Conditions: Critical Limb Ischemia
Keywords: Restenosis Critical Limb Ischemia Infrainguinal Percutaneous Transluminal Angioplasty Rivaroxaban Clopidogrel
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
Background: Up to 10% of patients with peripheral arterial disease (PAD) will develop critical limb ischemia (CLI) which is a decrease of blood flow in the arteries of the limb. CLI results in resting pain, ulcers, gangrene, and limb loss. The outcome for patients with CLI is poor. Within 3 months of onset, 12% of patients will require an amputation (removal of part of the limb) and 9% will die of major cardiovascular events (heart attack or stroke). Percutaneous angioplasty (PTA), a procedure used to open the blockages in blood flow, has become the first-line treatment for CLI given its effectiveness, lower cost, and lower risk of complications. However, 40% of patients will have re-narrowing of the arteries (restenosis) following the PTA procedure. This is thought to happen in part due to build up of blood cells called platelets which can also lead to the formation of blood clots. In order to try to avoid this problem, most patients are prescribed a combination of two blood thinning medications, acetylsalicylic acid (ASA or aspirin) and clopidogrel (the brand name is Plavix).

The purpose of this study is to determine if a new blood thinner called rivaroxaban, given in combination with aspirin, would be more effective in preventing re-narrowing of the arteries than the current standard of care (aspirin and clopidogrel).

Rivaroxaban is a pill and does not require blood test monitoring. It has been approved by Health Canada for use in prevention of blood clots in patients undergoing hip or knee surgery and to treat patients with blood clots in their legs and lungs. Low dose aspirin has been approved for reducing the risk of heart attacks and strokes. These medications have not been tested together in patients for prevention of re-narrowing of their arteries

This is a pilot study conducted at one center, The Ottawa Hospital.

It is a Phase 2 open label randomized controlled trial.

Following the PTA procedure, once all inclusion/exclusion criteria are met, the participant will be randomized into one of two groups:

1. Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily OR
2. Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily

Visits will occur at 7 days, 30 days, 90 days, 6 months and 12 months. Participants will be followed for 12 months (± 14 days) in total. All adverse events will be collected for the duration of the study.

Detailed description:

Arms:
arm 1: Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily arm 2: Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily

Interventions: intervention 1: rivaroxaban plus aspirin intervention 2: clopidogrel plus aspirin
Intervention descriptions: intervention 1: Rivaroxaban 2.5 mg twice daily for 90 days (rivaroxaban will be started 6 to 8 hours after the finalization of the procedure) and 81 mg of ASA daily for 90 days intervention 2: Clopidogrel 75 mg daily for 90 days (with a loading dose of 300 mg clopidogrel following PTA) and 81 mg of ASA daily for 90 days

Protocol document:
Prot_SAP_000.pdf: 


TITLE:    A Phase 2, open label, pilot study to examine the use of Rivaroxaban plus 
Aspirin  vs. clopidogrel plus Aspirin for the Prevention of Restenosis after 
Infrainguinal Percutaneous Transluminal Angioplasty for Critical Limb Ischemia 
 
 
        SHORT TITLE:  The RIFLE study 
 
 
Clinical Phase:  Phase 2 
 
 
Protocol:   Version: 3.0, 04 MAY 2015 
 
Protocol Number: OHRI-20130484 
 
Sponsor: Ottawa Hospital Research Institute 
  
 
Funding: This study is funded by the Departments of Medicine and Surgery from 
the University of Ottawa.   
 
 
 
 
INVESTIGATORS: 
 
co-Principal Investigator:    
Dr Esteban Gandara  
501 Smyth Road 
Ottawa, ON K1H 8L6 
 
Dr Prasad Jetty  
501 Smyth Road 
Ottawa, ON K1H 8L6 
 
Co-Investigators:             
 
Dr. Tim Ramsay 
501 Smyth Road 
Ottawa, ON K1H 8L6 
 
 


PROTOCOL SIGNATURE PAGE  
 
 
Version 3.0  , 04 MAY 2015 
   
 
 
 
A Phase 2, open label, pilot study to examine the use of Rivaroxaban plus Aspirin vs 
clopidogrel plus Aspirin for the Prevention of Restenosis after Infrainguinal Percutaneous 
Transluminal Angioplasty for Critical Limb Ischemia 
 
 
 
My signature below confirms that I have reviewed and approved this protocol prior to 
submission to Health Canada, and agree that it contains all necessary details for carrying 
out the study as described. I will conduct this protocol as outlined therein, and according to 
Good Clinical Practice and all applicable local regulations.  
 
 


TABLE OF CONTENTS 

1 
STUDY RATIONALE AND BACKGROUND 
4 
1.1 
Critical Limb Ischemia (CLI) 
4 
1.2 
Role Of Anticoagulation In CLI Patients Treated With PTA 
4 
1.3 
Direct Factor XA Inhibitors In PAD 
5 
1.4 
Rationale for treatment schedules 
6 
2 
HYPOTHESIS 
6 
3 
Study OBJECTIVE 
6 
4 
STUDY DESIGN 
7 
4.1 
Inclusion Criteria: 
7 
4.2 
Exclusion Criteria: 
7 
5 
Study medication 
8 
5.1 
Screening medication/standard of care 
8 
5.2 
Randomization 
8 
5.3 
Treatment Arms 
8 
5.3.1 
Treatment Arm 1: Experimental 
8 
5.3.2 
Treatment Arm 2: Standard of care 
8 
5.4 
Prohibited Medications during the study: 
9 
5.5 
Formulation Packaging and Labeling 
9 
5.6 
Accountability and Storage 
9 
5.7 
Individual Participant Compliance 
10 
5.8 
Concomitant Medications 
10 
6 
STUDY PROCEDURES and evaluations 
10 
6.1 
Study Visits 
10 
6.2 
Screening (-30 days to -1 day of PTA) 
10 
6.2.1 
Study Day 1: PTA, Randomization/Treatment Day 1 
11 


