: 902-473-4642 
University of Alberta Hospital 4-112 Clinical Sciences 
Building 11350 — 83 Ave. Edmonton, Alberta, CANADA 
T6G2G3 
STEERING COMMITTEE 
A Steering Committee comprised of the trial's co-investigators will manage the overall conduct 
of the trial. Drs. Ikesaka and Dr. Carrier, will regularly review the progress of the trial. The 
Steering Committee will review how the trial was conducted and review the various outcomes of 
the trial to determine if the evidence justifies a full randomized trial. 
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Table of Contents 
1. List of Abbreviations 
2. Study Synopsis 
3. Background 
3.1 Why is a Randomized Controlled Trial Needed? 
3.2 Why is a Clinical Trial needed now? 
3.3 Principal Research Questions 
3.4 Why is a pilot RCT needed before a full RCT can be completed? 
3.5 Why is an open-label trial design chosen? 
4. Trial Objectives and Design 
4.1 Trial Purpose 
4.2 Trial Design 
4.3 Trial Intervention 
4.4 Inclusion and Exclusion Criteria 
4.5 What are the Measured Outcomes for the Pilot Study 
4.6 Screening 
4.7 Randomization 
4.8 Treatment Arms 
4.9 Prohibited Medications 
4.10 Product Labelling 
4.11 Accountability and Storage 
4.12 Individual Participant Compliance 
4.13 Concomitant Medications 
4.14 Proposed frequency and duration of follow up 
4.15 Withdrawal of Subjects 
5. Safety 
5.1 Definitions 
5.2 Recording, Reporting and Follow-up of Adverse Events 
5.3 Management of Major Bleeding 
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6. Clinical Monitoring 
6.1 Monitoring 
6.2 Data and Safety Monitoring Board (DSMB) 
7.Protocol Deviation/Violations 
7.1 Protocol Deviations 
7.2 Protocol Violations 
7.3 Subject Information and Consent 
8. Statistics 
8.1 Statistical and Analytical Plans 
8.1.1 Analysis of Baseline Characteristics 
8.1.2 Pilot Trial Primary Analysis 
8.1.3 Pilot Trial Secondary Analyses 
8.1.4. Full Trial Analyses 
8.2 Determination of Sample Size 
10. Data Handling and Record Keeping 
10. Data Handling and Record Keeping 
10.1 Personal Health Information 
10.2 Case Report Forms 
10.3 Record Retention 
11. Study Dissemination Plan 
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1. 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ASA 
Aspirin 
bid 
Twice Daily 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CVC 
Central Venous Catheters 
DVT 
Deep Vein Thrombosis 
LMWH 
Low Molecular Weight Heparin 
od 
Once Daily  
po 
by mouth 
PE 
Pulmonary Embolism 
SAE 
Serious Adverse Event 
U/S 
Ultrasound 
ULN 
Upper Limit of Normal 
VTE 
Venous Thromboembolic Event 
2. 
STUDY SYNOPSIS 
Title: A pilot study assessing the feasibility of a randomized controlled trial investigating 
primary thromboprophylaxis with rivaroxaban in patients with malignancy and central venous 
catheters (CVC) 
Short Title: The TRIM-Line 
Protocol Version: 28Feb2018 Version 1.1 
Principal Investigators: Dr. Rick Ikesaka and Dr. Marc Carrier 
Sponsor: OHRI 
Study Centres: 
The Ottawa Hospital, General Campus, Ottawa, ON 
QEII Health Sciences Centre, Halifax, Nova Scotia 
University of Alberta Hospital, Edmonton, Alberta 
Timeline: February 2019-September2019 
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Purpose of Pilot Trial 
To determine the feasibility of conducting a multicentre randomized open label-controlled 
trial evaluating the use of prophylactic dose rivaroxaban to prevent CVC associated venous 
thromboembolism(VTE) among cancer patients. 
Purpose of Full Trial 
The purpose of the full trial is to determine the efficacy and safety of prophylactic dose 
rivaroxaban to prevent CVC associated VIE among cancer patients. 
Pilot Trial Endpoints 
The primary feasibility outcome for the pilot study is the number of participants recruited per 
centre per month. We will obtain baseline details of the patient's type, location and treatment 
of cancer, comorbidities and medications. Secondary feasibility outcomes of the pilot study 
will include, consent rates, loss to follow up, adherence to therapy defining 80% or greater 
medication taken as having good adherence to study drug, proportion of screened patients 
who meet eligibility criteria. 
We will document reasons for non-consent in order to assist recruitment for the larger 
multicentre trial. 
Full Trial Endpoints 
For the full multicentre trial the outcomes would be as follows: primary outcome 
symptomatic, radiographically confirmed VIE. Secondary outcomes include major and 
clinically relevant non-major bleeding (CRNMB), CVC life span, premature CVC removal, CVC 
lumen occlusion, CVC associated infection and death. 
Design 
This is a pilot study to be conducted at 3 Canadian Centres. The Ottawa Hospital, QEII Health 
Science Centre and University of Alberta Hospital. It is an open label randomized controlled 
trial. 
Consenting participants, meeting eligibility criteria will be randomized at the time of 
enrollment to one of two groups. 