6.2.2 
Study Day 7 (+/-3 days) 
11 
6.2.3 
Study Day 30 (+/- 14 days) (may be conducted by phone) 
11 
6.2.4 
Study Day 90 (- 14 days) 
12 
6.2.5 
Study Month 6 (+/-30 days) (may be conducted by phone) 
12 
6.2.6 
Study Month 12(+/-30 days): Final Visit (may be conducted by phone) 
12 
6.2.7 
Premature Discontinuation Visit 
12 
6.3 
Outcome Measures 
13 
6.3.1 
Rutherford scale 
13 
6.3.2 
Blood samples 
13 
6.3.3 
Duplex ultrasound arterial examination 
13 
6.4 
Withdrawal / Discontinuation Criteria 
13 
6.5 
Management Of Major Bleeding 
14 
6.5.1 
Treatment arm 1 
14 
6.5.2 
Treatment arm 2 
14 
7 
SAFETY 
15 
7.1 
Definitions 
15 
7.1.1 
Adverse Events 
15 
7.1.2 
Post-procedure adverse events 
15 
7.1.3 
Serious Adverse Events 
15 
7.1.4 
Pre-Existing Conditions 
16 
7.1.5 
Procedures 
16 
7.1.6 
Laboratory Test Abnormalities 
16 
7.2 
Grading Of Adverse Events 
16 
7.3 
Causality 
16 
7.4 
Expectedness 
17 
7.5 
Recording, Reporting And Follow-Up Of Adverse Events 
17 
7.5.1 
Adverse Events Recording 
17 
7.5.2 
Adverse Events Reporting 
17 
7.5.3 
Serious Adverse Events Reporting 
17 
7.5.4 
Adverse Events Follow-Up 
18 
7.6 
Stopping Rules 
18 
8 
STATISTIC ANALYSIS 
18 
8.1 
Study Outcomes 
18 
8.1.1 
Primary Outcome 
18 
8.1.2 
Secondary Outcomes 
19 
8.2 
Sample Size Calculation 
22 
8.3 
Statistical Analysis 
22 


9 
STUDY ADMINISTRATION 
22 
9.1 
Applicable Standards And Regulations 
22 
9.2 
Ethical Conduct Of The Study 
22 
9.2.1 
Ethics Committee 
22 
9.2.2 
Identification of potential participants 
23 
9.2.3 
Participant Information and Consent 
23 
9.3 
Steering Committee 
23 
9.4 
Data Management 
23 
9.5 
Data Quality 
23 
9.5.1 
Role of the Data Safety Monitoring Board 
23 
9.5.2 
Monitoring 
24 
9.5.3 
Audits 
24 
9.5.4 
Adjudication of outcomes 
24 
10 RECORD RETENTION 
24 
11 ANTICIPATED RESULTS- DISSEMINATION PLAN 
24 
12 CONFIDENTIALITY 
25 
APPENDIX I: REFERENCES 
26 
APPENDIX 1: SCHEDULE OF EVENTS 
30 
APPENDIX 2: RIFLE SAE FORM 
31 
APPENDIX 3 : CYP3A4 AND P GLYCOPROTEIN INHIBITORS 
36 
APPENDIX 4: PRODUCT INFORMATION 
37 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 1                                               



ABBREVIATIONS & ACRONYMS  
 
ABI 
Ankle Brachial Index 
ACS
Acute Coronary Syndrome 
AE
Adverse Event/Adverse Experience
ALT
Alanine Transaminase 
ASA
Acetyl Salicylic Acid 
AST
Aspartate Amino Transferase
CBC
Cell Blood (Cells) Count 
CEC
Clinical Event Committee 
CIOMS
Council for International Organizations of Medical Sciences
CLI 
Critical Limb Ischemia 
CRF
Case Report Form
CTA 
Clinical Trial Application 
DSMB
Data and Safety Monitoring Board
DVT 
Deep Vein Thrombosis 
EGR-1 
Early Growth Response 1 
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transferase 
HREB
Human Research Ethics Board 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
LMWH 
Low Molecular Weight Heparin 
MCP-1 
Monocyte Chemostatic Protein -1 
MOP
Manual of Procedures
N
Number (typically refers to Participants)
NEJM
New England Journal of Medicine
OHRI
Ottawa Hospital Research Institute 
OHSNREB
Ottawa Health Research Science Network Research Ethics Board 
PAD 
Peripheral Arterial Disease
PI
Principal Investigator
PTA 
Percutaneous Transluminal Angioplasty 
QI
Qualified Investigator 
QA
Quality Assurance
QC
Quality Control
SAE
Serious Adverse Event/Serious Adverse Experience
SMC
Smooth Muscle Cells 
SOP
Standard Operating Procedure
TCPS 
Tri-Council Policy Statement 
TLR 
Target Lesion Revascularization 
TNF
Tumor Necrosis Factor 
TVR 
Target Vessel Revascularization 
UFH
Unfractionated Heparin 
ULN
Upper Limit of Normal 
 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 2                                               



PROTOCOL SYNOPSIS 
Title:
A Phase 2, open label, pilot study to examine the use of Rivaroxaban plus Aspirin  vs 
clopidogrel plus Aspirin for the Prevention of Restenosis after Infrainguinal 
Percutaneous Transluminal Angioplasty for Critical Limb Ischemia 
Short Title:
The RIFLE study
Clinical Trial Phase:
Phase 2
Sponsor:
OHRI
Principal 
Investigators:
Dr Esteban Gandara  & Dr. Prasad Jetty
Indication:
Patients with Peripheral Artery Disease (PAD) requiring clopidogrel and aspirin 
following angioplasty 
Objectives:
 
The aim of the trial is to measure the number of relevant clinical outcomes comparing 
Rivaroxaban plus Aspirin to clopidogrel plus aspirin in patients treated for CLI following  
PTA, to inform a  large scale randomized controlled study. 
Duration:
It is expected to take 12 months to enroll 40 participants. Each participant will be in the 
study for 12 months.  
The entire trial should be completed in 24 months. 
Design:
This is a pilot study conducted at one center, The Ottawa Hospital.  
It is a Phase 2 open label randomized controlled trial. 
Consenting participants, meeting all eligibility criteria will be randomized, post PTA 
procedure, to  one of two groups:  
 
Rivaroxaban 2.5 mg BID X 90 days  plus ASA 81 mg daily 
                                             OR 
Clopidogrel 75 mg  daily X 90 days plus ASA 81 mg daily 
 
Participants will have study drug dispensed at Day 1 and take medication for 90 days.  
ASA may be continued after the study, for both groups, as per the standard of care. 
Visits will occur at 7 days, 30 days, 90 days, 6 months and 12 months.  
Participants will be followed for 12 months (± 14 days) in total. 
Adverse events will be collected for the first 90 days . 
 