Rivaroxaban 10mg po daily x 90 days 
OR 
Observation 
Participants in the treatment arm will have study drug dispensed at Day 1 and take medication 
for 90 days. Follow up visits (in person or phone) will occur at Day 30 (+/- 3 days) and Day 90 
(+/- 3 days) month and 3 months post enrollment. Overall, participants will be followed for 3 
months. Adverse events will be collected for the first 90 days. 
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Number of participants 
100 
Inclusion and Exclusion Criteria 
Inclusion criteria: 
Patients 18 years of age or older with a new or existing diagnosis of cancer with a CVC inserted 
in the last 72 hours. 
Exclusion criteria: 
1) 
CVC in place for >72 hours 
2) 
Patient requires anticoagulation for other indication 
3) 
Concomitant use of dual antiplatelet therapy 
4) 
Prior VTE 
5) 
Major bleeding event in the last 6 weeks 
6) 
Patient on concomitant medication with known interaction with rivaroxaban (eg. CYP3A4 
inhibitor) 
7) 
Pregnancy (documentation of use of effective contraception if sexually active or negative 
B- Hcg required) 
8) 
Known renal failure, based on Creatinine clearance <30 mL/min (Cockroft-Gault) (in the 
previous 3 months)* 
9) 
Documented severe liver disease (eg. acute clinical hepatitis, chronic active hepatitis, 
cirrhosis or ALT >3ULN) (in the previous 3 months)* 
10) 
Known thrombocytopenia <50x 109A (in the previous 3 months)* 
11) 
Allergy to rivaroxaban 
12) 
Life expectancy <6 months 
13) 
History of condition at increased bleeding risk including, but not limited to: 
a) Major surgical procedure or trauma within 30 days before the randomization visit 
b) Clinically significant gastrointestinal bleeding within 6 months before the 
randomization visit 
c) History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding 
d) Chronic hemorrhagic disorder 
e) Known intracranial neoplasm, arteriovenous malformation, or aneurysm 
f) Sustained uncontrolled hypertension: systolic blood pressure ?_180 mmHg or diastolic 
blood pressure ?..100 mmHg 
14) 
Primary malignancy diagnosis of basal cell or squamous cell carcinoma of the skin or 
acute leukemia or myelodysplastic syndrome 
15) 
Geographic inaccessibility 
16) 
Refused or unable to obtain consent 
* Baseline platelet count for inclusion/exclusion to be drawn within 2 weeks of enrolment. 
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SCHEDULE OF MANDATORY EVENTS 
Screening, Baseline 
and Randomization 
Day 30 +/- 3 
days 
Day 90 +/- 3 
days 
Consent 
'‘,1  
Inclusion/Exclusion 
 
Demographic 
 
Randomization 
1I 
Labs 
 
History 
 
Cancer Treatments 
1  
Dispense IP (Group 1) 
1  
Concomitant Medications 
 
IP Compliance 
 
(Section 4.5) 
Outcome Information 
 
Adverse Events 
'q 
3. STUDY RATIONALE AND BACKGROUND 
3.1 WHY IS A RANDOMIZED CONTROLLED TRIAL NEEDED? 
Venous thromboembolism is a common but potentially fatal disease. A subtype of VIE, upper 
extremity deep vein thrombosis (UEDVT) accounts for approximately 4-11% of all VIE but unlike 
lower extremity deep vein thrombosis, UEDVT are poorly described and their risk and optimal 
treatment are not known (1). Many patients with cancer require insertion of a CVC in order to 
maintain venous access, administer chemotherapy, draw blood work and provide supportive 
care. UEDVT seems to be a frequent complication of CVC in this patient population receiving 
chemotherapy (3). 
Pharmacologic thromboprophylaxis has been shown to be effective in reducing VTE in other 
high-risk populations such as hospitalized medical patients, those that have had hip or knee 
arthroplasty and in myeloma patients receiving immunomodulatory drugs (4, 5). While 
thromboprophylaxis is recommended in high risk cancer subgroups (e.g. hospitalized medically 
ill, post-major abdominal surgery, etc.) (6), it is not routinely recommended for the prevention 
of CVC associated VIE in outpatients with cancer. Previous comparative studies have not 
shown consistent clinical benefits (7-9). 
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3.2 WHY IS A CLINICAL TRIAL NEEDED NOW? 
A recent meta-analysis by D'Ambrosio et al. suggests that prophylactic anticoagulation might 
reduce the risk of UEDVT in this high-risk patient population but notes heterogeneity in study 
results and highlights the need for a large prospective randomized trial in order to definitively 
answer this question (10). 
Rivaroxaban is an oral factor Xa inhibitor with predictable pharmacokinetics that obviates the 
need for routine laboratory monitoring (11). The use of prophylactic rivaroxaban has been 
studied and proven efficacious to reduce VTE complications in other high-risk populations (post 
hip and knee arthroplasty, secondary prevention of VTE, etc.) (12). Furthermore, it is also 
currently under investigation in other high-risk cancer subgroups (CASSINI-Clinicaltrials.gov  
NC102555878) (13). Until recently, the only options for pharmacologic prophylaxis were either 
a costly daily injection or warfarin which is difficult to manage safely in the context of cancer 
and chemotherapy. The convenience of an oral medication which does not require laboratory 
monitoring and its relatively short half-life are positive attributes which position rivaroxaban 
very well as an ideal agent for thromboprophylaxis of patients with cancer and a CVC (11). 
These qualities may potentially alter the risk versus benefit ratio of thromboprophylaxis use in 
favor of anticoagulation. 