Intervention 
Description: 
Treatment Arm 1
Rivaroxaban 2.5 mg twice daily for 90 days (rivaroxaban will be started  6 to 8 hours 
after the finalization of the procedure) and 325mg of ASA on day 1 then 81 mg of ASA 
daily for 89 days 
Treatment Arm 2 
Clopidogrel 300mg on Day 1 (loading dose) then 75 mg daily for 89 days and 325mg of 
ASA on Day 1, then 81 mg of ASA daily for 89 days 
 
Number of 
participants: 
40





OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 3                                               



Inclusion and 
Exclusion  
Criteria 
Inclusion Criteria:
1. Written informed consent and able to comply with protocol.  
2. Infra-inguinal PAD presenting as CLI with Rutherford category ≥ 1. 
3. More than 50% stenosis in the target infrainguinal vessel. 
4. Good candidates for PTA using POBA (plain old balloon angioplasty) with or 
without stenting defined as TASC a, b, c and d lesions 
 
Exclusion Criteria: 
1. Acute limb-threatening ischemia (e.g. embolic disease) 
2. Hybrid procedures 
3. Creatinine clearance < 30 mL/min  
4. Platelet count <100x109/L; Hbg <100 g/L  
5. INR >1.5;  
6. History of or condition associated with 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 
7. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 
months or any stroke within 14 days before the randomization visit  
8. Aspirin in combination with thienopyridines within 5 days before randomization  
9. Intravenous antiplatelets within 5 days before randomization  
10.Fibrinolytics within 10 days before randomization  
11.Known significant liver disease (e.g., acute clinical hepatitis, chronic active 
hepatitis, cirrhosis or ALT >3ULN) 
12.Childbearing potential without proper contraceptive measures, pregnancy or 
breast feeding 
13.Drug addiction or alcohol abuse within 12 months before the randomization visit 
14.Systemic treatment with strong CYP 3A4 and P-glycoprotein 
 inhibitors : such as ketoconazole, itraconazole, posaconazole, or ritonavir 
15.Known allergy or hypersensitivity to any component of rivaroxaban, ASA or 
clopidogrel 
16.Need for long term anticoagulation or double antiplatelet agents for reasons other 
than PAD such as atrial fibrillation, heart valve replacement, acute coronary 
syndrome, stroke or venous thromboembolism 
17.Anticipated need for chronic (> 4 weeks) therapy with non-steroidal anti-
inflammatory drugs. 
18.Concomitant treatment with any other anticoagulant, including oral 
anticoagulants, such as warfarin, dabigatran, apixaban, except under 
circumstances of switching therapy to or from study treatment. 
19.Severe concomitant condition or disease (e.g. life expectancy <6 months 
secondary to cancer, advanced liver disease or dementia) 
  
 
 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 4                                               



1 STUDY RATIONALE AND BACKGROUND  
1.1 CRITICAL LIMB ISCHEMIA (CLI)  
Peripheral arterial disease (PAD) affects over 27 million people in the industrialized world, and is 
associated with significant morbidity and mortality1. Up to 10% of patients with PAD2will develop 
critical limb ischemia (CLI) presenting as resting pain, ulcers, gangrene, and limb loss1;3;4. The typical 
prognosis of CLI is poor. Within 3 months of onset, 12% of patients will require an amputation and 
9% will die; by one year the mortality rate is 22% 2.  With rates surpassing those of patients with 
coronary artery disease (CAD), patients with CLI are also at high risk of stroke, acute coronary 
syndrome (ACS), and cardiovascular (CV) death5;6. 
Treatment goals for CLI are to preserve life and limb; maintain function; relieve pain; and minimize 
the frequency and magnitude of repeated interventions7;8. Percutaneous transluminal angioplasty 
(PTA) procedures have revolutionized the management of patients with peripheral vascular disease 
and critical limb ischemia, providing a minimally invasive alternative to open bypass surgery in what 
is typically  an elderly population with multiple co-morbidities and with limited life expectancy8. In 
addition, PTA has enabled treatment to be on an outpatient basis at a relatively low cost, and thus 
a low overall burden to the health care system. In the United States9 the use of endovascular 
interventions grew substantially between 1996 and 2006, while bypass surgery decreased by 42%. 
Unfortunately, durability of these procedures is countered by restenosis and re-occlusions within 
the treated segment, ranging from ~40-60% primary patency rates at 1 year. Restenosis of the 
treated arterial segment is a major multi-factorial clinical problem following a PTA in patients with 
CLI, especially in those affected with infra-inguinal disease2;10;11. Acute restenosis of the treated 
segment (<4weeks post-PTA) is secondary to platelet and coagulation system activation whereas 
late restenosis is usually associated with myointimal proliferation, negative remodeling, and 
arterial recoil a process starting as early as 5 days post procedure11. In order to prevent early re-
thrombosis, restenosis, and cardiovascular events, most guidelines agree that aspirin (ASA) or ASA-
clopidogrel should be given to all patients undergoing PTA7;12. Based on the findings of the 
CHARISMA trial13 (which suggest that patients with symptomatic PAD would benefit from the 
combination of ASA plus antiplatelet compared to ASA alone) and studies of post coronary PTA 
supporting the superiority of ASA-clopidogrel14, the general consensus is that post lower limb PTA 
patients should receive ASA-clopidogrel over ASA alone7;8. According to a recent survey we 
conducted, in Canada, 44.6% of vascular surgeons use ASA-clopidogrel, 27.6% use ASA alone, and 
23.4% use clopidogrel alone. 
1.2 ROLE OF ANTICOAGULATION IN CLI PATIENTS TREATED WITH PTA  
Although not fully understood, the complex pathogenesis of restenosis is most likely caused by one 
or more of the following: Platelet activation and aggregation, mural thrombus, myointimal 
hyperplasia. Active thrombin remains abundant in mural thrombi following PTA and may be 
important for vessel repair processes15as it directly stimulates vascular smooth muscle cell (SMC) 
proliferation and migration15 via interaction and proteolytic activation of its direct cellular targets 
(PAR-1, 3, and 4). In animal models direct thrombin inhibition reduces atherosclerosis progression, 
promotes plaque stability, and reduces restenosis in rabbits with atherosclerosis after PTA. 
Compared to healthy controls, patients with PAD, especially those with CLI,  have higher levels of 
circulating D-dimers and thrombin-AT complex suggesting a prothrombotic state15;16, especially 
after a PTA.  This prothrombotic state could have important prognostic implications. Namely, in 
patients with ACS, elevations of D-dimers are associated with higher risk of cardiovascular death, 
myocardial infarction, stroke and stent thrombosis17;18. Treatment with ASA19 or clopidogrel20 does 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 5                                               



not reduce D-dimers levels, but the use of anticoagulant drugs has shown to reduce D-dimers and 
thrombin fragment levels19. Anticoagulant drugs are not usually recommended for the prevention 
of restenosis and vascular events following PTA for PAD12;21 but small studies have suggested that 
anticoagulation with LMWH given to either surgical22 or PTA23-27treated CLI patients improve 
restenosis rates in comparison to ASA, and also improve ulcer healing28;29. LMWHs produce their 
major anticoagulant effect by catalyzing antithrombin-mediated inhibition of coagulation factors. In 
addition to the antithrombotic properties, LMWH have SMC antiproliferative effects19;30;31;  which 
could explain the benefits of anticoagulation in patients with CLI requiring PTA18. Although, the 
effects of LMWH on smooth muscle activation are not clearly understood, recent evidence has 
suggested that LMWH upregulates CD44 expression32 leading to an antiproliferative function 
mediated by differential activation of ERK and Rac genes33. A recent randomized trial demonstrated 
that ERK 1/2 activation (a surrogate marker of smooth muscle cell proliferation) was increased 
post-PTA in patients with CLI and that the combination ASA-clopidogrel has no effects on its 
expression30 thereby supporting the hypothesis that the use of anticoagulant drugs could be 
beneficial after PTA.  
1.3 DIRECT FACTOR XA INHIBITORS IN PAD  
Direct FXa inhibitors, such as rivaroxaban, are oral agents that inhibit factor Xa leading to a 
decrease in thrombin formation and potentially, a decrease in platelet activation. Rivaroxaban is 
detected 2–4 hours after oral administration, has half-life of 7 to 11 hours, and is associated with 
few drug interactions34. In phase III randomized trials; rivaroxaban and apixaban have shown to be 
effective for stroke prevention in patients with AFIB35;36; DVT prevention after surgery37-39; and 
treatment of VTE40-42. In patients with ACS43, rivaroxaban reduced mortality, ACS, stroke, and stent 
thrombosis, although, along with these benefits is an increased risk of major bleeding43. It is widely 
believed that activated FXa has limited functions other than serving as the principal mediator of 
thrombin generation from prothrombin via the prothrombinase complex44. Factor Xa occupies a 
critical juncture in the coagulation cascade45 and controls thrombin generation. The activation of 
one molecule of FXa results in the generation of 1000 molecules of FIIa46. FXa initiates intracellular 
signaling in various cell types of the cardiovascular system, preferentially mediated via PAR-247 
which contributes to the production of proinflammatory cytokines, tissue factor up-regulation, SMC 
proliferation, and the release of vascular endothelial growth factor. Inhibition of FXa prevents 
thrombin generation via inhibition of free, prothrombinase-bound, and clot-associated Factor Xa 
and consequently attenuates thrombus-associated procoagulant activity34 . This explains why 
compared to heparin, that allows persistent thrombin generation and direct thrombin inhibitors 
that aggravate thrombin generation, direct FXa inhibitors allow for small amounts of thrombin 
generation and protein C activation. The potential effects of FXa inhibition for the prevention of 
restenosis following PTA could be caused by the reduction of clot-induced mitogenesis and 
inflammatory gene expression in human vascular SMC48;inhibition of the procoagulant activity of 
activated monocytes and macrophages49; and effects on the intrinsic coagulation pathways. To our 
knowledge only one study conducted in healthy volunteers suggested that rivaroxaban reduced 
thrombus associated mitosis of SMC of the aortic arch 48. In animal models, vascular remodeling 
and myointimal formation were reduced on targeted delivery of nonspecific factor Xa 
inhibitors34;44;50-52. Animal models have suggested that rivaroxaban decreases mRNA expression of 
inflammatory mediators, such of IL-6, TNF-α, MCP-1, and Egr-1 promoting arterial plaque stability. 
In stent thrombosis models, rivaroxaban either alone or in combination with ASA+/-clopidogrel 
initiated a dose-dependent inhibition of FXa-induced, tissue factor-induced, thrombin-induced 
platelet aggregation, and ADP-induced platelet aggregation53. In conclusion, evidence suggests that 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 6                                               



inhibition of Factor Xa with rivaroxaban could reduce major vascular outcomes and thrombin 
associated SMC proliferation leading to restenosis after PTA for CLI24. 
1.4 RATIONALE FOR TREATMENT SCHEDULES  
We selected rivaroxaban 2.5mg twice daily because:  
1. Rivaroxaban is the only FXa inhibitor that has shown to improve cardio-vascular outcomes 
in patients with1 and without ACS2, 3 ; furthermore, it has shown to reduce systemic non-
CNS systemic4  embolism and stent thrombosis post PTA5. 
2. A 2.5 mg twice daily dose appears to provide the best risk/ratio in combination with 
antiplatelet agents for the prevention of vascular events in patients treated with 
antiplatelet agents. The risk of bleeding in patients receiving rivaroxaban and antiplatelet 
appears to be increased regardless of the treatment indication. Mega et al suggested that a 
10 mg daily dose of Rivaroxaban in combination with aspirin was associated with a 2.2% 
risk of TIMI major bleeding whereas  it was 0% in those treated with a 5 mg daily dose plus 
aspirin. In participants treated with a total daily dose 5 mg of rivaroxaban, those who  
received 2.5 mg twice daily had a lower bleeding risk than those treated with 5 mg once 
daily (1.4 vs. 2.9%); furthermore twice daily dosing was associated with a lower number of 
cardiovascular events (6.6 vs. 9.4%)(6).  In ATLAS ACS 2–TIMI 51, the 2.5-mg twice-daily 
dose of rivaroxaban compared with placebo was associated with reductions of 34% for 
cardiovascular death and 32% for all-cause death, which were not seen with the 5-mg 
twice-daily dose(1). 
3. Although previous studies looking at the role of anticoagulation post PTA for CLI have used 
prophylactic doses of LMWH(7), our concern is that patients with CLI are older and sicker 
and a dose of rivaroxaban of 10 mg once daily in combination with aspirin will be 
associated with a higher bleeding risk without significant improvement in outcomes.    
 
We selected ASA-clopidogrel as comparator because it is the treatment recommended by 
guidelines7;8, and is used by 50% of vascular surgeons in Canada 
 
 Since optimal medical management to decrease restenosis and thrombosis rates following PTA 
would make an important contribution to the sustained success of endovascular treatment, the 
proposed study will evaluate indicators of the effect of rivaroxaban in patients with CLI requiring 
PTA. 
 
2 HYPOTHESIS   
We hypothesize that the addition of rivaroxaban to antiplatelet agents (ASA) following PTA will lead 
to a reduction in the rate of any/all of the following:  restenosis , amputation, and/or major 
cardiovascular events in patients with CLI, as compared to the treatment of clopidogrel plus ASA. 
 