3.3 PRINCIPAL RESEARCH QUESTION 
To assess the feasibility of conducting a multicentre randomized open label trial using Canadian 
centres and to assess the safety and efficacy of rivaroxaban to prevent CVC associated VTE 
among cancer patients. 
3.4 WHY IS A PILOT RCT NEEDED BEFPRE A FULL RCT CAN BE COMPLETED? 
Recruitment of patients to a prophylaxis study which would add an additional medication and 
potentially further burden or complicate their care, may be challenging as patients may feel 
overwhelmed or be unwilling to accept the bleeding risks for a condition which they currently 
do not have. Thus, a pilot trial to assess feasibility of the larger RCT is needed first. 
3.5 WHY IS AN OPEN-LABEL TRIAL DESIGN CHOSEN? 
The current standard of care in most cancer patients is to not use outpatient 
thromboprophylaxis. Patients often receive thromboprophylaxis only when admitted to 
hospital or subject to additional risks. Not using a placebo tablet reduces study expense and 
complexity while improving patient acceptance and potentially enrollment into the trial. Since 
the primary endpoints in the larger planned multicentre study are objective, imaging confirmed 
thrombosis and bleeding outcomes and not expected to be adversely affected with an open 
label design. 
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4. TRIAL OBJECTIVES AND DESIGN 
4.1 TRIAL PURPOSE 
To determine the feasibility of conducting a multicentre randomized controlled trial comparing 
rivaroxaban at a prophylactic dose of 10mg daily versus standard of care (no prophylaxis) in 
patients with confirmed malignancy and insertion of a central venous catheter. 
With the large sample size calculated to be required to demonstrate a difference using this 
intervention, confirmation of the ability to meet minimum recruitment rates is required prior to 
a launch of a large multicentre trial. 
The overall goal of the full randomized trial is to demonstrate the safety and efficacy of using 
low dose rivaroxaban prophylaxis at preventing upper extremity venous thrombosis in patients 
with a diagnosis of malignancy and insertion of a central venous catheter. 
4.2 TRIAL DESIGN 
TRIM-Line is an open-label, randomized controlled feasibility pilot trial comparing rivaroxaban 
10mg po daily vs standard of care (no treatment) in patients with active cancer and indwelling 
CVC. This will involve 3 centres, Ottawa as the coordinating centre, Halifax and Edmonton. 
Cancer patients with insertion of CVC will be eligible. 
While the primary outcome is feasibility based clinical data will be collected using the same 
methodology as the proposed full-sized trial. Should there be no major changes to the trial 
design based on the findings of this pilot study's feasibility data that would render the collected 
data inappropriate for inclusion, the clinical data collected during this trial will be included in 
the primary and secondary analysis for the full trial. 
4.3 TRIAL INTERVENTION 
Eligible and consenting patients will receive rivaroxaban 10 mg tablets to be taken once daily, 
starting within 72 hours of CVC placement. Randomization will occur in a 1:1 ratio via a central 
web-based randomization system. 
The study drug will be continued until the CVC is removed, until one of the study outcomes is 
achieved, or until the end of the follow-up (90 Days +/- 3 days). Study medication will be held if 
the platelet count is 50 x 109/L or less, the CrCI falls below 30mL/min, the patient experiences 
bleeding or the patient is required for treatment of cancer to start on a medication or 
chemotherapy which has a major interaction with rivaroxaban. All patients will be followed for 
90 days (+/-3 days), unless they die or withdraw permission for follow up. At the end of the 
trial, VTE prophylaxis will be left to the discretion of the local investigator. 
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4.4 ELIGIBILITY 
Inclusion and Exclusion Criteria 
Inclusion criteria: 
Patients 18 years of age or older with a new or existing diagnosis of cancer with a CVC inserted in 
the last 72 hours. 
Exclusion criteria: 
17) 
CVC in place for >72 hours 
18) 
Patient requires anticoagulation for other indication 
19) 
Concomitant use of dual antiplatelet therapy 
20) 
Prior VTE 
21) 
Major bleeding event in the last 6 weeks 
22) 
Patient on concomitant medication with known interaction with rivaroxaban (eg. CYP3A4 
inhibitor) 
23) 
Pregnancy (documentation of use of effective contraception if sexually active or negative 
B- Hcg required) ** 
24) 
Known renal failure, based on Creatinine clearance <30 mL/min (Cockroft-Gault) (in the 
previous 3 months)* 
25) 
Documented severe liver disease (eg. acute clinical hepatitis, chronic active hepatitis, 
cirrhosis or ALT >311LN) (in the previous 3 months)* 
26) 
Known thrombocytopenia <50x 109/L (in the previous 3 months)* 
27) 
Allergy to rivaroxaban 
28) 
Life expectancy <6 months 
29) 
History of condition at increased bleeding risk including, but not limited to: 
g) Major surgical procedure or trauma within 30 days before the randomization visit 
h) Clinically significant gastrointestinal bleeding within 6 months before the 
randomization visit 
I) 
History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding 
j) 
Chronic hemorrhagic disorder 
k) Known intracranial neoplasm, arteriovenous malformation, or aneurysm 
I) 
Sustained uncontrolled hypertension: systolic blood pressure ?_180 mmHg or diastolic 
blood pressure k100 mmHg 
30) 
Primary malignancy diagnosis of basal cell or squamous cell carcinoma of the skin or acute 
leukemia or myelodysplastic syndrome 
31) 
Geographic inaccessibility 
32) 
Refused or unable to obtain consent 
** Women of child-bearing potential will be asked to have a baseline pregnancy test done. She must 
agree to ongoing pregnancy testing during the study, and after end of study therapy. This applies 
even if the subject practices true abstinence from heterosexual contact. She must either commit 
to true abstinence from heterosexual contact (which must be reviewed at subsequent study visits 
and source documented) or agree to use and be able to comply with highly effective 
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contraception without interruption, during the study therapy (including dose interruptions), and 
for 30 days after discontinuation of study therapy. 
Male subjects must practice true abstinence (reviewed at subsequent study visits) or agree to use 
a condom during sexual contact with a pregnant female or a female of childbearing potential 
while participating in the study, during dose interruptions and for at least 30 days following 
investigational product discontinuation, even if he has undergone a successful vasectomy. 
Acceptable methods of contraception include: combined (estrogen and progestogen containing) 
hormonal contraception: oral; Intravaginal; transdermal; progestogen-only hormonal 
contraception associated with inhibition of ovulation: oral; Injectable hormonal contraception; 
Implantable hormonal contraception; placement of an intrauterine device; placement of an 
intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner. 
4.5 WHAT ARE THE MEASURED OUTCOMES FOR THE PILOT STUDY? 
The primary feasibility outcome for the pilot study is the number of participants recruited per 
centre per month. We will obtain baseline details of the patient's type, location and treatment 
of cancer, and medications. Secondary feasibility outcomes of the pilot study will include, 
consent rates, loss to follow up, adherence to therapy defining 80% or greater medication taken 
as having good adherence to study drug, proportion of screened patients who meet eligibility 
criteria. We will document reasons for non-consent in order to assist recruitment for the larger 
multicentre trial. 
For the full multicentre trial the outcomes would be as follows: primary outcome of 
symptomatic, radiographically confirmed VTE. Secondary outcomes include major and CRNMB, 
CVC life span, premature CVC removal, CVC lumen occlusion, CVC associated infection and 
death. 
4.6 SCREENING 
Participants will be screened within 72 hours of CVC insertion. 
4.7 RANDOMIZATION 
Consenting subjects will be randomized at 1:1 ratio to treatment or non-treatment arms at study 
enrollment with treatment allocation determined by central web-based randomization. 
Randomization will be stratified by gender and the type of central venous catheter (Peripherally 
Inserted Central Catheter or Hickman/Port-a-Cath/Central line). 
Participants will be randomized once the participant has consented and all eligibility criteria 
have been confirmed. 
Randomization will be conducted using a customized web-based program developed for this 
study. The randomization process will be initiated by the local study coordinator who will access 
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the web-based system and enter the patient's unique identifier and confirmation of eligibility 
and informed consent. Specific patient allocation will then be electronically delivered, to the 
research pharmacy who will prepare and dispense trial medication. 
4.8 TREATMENT ARMS 
Treatment Arm 1: Experimental 
Rivaroxaban 10 mg po daily for 90 (+/-3) days. After the Day 90 follow up, the study 
treatment will be discontinued, and subsequent treatment will be at the discretion of the 
attending physician. 
Treatment Arm 2: Standard of care 
No rivaroxaban prophylaxis. Management will be at the discretion of the attending physician. 
4.9 PROHIBITED MEDICATIONS DURING THE STUDY 
Systemic treatment with strong CYP 3A4 and P-glycoprotein inhibitors (such as ketoconazole, 
itraconazole, posaconazole, or ritonavir) is a contra-indication to treatment with rivaroxaban 
and is therefore an exclusion criterion for study entry. 
If a participant in the rivaroxaban arm requires initiation of treatment with strong CYP 3A4 and 
P-glycoprotein inhibitor while on study treatment the participant will be withdrawn 
from study treatment. The participant may then be switched to an alternative anticoagulant 
treatment at the discretion of the attending physician. 
4.10 
PRODUCT LABELLING 
Rivaroxaban will be purchased through the research pharmacy and relabeled for this trial 
according to the template below. Each participant in the treatment arm will be given a 93-day 
supply of study drug (according to the randomization scheme) at Day 1. 
Product information for each of the study medications is listed in Appendix 4. 
Rivaroxaban 10 mg 
Expiration: DD-MMM-YYYY 
Store at room temperature between +15°C and +25°C 
Lot # 
 
Protocol : TRIM-Line Trial 
Sponsor: The Ottawa Hospital Research Institute, 725 Parkdale Ave, 
Ottawa ON K1Y 4E9 
Investigational drug to be used only by a qualified Investigator 
Rivaroxaban 10 mg 
Expiration: 11-MM-AAAA 
Conserver à l'air ambient, entre +15°C et +25°C, 
Lot # 
 
Nom du Protocole:  TRIM-Line Trial 
Commanditaire: Institut de recherche de l'Hôpital d'Ottawa 
725 Parkdale Ave., Ottawa ON K1Y 4E9 
Médicament expérimental -- à être utilisé seulement par un 
Investigateur qualifié  
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4.11 ACCOUNTABILITY AND STORAGE 
Study drug will be stored and maintained by the Clinical Trial pharmacy technicians at The Ottawa 
Hospital. Bulk accountability logs and individual accountability logs will be completed and 
maintained by the pharmacy technicians. Participants will keep a medication diary. Drug 
accountability (pill count & review of diary) will be done on Day 90 +/- 3 days when the 
medication is returned. 