3 STUDY OBJECTIVE  
The aim of the trial is to establish if the use of rivaroxaban 2.5 mg twice a day plus ASA would 
improve relevant clinical outcomes, as compared to dual antiplatelet agents in patients treated 
with CLI following PTA.  The data from this pilot trial will inform us if a multi center, large scale, 
randomized trial is warranted. 
 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 7                                               



4 STUDY DESIGN  
This is an open label single center randomized controlled pilot study. 
4.1 INCLUSION CRITERIA:  
1. Written informed consent and able to comply with protocol.  
2. Infra-inguinal PAD presenting as CLI defined with Rutherford category of ≥ 1. 
3. More than 50% stenosis in the target infrainguinal vessel 
4. Participant must be a good candidate for PTA using POBA (plain old balloon angioplasty) 
with or without stenting defined as TASC a, b, c and d lesions. 
4.2 EXCLUSION CRITERIA: 
1. Acute limb-threatening ischemia (e.g. embolic disease) 
2. Hybrid procedures 
3. Creatinine clearance <30 mL/min  
4.  Platelet count <100x109/L;  Hbg < 100 g/L. 
5. INR >1.5 
6. History of or condition associated with 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 
7. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any 
stroke within  14 days before the randomization visit 
8. Aspirin in combination with thienopyridines within 5 days before randomization  
9. Intravenous antiplatelets within 5 days before randomization  
10.Fibrinolytics within 10 days before randomization  
11.Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, 
cirrhosis or ALT >3ULN) 
12.Childbearing potential without proper contraceptive measures, pregnancy or breast 
feeding* 
13.Drug addiction or alcohol abuse within 12 months before the randomization visit 
14.Systemic treatment with strong CYP 3A4 and P-glycoprotein inhibitors : such as 
ketoconazole, itraconazole, posaconazole, or ritonavir 
15.Known allergy or hypersensitivity to any component of rivaroxaban, ASA or clopidogrel 
16.Need for long term anticoagulation or double antiplatelet agents for reasons other than 
PAD such as atrial fibrillation, heart valve replacement, acute coronary syndrome, stroke 
or venous thromboembolism 
17.Anticipated need for chronic (> 4 weeks) therapy with non-steroidal anti-inflammatory 
drugs. 
18.Concomitant treatment with any other anticoagulant, including oral anticoagulants, such 
as warfarin, dabigatran, apixaban, except under circumstances of switching therapy to or 
from study treatment. 
 



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19.Severe concomitant condition or disease (e.g. life expectancy <6 months secondary to 
cancer, advanced liver disease or dementia) 
 
* Sexually active women of child bearing potential must undergo a serum pregnancy test ((β-
HCG) before study entry and use highly effective methods of contraception. These may include: 
hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and 
implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy and tubal ligation. 
Highly effective methods of contraception might not always be achievable in the clinical trial 
setting and, therefore, the most effective alternative can be achieved using methods in 
combination. 
The "double barrier" methods of contraception (e.g. male condom with diaphragm, male 
condom with cervical cap) can be used as an effective alternative to the highly effective 
contraception methods described above. The use of a male condom in association with 
spermicide should not  be  considered a suitable double barrier method for contraception. 
5 STUDY MEDICATION  
5.1 SCREENING MEDICATION/STANDARD OF CARE 
Participants will be screened within 30 days prior to the PTA procedure. All participants enrolled in 
the study will receive a loading dose of 325 mg of ASA and IV heparin as per the TOH protocol 
during the procedure. The 325mg loading dose of ASA will be considered and recorded as the day 1 
dose of ASA. 
5.2 RANDOMIZATION  
Participants will only be randomized once the surgeon has completed the PTA +/- stent .  PTA will 
be considered successful once the target lesion is crossed with a wire and catheter and a balloon 
angioplasty has been successfully performed.  
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 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.  
5.3 TREATMENT ARMS  
5.3.1 Treatment Arm 1: Experimental  
Rivaroxaban 2.5 mg  twice daily for 90 days (rivaroxaban will be started  6 to 8 hours after the 
finalization of the procedure37) and 325mg of ASA on Day 1, plus 81 mg of ASA daily for 89 days.  
After 90 days, the study treatment will be discontinued and subsequent treatment will be at the 
discretion of the attending physician.  
5.3.2 Treatment Arm 2: Standard of care    
Clopidogrel 300mg on Day 1 (loading dose), then 75 mg daily for 89 days and 325mg of ASA on Day 
1 then 81 mg of ASA daily for 89 days. After 90 days, the study treatment will be discontinued and 
subsequent treatment will be at the discretion of the attending physician 



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5.4 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 criteria 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.    See appendix 3 for a list of CYP 3A4 and P glycoprotein 
inhibitors.  
5.5 FORMULATION PACKAGING AND LABELING 
ASA and clopidogrel will be purchased and relabeled for this trial according to the template below.  
Rivaroxaban will be provided by Bayer and will be labeled according to the template below. All 
three study medications will be provided to the participants in bulk format.  Each participant will be 
given a 90 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  2. 5 mg
Expiration: DD-MMM-YYYY 
Store at room temperature between +15°C and +25°C 
Lot # ------- 
Protocol name : RIFLE 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  2. 5 mg
Expiration: DD-MM-YYYY 
Conserver au l’air ambient , entre +15°C et +25°C,  
Lot # ------- 
Nom du Protocole: RIFLE  TrialCommenditaire:  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
Clopidogrel 75 mg
Expiration: DD-MMM-YYYY 
Store at room temperature between +15°C and +25°C 
Lot # ------- 
Protocol name : RIFLE Trial 
Sponsor: The Ottawa Hospital Research Institute, 725 Parkdale 
Avenue, Ottawa ON K1Y 4E9 
 
 
Investigational drug -- to be used only by a qualified Investigator
Clopidogrel 75 mg
Expiration: DD-MM-YYYY 
Conserver au l’air ambient , entre +15°C et +25°C,  
Lot # ------- 
Nom du Protocole: RIFLE Trial 
Commenditaire: 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
ASA 81 mg
Expiration: DD-MMM-YYYY 
Store at room temperature between +15°C and +25°C 
Lot # ------- 
Protocol name : RIFLE Trial 
Sponsor: The Ottawa Hospital Research Institute, 725 Parkdale 
Avenue, Ottawa ON K1Y 4E9 
 
Investigational drug -- to be used only by a qualified Investigator
ASA 81 mg
Expiration: DD-MM-YYYY 
Conserver au l’air ambient , entre +15°C et +25°C,  
Lot # ------- 
Nom du Protocole: RIFLE Trial 
Commenditaire: 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

5.6 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 diary card.   Drug accountability 
(pill count & review of diary cards) will be done on Day 90 when the medication is returned.  



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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. 
5.7 INDIVIDUAL PARTICIPANT COMPLIANCE 
When discharged from hospital 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.  
5.8 CONCOMITANT MEDICATIONS 
Medication that the participant is taking from the screening time point until study end at 12 
months will be recorded by the Research Coordinator. This includes any herbal supplements and 
vitamins and over the counter medications. 
 
6 STUDY PROCEDURES AND EVALUATIONS 
6.1 STUDY VISITS  
 
All participants will be followed for 12 months following their angioplasty. Participants will return 
to The Ottawa Hospital or will be evaluated as an inpatient at 7 days. There are follow up visits at 
30 days, 90 days, 6 months, and 12 months post randomization. All primary and secondary 
outcome data will be collected during the trial (7 days, 30 days, 90 days, 6 months and 12 months) 
so that procedures can be evaluated and optimized for future studies. The schedule of study events 
is summarized in a table in appendix 1.   
6.2 SCREENING (-30 DAYS TO -1 DAY OF PTA) 
Participants will be screened within 30 days of the PTA procedure.  
The following will occur at the screening visit: 

Physical examination (Height and Weight plus BMI) 

Demographics (age, gender, race) 

Tobacco use  

Medical History including: 
-
Bleeding history  
-
History of stroke, TIA, CAD, CKD, COPD, Hypercholesterolemia 
-
History of acute coronary syndrome 

Medication history 

Previous tissue loss 

Co-morbidities including  
-
Exclusion criteria 
-
Hypertension 
-
Obesity 
-
Diabetes 

Disease severity (Rutherford scale ) and ABI index from medical record 



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Anatomic level of disease56.  

Obtain bloodwork results for CBC, coagulation tests (INR, PTT),  and serum creatinine   
6.2.1 Study Day 1: PTA, Randomization/Treatment Day 1  
All participants enrolled in the study will receive a loading dose of 325 mg of ASA and IV heparin as per 
TOH protocol prior to the procedure. 
 
Once the surgeon has completed the PTA +/- stent, participants will be randomized using a web-based 
program as per section 5.2.  Participants will receive study medication as per section 5.3.1 and 5.3.2 
for the group to which they are allocated. 
At randomization the research coordinator will provide the appropriate training for each participant 
on: 

Monitoring of outcome events and adverse events.  

Review signs and symptoms of bleeding and provide instructions and study contact 
numbers.   

Details of the study requirements (follow-up schedule) and the importance of follow-up  

Storage and administration of study drug 

How to complete the Medication Diary 
 
             Data collected at Day 1 :  

Vascular access speciﬁcations:  Access routes, size of introducer sheaths used, 
speciﬁcations of device used (length and diameters of balloons/devices implanted) 

Device to artery ratio for balloons and implants, length of treated segment 

Immediate procedural outcome 

Bleeding (approximate blood loss) 

Concomitant medications 

Blood collection  (stored for future evaluation of platelet activation , coagulation 
markers. smooth muscle activation markers  and inflammation markers)  
6.2.2 Study Day 7 (+/-3 days) 
                    Data collected :  

Adverse Events  

Drug compliance review 

Blood collection  (stored for future evaluation of platelet activation , coagulation 
markers. smooth muscle activation markers  and inflammation markers 
 
6.2.3 Study Day 30 (+/- 14 days) (may be conducted by phone) 
                        Data collected :  

Disease severity (Rutherford scale ) 

Major Cardiac events  

TVR  

TLR   

Amputation 

Bleeding 



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Adverse Events 

Compliance 

Concomitant medications  

Ultrasound + ABI index 
6.2.4 Study Day 90 (- 14 days) 
                     Data collected :  

Major Cardiac events  

TVR  

TLR  

Amputation 

Bleeding 

AEs  

Compliance 

Concomitant medications 

Blood collection  (stored for future evaluation of platelet activation , coagulation 
markers. smooth muscle activation markers  and inflammation markers  
 
Study treatment will be discontinued and subsequent treatment will be at the discretion of the 
attending physician (long term use of ASA, as an example).  
6.2.5 Study Month 6 (+/-30 days) (may be conducted by phone) 
                      Data collected :  

Disease severity (Rutherford scale) 

Major Cardiac events  

TVR  

TLR 

Amputation  

Bleeding 

Ultrasound + ABI index (standard of care) 
6.2.6 Study Month 12(+/-30 days): Final Visit (may be conducted by phone) 
                     Data collected :  

Disease severity (Rutherford scale) 

Major Cardiac events   

TVR  

TLR  

Amputation 

Bleeding 

Ultrasound + ABI index (standard of care) 
 
6.2.7 Premature Discontinuation Visit 
In case of premature discontinuation participants will be asked to come for a final visit to assess 
potential adverse events and return unused study medication.  



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6.3 OUTCOME MEASURES   
6.3.1 Rutherford scale  
Participants will be evaluated according to Rutherford scale at screening, and at the day 30, month 
6 and month 12 follow-up visits.  
Classes in the Rutherford scale are defined as:  

Stage 0 – Asymptomatic 

Stage 1 – Mild claudication 

Stage 2 – Moderate claudication – The distance that delineates mild, moderate and severe 
claudication is not specified in the Rutherford classification, but is mentioned in the 
Fontaine classification as 200 meters. 

Stage 3 – Severe claudication 

Stage 4 – Rest pain 

Stage 5 – Ischemic ulceration not exceeding ulcer of the digits of the foot 

Stage 6 – Severe ischemic ulcers or frank gangrene 
6.3.2 Blood samples  
During the entire trial, a  volume of approximately 40ml blood will be sampled from each 
participant for research purposes, in addition to standard of care blood samples: ~10ml of blood  (2 
x5 ml tubes) will be obtained for research purposes at Day 1, Day 7, and Day 90 for evaluation of 
platelet activation (including D-dimers), coagulation markers, smooth muscle activation markers 
(soluble CD40/44 ligands, and ERK ½) and inflammation markers.  
All research blood samples will be processed and stored in a freezer at the Thrombosis Group 
Research Laboratory and analyzed at the conclusion of the study after enrollment has been 
completed. 
6.3.3 Duplex ultrasound arterial examination 
Duplex ultrasound arterial examination will be performed at the Ottawa Civic Hospital (Diagnostic 
Imaging) at 30 days, 6 and 12 months as part of the routine care. The following will be recorded in 
the CRF : re-stenosis as defined by peak velocity flow, and the Ankle Brachial Index (ABI).   
The Ankle Brachial Index(ABI) is the ratio of the blood pressure in the lower legs to the blood 
pressure in the arms. The ABI is calculated by dividing the systolic blood pressure at the ankle by 
the systolic blood pressures in the arm.  
6.4 WITHDRAWAL / DISCONTINUATION CRITERIA 
Participants have the right to withdraw from the study treatment at any time for any reason. The 
Investigator has the right and obligation to withdraw participants from the study treatment in the 
event of: 
 
1. Adverse event(s) which would, in the judgment of the investigator, require discontinuation 
of study product(s)  
2. Request by the participant or their legally authorized representative (consent withdrawal) 
3. Non compliance to the study protocol  
4. Participants needs additional medication that would interfere with the study 
5. Participant is lost to follow-up 



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6. The sponsor, or the principal investigator or the Data and Safety Monitoring Board or a 
government agency such as Health Canada cancels the study. 
 