Participants will be counseled to keep the study drug in room temperature conditions. The study 
medication which they take home should not be exposed to extreme temperatures. 
4.12 
INDIVIDUAL PARTICIPANT COMPLIANCE 
Participants will be given a diary and will record the date and time of administration of each 
dose. If a dose is missed the participant should take it as soon as it is remembered and record 
the time. The next dose should be taken at the new time. Non-adherent participants may be 
removed from the study at the discretion of the primary investigator. In order to allow drug 
accountability by research staff participants will be instructed to return all bottles of study 
medication. 
4.13 
CONCOMITANT MEDICATIONS 
Concomitant use of antiplatelet agents or NSAIDS must be documented in the patient's study 
record and carefully monitored by the treating physician/site investigator. The use of dual 
antiplatelet therapy is an exclusion to participation in this study. 
4.14 
PROPOSED FREQUENCY AND DURATION OF FOLLOW UP 
In addition to the initial enrollment visit, patients that are enrolled will receive a telephone 
follow up at Day-30 +/- 3 days and an in person follow up at Day 90 +/- 3 days. 
Post-enrollment follow up visits will include assessment and history for major and minor 
bleeding, CVC life span, premature CVC removal, CVC lumen occlusion, CVC associated infection 
and death and assessment of adherence to study drug. Patients will be followed for 90 days 
+/- 3 days. 
4.15 
WITHDRAWAL OF SUBJECTS 
A subject has completed the study once all follow-up procedures have been completed. 
Study drug is discontinued, and appropriate clinical management is initiated in the case of 
the following outcome events (as defined in section 4.5). 
For the subjects who reach a study endpoint, subsequent treatment will be left up to the 
discretion of the treating physician and documented. 
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If the subject is prematurely discontinued from participation in the study, the study personnel 
will make every effort to obtain, and record, information about the reasons for discontinuation 
and any adverse events and if possible perform all safety assessments. 
A subject may voluntarily withdraw participation in this study at any time, including for future 
data collection. If the subject does not return for a scheduled visit, every effort will be made to 
contact the subject. In any circumstance, every effort will be made to document the reason for 
withdrawal and when possible, all safety assessments will be done. 
All data will be reported for any subject randomized and not completing the study. Subjects 
withdrawn as a result of an adverse event thought to be related to the study drug will not be 
replaced. All safety data collected from all subjects during the study will be analyzed. 
5 
SAFETY 
The adverse event reporting period will begin with the first dose of study medication and end on 
Day-90 +/- 3 days. Adverse events may be collected from participant report or by review of the 
clinical chart. Adverse events will be documented in the CRF. 
Clinical investigators and ultimately the Qualified Investigator (01) have the primary responsibility 
for adverse event identification, documentation, grading, assignment of attribution and 
reporting. 
5.1 DEFINITIONS 
Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a participant administered at least 
one dose of study medication; the event does not necessarily have a causal relationship with that 
treatment or usage. All adverse events (see exception for cancer-related chemotherapy below) 
will be reported 
An adverse event can therefore be: 
• 
All suspected adverse medication reactions. 
• 
All reactions from medication abuse, withdrawal, sensitivity, or toxicity. 
• 
Apparently unrelated illnesses, including the worsening of a pre-existing illness 
(definition below). 
• 
Injury or accidents. 
o Note that if a medical condition is known to have caused the injury or accident 
(e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) will be reported as two separate AEs. 
• 
Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test). 
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e 
Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an 
already reported clinical event. Laboratory abnormalities associated with a clinical 
event (e.g., elevated liver enzymes in a subject with jaundice) will be described as a 
separate AE. 
Serious Adverse Events 
Serious Adverse Event (SAE) 
- 
An event that results in death 
- 
An event that places the participant at immediate risk of death (a life-threatening 
event). This does not include an event that, had it occurred in a more severe form, 
might have caused death. 
- 
Requires participant hospitalization or prolongation of existing hospitalization. For 
this study, the following exceptions apply to the index hospitalization: 
. Hospitalization for routine administration of chemotherapy/radiation 
therapy or monitoring of chemotherapy/radiation therapy side effects will 
not be recorded as a serious adverse event. 
- 
Results in persistent or significant disability/incapacity. 
- 
Is a congenital anomaly/ birth defect 
- 
Other medically important events that, in the opinion of the Site Investigator, may 
jeopardize the participant or may require intervention to prevent one of the other 
outcomes listed in the definition above. 
Some conditions may not be immediately life threatening or require hospitalization. Should the 
investigator feel that the event may jeopardize the participant or may require intervention to 
prevent more serious outcomes, then it should be treated as serious. 
Pre-Existing Conditions 
In this trial, a pre-existing condition (i.e., a disorder present before the adverse event 
reporting period started) should not be reported as an adverse event unless the condition 
worsens during the adverse event reporting period. 
Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. 
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Laboratory Test Abnormalities 
Laboratory test value abnormalities will be reported as an AE if they satisfy one or more of the 
following conditions for clinical significance: 
1. Accompanied by clinical symptoms 
2. Leading to a change in study medication (e.g. Dose modification, interruption or 
permanent discontinuation) 
3. Requiring a change in concomitant therapy (e.g. Addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
Please note: any laboratory result abnormality fulfilling the criteria for a serious adverse event 
(SAE) should be reported as such, in addition to being recorded as an adverse event in the CRF. 