When a participant withdraws consent after starting the protocol treatment the investigator or 
delegate should make every effort to contact the participant to determine, as completely as 
possible, the reason for the withdrawal and to schedule an end-of-study visit for assessing potential 
adverse events. The participant will be asked to return unused study products and will be switched 
to standard of care, as per their own treating physician. 
6.5 MANAGEMENT OF MAJOR BLEEDING  
All participants with major bleeding will have study drug held until judged safe to resume by the 
investigator. 
6.5.1 Treatment arm 1 
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 antithrombotic 
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 one of the 
following pro-coagulants: 

activated prothrombin complex concentrate (APCC), eg., FEIBA 

prothrombin complex concentrate (PCC) 

recombinant Factor-VIIa (rFVIIa) 
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. 
 
6.5.2 Treatment arm 2  
In the event of hemorrhagic complications in a participant receiving Clopidogrel, treatment should 
be temporarily discontinued, and the source of bleeding investigated. A specific antidote for 
Clopidogrel  is not available.  
Management of bleeding should be individualized according to the severity and location of the 
hemorrhage. 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).  
Platelet transfusion may be used to reverse the pharmacological effects of clopidogrel and aspirin 
when quick reversal is required. 
 
 



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7 SAFETY 
The adverse event reporting period will begin with the first dose of study medication and end on 
day 90 (at least 48 hours after last dose of study medication).  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 (QI) have the primary responsibility 
for adverse event identification, documentation, grading, assignment of attribution and reporting.  
7.1 DEFINITIONS 
7.1.1 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. An adverse event can therefore be:  
-
any unfavorable and unintended sign, symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product  
-
pre-existing symptoms or conditions which worsen during a study. 
 
7.1.2 Post-procedure adverse events  
Bruising and discomfort at the puncture site is expected in the first week after the PTA procedure 
and will not be collected as an adverse event. 
7.1.3 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:   

The index hospitalization for PTA procedure will not be recorded as a 
serious adverse event 

Prolonged hospitalization after the index hospitalization will not be 
recorded as a serious adverse event unless the prolongation is secondary 
to complications related to the study medication.  

Hospitalizations for routine procedures and investigations are not 
considered a SAE in this protocol.  
-
Results in persistent or significant disability/incapacity. For this study, the following 
exception applies to this criterion: 

Disability/incapacity secondary to tissue loss (amputation) is not considered 
a SAE for this protocol. 
-
Is a congenital anomaly/ birth defect 



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-
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. 
7.1.4 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.  
7.1.5 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.  For example, an acute 
appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event and the resulting appendectomy noted under Comments. 
7.1.6 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. 
7.2 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 
7.3 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. 



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• 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. 
7.4 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. 
 
7.5 RECORDING, REPORTING AND FOLLOW-UP OF ADVERSE EVENTS 
7.5.1 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. 
7.5.2 Adverse Events Reporting  
The QI 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.  
7.5.3 Serious Adverse Events Reporting 
SAEs require prompt or immediate reporting to the QI or delegate. The QI is ultimately responsible 
for reporting the SAEs to Health Canada, the OHSNREB, the Data and Safety Monitoring Board and 
Bayer.  
 
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.  
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 
II.
where it is fatal or life-threatening, immediately where possible and, in any event, within 7 
days after becoming aware of the information 



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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 RIFLE 
SAE form (see Appendix 2).  
 
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 
 
Reporting to Bayer   
SAEs will be reported to Bayer as per procedure outlined in the grant agreement. 
7.5.4 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. 
7.6 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 DSMB as per 
section 9.5.1. 
8 STATISTIC ANALYSIS 
8.1 STUDY OUTCOMES  
8.1.1 Primary Outcome   
The primary outcome is a combined endpoint consisting of any Reintervention , Above ankle amputation 
and Stenosis  (RAS) 2at one year  The 3 components of RAS are defined as follows: 
8.1.1.1 REINTERVENTION 
Classified as major/minor and only considers first occurrence. Major reinterventions include placement 
of a new surgical bypass graft, use of thrombectomy or thrombolysis, or a major surgical revision (jump 
or 
interposition 
graft). 
Minor 
reinterventions 
include 
endovascular 
procedures 
without 
thrombectomy/thrombolysis and minor surgical revisions (patch angioplasty).  



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Re-interventions will be classified as target lesion revascularization (TLR), target vessel revascularization 
(TVR) and clinically-driven target lesion revascularization (CDTLR). TLR is defined as either repeat 
percutaneous or surgical revascularization for a lesion anywhere within previous treated area*. TVR is 
any repeat percutaneous intervention or surgical bypass of any segment of the target vessel**. CDTLR 
revascularization is a target lesion revascularization prompted by recurrent ipsilateral limb symptoms 
(intermittent claudication, critical limb ischemia) or objective imaging evidence of target lesion 
restenosis (i.e., most commonly with duplex ultrasonography).  
*A target lesion is any lesion treated or attempted to be treated with PTA. The target lesion is the 
treated segment starting 5 mm proximal and ending 5 mm distal to the index procedure (stent, in most 
cases).  
**A target vessel is the vessel that contains the target lesion. The target vessel  includes the target 
lesion as well as the entire vessel upstream and downstream to the target lesion, including side 
branches (native vessel). 
8.1.1.2 AMPUTATION 
Minor and major amputations (above the ankle) differentiating below-the-knee vs. above-the-knee 
amputation will be collected at each follow-up visit. 
8.1.1.3 RE-STENOSIS 
             Reported in a time-to-event fashion, defined as:  
-
Decrease in ABI by 0.15 (or TBI drop of 0.10) or greater as compared to post-procedure 
value 
-
Duplex ultrasound demonstrating occlusion of the graft or treated vessel 
-
Duplex ultrasound demonstrating critical graft stenosis (Peak Systolic Velocity _300 cm/s or 
velocity ratio 3.0) 
-
Angiogram, MRI or CTA demonstrating occlusion of graft or of any treated vessel, or >50% 
stenosis in the presence of recurrent clinical symptoms 
 
8.1.2 Secondary Outcomes 
1. Clinical improvement defined as cumulative improvement of 2 classes of the 
Rutherford scale without the need for repeated TLR in surviving patients. 
2. Event-free survival 
3. Overall survival 
4. Target lesion revascularization (TLR) between day 1 and final visit 
5. Target vessel revascularization (TVR between day 1 and final visit 
6. Peri-procedure death within 30 days 
7. Cumulative rate of major adverse cardiovascular events (as defined in 8.1.2.1) between 
day 1 and final visit  
8. Cumulative rate of major bleeding (as defined in 8.1.2.2) between day 1 and day 90.  
9. Cumulative rate of  minor bleeding (as defined in 8.1.2.2) between day 1 and day 90 
10.Biological plausibility by measuring coagulation changes and SMC proliferation markers 
within 7 and 90 days based on the following markers: D-dimer, soluble CD40/44 
ligands, and ERK 1/2. 
11.Patency rates based on the ABI index and with an ultrasound at 6 and 12 months  
12.Information about feasibility of a future study:  
a. The total number of eligible candidates identified;  