GRADING OF ADVERSE EVENTS 
All adverse events will be graded by the Investigator using the scale below. 
1=Mild 
Discomfort noticed but no disruption of normal daily activity 
2=Moderate 
Discomfort sufficient to reduce or affect daily activity 
3=Severe 
Inability to work or perform normal daily activity 
CAUSALITY 
Relationship of all adverse events and serious adverse events to the study interventions 
(causality) should be assessed by the investigator as follows: 
• 
Unrelated: There is not a reasonable possibility that the adverse event may have been 
caused by the study drug. 
• 
Possibly related: The adverse event may have been caused by the study drug, however 
there is insufficient information to determine the likelihood of this possibility. 
• 
Related: There is a reasonable possibility that the adverse event may have been caused 
by the study drug. 
EXPECTEDNESS 
Adverse events and serious adverse events will also be assessed according to the following 
categories: 
• 
Expected (anticipated): the event is identified in nature, severity, or frequency in the 
investigator brochure, product monograph or in the protocol. 
• 
Unexpected (unanticipated): the event is not identified in nature, severity, or frequency 
in the investigator brochure, the product monograph or in the protocol. 
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CANCER RELATED AES 
For this study, adverse events that are possibly related or related to cancer and its treatment 
will not be recorded as an adverse event. However, if the cancer related event meets the criteria 
of a SAE, the event will be recorded and reported accordingly regardless of the causality. These 
include but are not limited to: 
• Nausea 
• Vomiting 
• Changes in bowel function — including constipation, diarrhea, bloating or flatulence 
• Abnormal white blood cell count 
• Urinary symptoms 
• Appetite changes 
• Fatigue or lethargy 
• Hair loss 
• Mouth or throat changes 
• Weight loss 
• Confusion or altered level of consciousness 
• Progression of cancer 
5.2 RECORDING, REPORTING AND FOLLOW -UP OF ADVERSE EVENTS 
Adverse Events Recording 
Adverse events will be recorded on the CRF. 
The investigator and delegates will record all directly observed adverse events and all adverse 
events spontaneously reported by the participant. In addition, each participant will be 
questioned about adverse events at each visit. 
Adverse Events Reporting 
The 01 or delegate will be responsible for reporting the AEs to the OHSNREB, and the Data and 
Safety Monitoring Board (DSMB) as follows: 
• 
Adverse events will be reported to the OHSNREB as per their guidelines 
• 
Adverse events will be summarized in a table and provided to the Data and Safety 
Monitoring Board (DSMB) before DSMB meetings. 
Serious Adverse Events Reporting 
SAEs require prompt or immediate reporting to the 01 or delegate. The 01 is ultimately 
responsible for reporting the SAEs to Health Canada, the OHSNREB, the Data and Safety 
Monitoring Board and Bayer. 
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Reporting to Health Canada 
Serious adverse events that are both unexpected and related or possibly related are subject to 
expedited reporting to Health Canada. SAEs that are expected or that are unrelated to the study 
drug are not reportable. 
All sites will report to the coordinating centre and the sponsor of the trial will be responsible for 
reporting the SAE to Health Canada 
Report must be filed in the cases: 
I. 
where the SAE is neither fatal nor life-threatening; within 15 days after becoming 
aware of the information 
IL 
where it is fatal or life-threatening, immediately where possible and, in any event, 
within 7 days after becoming aware of the information 
Within 8 days after having informed Health Canada of the SAE, the Qualified investigator will 
submit as complete as possible, a report which includes an assessment of the importance 
and implication of any findings. 
Each SAE which is subject to expedited reporting should be reported individually using the TRIM-
Line form (see Appendix). 
Any updated follow up information that becomes available regarding the SAE should be reported 
in a follow up report. 
Reporting to the OHSNREB 
All SAEs will be reported to the OHSNREB as per their guidelines. 
Reporting to the Data Safety Monitoring Board (DSMB) 
SAEs that are related or possibly related and unexpected will be reported immediately to the 
Chair of the DSMB. 
All SAEs, whether related to the study interventions or not will be summarized in a table, and 
provided to the DSMB before each scheduled DSMB meeting. 
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Reporting Procedures for Adverse Events by all sites 
1 
Gravity 
Reporting Timer Report to 
Type of Report 
Serious (fatal or life- 
threatening) if 
unexpected and 
Immediately 
1) Local REB 
2) PI (Ottawa/coordinating 
Centre) by fax and email 
Initial Report 
Within 7 days 
post initial 
Follow-up/Final 
Report 
related/possibly 
related) 
report then 
every 15 days if 
Serious (non-fatal or 
non-life-threatening) 
whether 
expected/unexpected 
or related/unrelated) 
Within 24 hours 
1) Local REB 
2) PI (Ottawa/coordinating 
Centre) by fax and email 
Initial Report 
Within 15 days 
post initial 
report then 
every 15 days if 
ongoing until 
end of event 
Follow-up/Final 
Report 
AEs 
7days 
1) PI (Ottawa/coordinating 
Centre) by entering in 
Adverse Event 
Form in eCRFs 
NOTE: In the rare event that the investigator does not become aware of the occurrence of a 
SAE immediately (e.g., if a trial participant initially seeks treatment elsewhere), the investigator 
is to report the event within 24 hours after learning of it and document his/her first awareness 
of the AE. 
Adverse Events Follow-Up 
Follow-up of adverse events considered related or possibly related to study drugs should 
continue until they have returned to baseline status or stabilized, or the causal relationship has 
been changed from related to unrelated to study drug. 
Stopping Rules 
The study has no formally defined stopping rules. Data will be monitored as they accumulate, 
and the use of the experimental therapy will cease if there is clear evidence of rivaroxaban- 
related adverse events or of a lack of efficacy. This decision will be at the discretion of the 
DS MB 
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5.3 
MANAGEMENT OF MAJOR BLEEDING 
All participants with major bleeding (ISTH definition) will have study drug held until judged safe 
to resume by the investigator. 
Treatment Arm 
In the event of hemorrhagic complications in a participant receiving rivaroxaban, treatment 
should be temporarily discontinued, and the source of bleeding investigated. Rivaroxaban has 
a half-life of approximately 5 to 13 hours. Consideration should be given to the resumption of 
anticoagulant therapy at the discretion of the treating physicians, when clinically appropriate 
to adequately control risk of underlying thrombosis. 
Management of bleeding should be individualized according to the severity and location of the 
bleeding. Appropriate symptomatic treatment should be used as needed, such as mechanical 
compression (eg, for severe epistaxis), surgical hemostasis with bleeding control procedures, 
fluid replacement and hemodynamic support, blood products (packed red cells or fresh frozen 
plasma, depending on associated anemia or coagulopathy) or platelets. 
If bleeding cannot be controlled by the above measures, consider administration of 
prothrombin complex concentrate (PCC). However, there is currently only very limited 
experience with the use of these products in individuals receiving rivaroxaban. A specific 
antidote for rivaroxaban is not available. 
Non-treatment arm 
Management of bleeding will be at the discretion of the attending physician. 
6 
STUDY MONITORING 
6.1 MONITORING 
The investigator/institution will permit trial-related monitoring, audits, REB review and 
regulatory inspections(s), and will provide direct access to source data/documents as required. 
The multicentre research coordinator will be responsible for the training of research staff and 
conducting monitoring visits in the anticipated 3 centers. Remote monitoring methods will be 
used. An initiation teleconference will be performed in each center before commencement of 
the trial. Monitoring at each center will be performed to ensure that patient safety, study 
procedures, and data collection are performed in accordance with the research protocol and 
GCP/ICH guidelines. The detailed monitoring plan can be found in the resource manual. 
7.2 DATA AND SAFETY MONITORING BOARD 
The DSMB will be comprised of clinicians and methodologists who are independent of the 
sponsor and study investigators but have experience with clinical trials and can be relied upon 
to exercise good judgment in weighing the potential risks and benefits to patients as data 
accumulate in the trial. The committee will review data on a regular basis for monitoring safety 
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of the patients exposed to the study medication. The DSMB will have an independent 
associated statistician who will receive study data from the central database and will remain 
independent of the trial management team. 
7 
PROTOCOL DEVIATIONS/VIOLATIONS 
Study related procedures must be conducted in compliance with the protocol, amendments, 
regulations and guidelines, in order to ensure participant safety and data integrity. Any 
deviations from the protocol, or violations of the protocol, will be accurately documented, 
reported and reconciled. 
7.1 PROTOCOL DEVIATIONS 
Protocol deviations  refer to incidents involving non-compliance with the protocol that are 
unlikely to have a significant impact on the participant's rights, safety or welfare, or on data 
integrity. Examples of deviations include: forgetting to complete a procedure at a specified visit 
(weight, missing lab value, etc.). 
If a protocol deviation occurs the following procedures will be followed: 
• 
The local investigator or delegate will document and explain any deviation from the 
approved protocol 
• 
Deviations from the protocol must be reported in the study source document 
• 
Deviations will be reviewed during monitoring visits. 
7.2 PROTOCOL VIOLATIONS 
Protocol violations  refer to more serious incidents involving non-compliance with the protocol 
that may result in significant effect on the participant's rights, safety, or welfare or data 
integrity. 
Protocol violations could result in the participant being excluded from the eligibility analysis 
and/or result in the participant being discontinued from the trial. Examples of violations 
include: non-compliance with inclusion/exclusion criteria and dosing administration. 
If non-compliance is identified, the following procedures will be followed: 
• 
All protocol deviations will be recorded in a log 
• 
The site investigator or delegate will notify the coordinating centre in Ottawa as soon as 
possible after discovering the violation. 
• 
The site investigator or delegate will document: the details and reason for the protocol 
violation. The documentation will also include an assessment by the site investigator 
with regards to the impact of the protocol deviation on the participant or trial data. 
Follow-up procedure and corrective action to prevent future violations will also be 
documented. 
• 
Violations will be recorded in the study source document and on the protocol violation 
form 
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• 
All violations will be reported to the local research ethics board (according to local 
policies) 
• 
All violations will be reported and reviewed by the Data and Safety Monitoring Board. 
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8 
STATISTICS 
8.1 STATISTICAL AND ANALYTIAL PLANS 
8.1.1 ANALYSIS OF BASELINE CHARACTERISTICS 
Descriptive statistics will be used to examine the baseline characteristics of excluded 
subjects and those in the experimental and standard of care arm. Standard deviations will be 
reported for all characteristics expressed as continuous variables. Medians and ranges will be 
presented for discrete data. 
8.1.2 PILOT TRIAL PRIMARY ANALYSIS 
The primary analysis will involve a simple estimate of the mean monthly recruitment rate per 
site along with the 95% confidence interval of the mean. 
8.1.3 PILOT TRIAL SECONDARY ANALYSES 
Proportions with 95% confidence intervals will be calculated using Wilson's score method for 
the following secondary analyses: 1) proportion of screened subjects who meet eligibility 
criteria, 2) proportion of eligible subjects who provide consent, 3) proportion of 
withdrawals/losses to follow-up among randomized subjects, 4) proportion of sites requiring 
>18 months to obtain all required approvals/contracts from time of delivery of all study 
documents, and 5) proportion of crossover between study arms. Reasons for non-consent will 
be collected and analyzed using qualitative thematic analysis. 
8.1.4 FULL TRIAL ANALYSES 
Primary analysis: Analysis will be performed by intention to treat. Intention to treat analysis 
will be supplemented by a sensitivity analysis that excludes subjects who did not complete the 
allocated treatment plan. Primary outcome event rates will be compared in the experimental 
and standard of care arm by an unadjusted Fisher's test of proportions, with 95% confidence 
intervals provided. 
Secondary analysis: Analysis will be performed by intention to treat. Intention to treat analysis 
will be supplemented by a sensitivity analysis that excludes subjects who did not complete the 
allocated treatment plan. Proportions will be compared between study arms by an unadjusted 
Fisher's test, with 95% confidence intervals reported. The following outcomes will be analyzed: 
symptomatic VTE, symptomatic ATE, major bleeding, CRNMB, non-major non-CRNMB, 
medication intolerance/reaction, and all-cause mortality. 
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8.2 DETERMINATION OF SAMPLE SIZE 
Using an alpha=0.05, 80% power and event rate estimates of 6.8% in the untreated and 3.7% in 
the treated population, the estimated sample size would be 860 patients per arm or 1720 
patients in total for the full trial. Estimating a 10% lost to follow up this would lead to a 
required sample of 1892 patients. Enrollment data, event rates, and study drop out will be 
assessed in this pilot trial will aid in the calculation of the required sample size for the full trial. 
Due to the low event rates, small differences in the event rates in either patient population will 
lead to large changes in the sample size required. 
For the purposes of the pilot the target sample size is 100 patients with plans to run the pilot 
trial for1 year. This would involve 4-6 enrollments/month at the coordinating centre in 
Ottawa, and 2 enrollments per month at the sites of Halifax and Edmonton. 
9 
ETHICS 
9.1 ETHICAL CONDUCT OF THE TRIAL 
The trial will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects adopted by the 18th World Medical Assembly 
(Helsinki, Finland, 1964 and later revisions), the Tri-Council Policy Statement and the ICH GCP 
Guidelines. 
9.2 RESEARCH ETHICS BOARD (REB) 
This study will be and approved with annual renewal by the Ottawa Health Science Network 
Research Ethics Board. REB approval will be obtained from all other participating centres prior to 
initiating the study at these sites. 
9.3 SUBJECT INFORMATION AND CONSENT 
The investigator, or his designee, will inform each subject (or the subject's acceptable 
representative) prior to inclusion in the trial, full and adequate verbal and written information 
regarding the objective and procedures of the trial and the possible risks involved. The subjects 
must be informed about their right to withdraw from the trial at any time. Written subject 
information will be given to each subject before enrolment. 
Furthermore, it is the responsibility of the investigator or his designee to obtain signed informed 
consent (or witnessed verbal consent according to applicable regulations) from all subjects prior 
to inclusion in the trial. 
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10 
DATA HANDLING AND RECORD KEEPING 
10.1 PERSONAL HEALTH INFORMATION 
Personal health information including Case Report Forms, evaluation forms, reports, etc. will be 
kept strictly confidential. All records will be stored on-site in a secure, locked facility. 
Records will be destroyed after 25 years, in accordance with Health Canada Regulations. 
10.2 CASE REPORT FORMS 
A Case Report Form (CRF) is required and will be completed for each randomized subject. The 
completed original CRFs are the sole property of The Ottawa Hospital and are not to be made 
available in any form to third parties, except for authorized representatives of appropriate 
Regulatory Authorities. 
10.3 RECORD RETENTION 
To enable evaluations and/or audits, the investigator will keep records, including the identity of 
all participating subjects (sufficient information to link records, e.g., CRFs and hospital records), 
all original signed Informed Consent Forms, copies of all CRFs and detailed records of drug 
disposition. To comply with international regulations, the records are to be retained for 25 
years. 
11 
STUDY DISSEMINATION PLAN 
The results of our trial will be used by the investigators to evaluate the feasibility of a larger trial 
evaluating the role of the prophylactic dose rivaroxaban to reduce upper extremity DVT in 
cancer patients with central venous catheters. The results will provide justification to external 
funding agencies before a commitment is made to fund a full trial. Regardless of the results of 
the trial, we will strive to publish and present our data and conclusions about feasibility such 
that future researchers might benefit from this work. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a trials-registration policy as a condition for publication. This policy requires that all clinical trials 
be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. It is the responsibility of the 01 to register this trial in an acceptable 
registry on or before patient enrollment. 
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