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b. The percentage of eligible patients referred to our study;  
c. The percentage of eligible patients who consent to be enrolled 
8.1.2.1 MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) 
 Any of the following events during follow up 

1. Ischemic 
Stroke 
Sudden onset of a neurological deficit that persists for more than 24 hours and 
involves one or more of the following: 
a) Hemiparesis: involving the face, arm and/or leg unilaterally 
b) Hemisensory  loss;  involving face, arm and/or leg unilaterally 
c) Speech impairment; (ie. Aphasia) 
d) Visuo-spatial impairment 
e) Visual loss (monocular or binocular) 
f) Two or more of the following symptoms which suggest 
vertebrobasilar involvement: 
i. incoordination/ataxia 
ii. cranial nerve abnormality 
iii. dysarthria 
iv. dysphagia 
v. vertigo 
vi. reduction/loss of consciousness 
vii. diplopia 
g) Objective and persistent (more than one week) worsening of a 
previous deficit or worsening associated with an appropriate new 
finding on CT scan or MRI. 
2. Transient 
Ischemic 
Attack 
A transient ischemic attack is defined for the purposes of this trial as a sudden 
onset of a neurological deficit lasting at least one minute but less than 24 hours. 
(Isolated syncope will not be considered a TIA unless this occurs with one or 
more of the following neurological symptoms suggesting vertebrobasilar 
involvement. 
a) Hemiparesis; involving face, arm and/or leg unilaterally 
b) Hemisensory loss; involving face, arm and/or leg unilaterally 
c) Speech impairment; (ie. Aphasia) 
d) Visuo-spatial impairment 
e) Visual Loss (monocular or binocular) 
f) Two or more of the following symptoms:  
i. Incoordination/ataxia,  
ii. Cranial nerve   abnormality,  
iii. Dysarthria,  
iv. Dysphasia,  
v. Vertigo,  
vi. Reduction/loss of consciousness,  
vii. Diplopia 





OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 21                                             



3. Myocardial 
Infarction 
At least two of: 
a) Ischemic chest pain,  
b) EKG changes compatible with a MI(hyper acute T wave, elevated ST 
segment, T wave inversion, presence of new bundle branch block, loss 
of R wave height, development of Q waves) or  
c) elevation of cardiac enzymes (troponin, CK, CKMB isoenzyme, or other 
cardiac enzymes) to at least 2X the upper limit of the normal reference 
range or 3X the upper limit of normal within 48 hours after 
percutaneous coronary intervention (or if markers are already 
elevated, greater than 50% of the lowest recovery level from the index 
infarction 
4. Vascular 
Death 
Cardiac or cerebrovascular death excluding subarachnoid or primary 
intracranial haemorrhage or fatal pulmonary embolism. 

8.1.2.2 BLEEDING  
Bleeding will be classified as per the Thrombolysis in Myocardial Infarction (TIMI) bleeding 
classification scheme: 
 
 Major Bleeding:  
 Any intracranial bleeding  
 Clinically significant overt signs of bleeding associated with a drop in hemoglobin of 
> 50 g/L (or, when hemoglobin is not available, an absolute drop in hematocrit of > 
15%),  
 Fatal bleeding that directly results in death within 7 days.  
 
Minor Bleeding:  
 Any clinically overt sign of bleeding (including imaging) that is associated with a fall 
in hemoglobin of 30 to  50 g/L (or, when hemoglobin is not available, a fall in 
hematocrit of 9 to 15%).  
 Any overt sign of hemorrhage that meets one of the following criteria and does not 
meet criteria for a major or minor bleeding event, as defined above  

Requiring intervention (medical practitioner-guided medical or surgical 
treatment to stop or treat bleeding, including temporarily or 
permanently discontinuing or changing the dose of a medication or 
study drug)  

Leading to or prolonging hospitalization  

Prompting evaluation (leading to an unscheduled visit to a healthcare 
professional and diagnostic testing, either laboratory or imaging)  
Minimal Bleeding:  
 Any overt bleeding event that does not meet the criteria for major or minor 
bleeding listed above 
 Any clinically overt sign of bleeding (including imaging) that is associated with a fall 
in hemoglobin < 30 g/L (or, when hemoglobin is not available, a fall in hematocrit 
of < 9%). 



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Bleeding will be further identified using the following criteria: 
-
Significant: major bleeding or minor bleeding requiring medical attention.  
-
Instrumented: any bleeding that occurs as a result of an invasive procedure. 
-
Spontaneous: any bleeding that is not the direct result of an invasive procedure (e.g. 
gingival bleeding, epistaxis, gastrointestinal bleeding).  
 
8.2 SAMPLE SIZE CALCULATION  
Based on recent data published by Conte et al2 we expect that during 1 year of follow up, 54% of 
participants will experience the primary outcome. A total sample of 40 participants was selected 
and is within the recommended approach for pilot studies evaluating effects when no prior 
information upon which to base the sample size is available.  This sample size will allow us to detect 
an absolute 20% reduction in the main clinical outcome with a single sided alpha of 0.2 and power 
of 0.6 as recommended for pilots studies59-61.  The study will be considered successful if we can 
demonstrate a reduction in events in the intervention group supported by changes in biomarkers 
levels (biological plausibility). 
 
8.3 STATISTICAL ANALYSIS  
All the continuous outcomes will be evaluated with the paired T-test or Wilcoxon-rank sum; 
proportions will be evaluated using the Fisher’s exact test. 
 
9 STUDY ADMINISTRATION  
9.1 APPLICABLE STANDARDS AND REGULATIONS  
The trial will be performed in compliance with the Canadian Tri-Council Policy Statement version 2 
(TCPS2), the World Medical Association Declaration of Helsinki, adopted by the 18th World Medical 
Assembly, Helsinki, Finland, June 1964, and last amended by the 52nd WMA General Assembly, 
Edinburgh, Scotland, October 2000, the Canadian Food and Drug Regulations, Division 5 Part C, the 
Canadian Ontario's Personal Health Information. Protection Act (PHIPA), and the ICH Good Clinical 
Practices (GCP).   
9.2 ETHICAL CONDUCT OF THE STUDY  
9.2.1 Ethics Committee  
The trial may only be initiated after the Investigator has obtained written approval of the protocol, 
Informed Consent form and other study documents, and any amendments (if applicable), by the 
Ottawa Health Science Network Research Ethics Board (OHSNREB). Changes in protocol 
(amendments) must be submitted to the OHSNREB for approval.  Reports on, and reviews of, the 
trial, its safety aspects and its progress will be submitted to the OHSNREB by the Investigator at 
intervals according to the institutional guidelines.  
 
 



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9.2.2 Identification of potential participants  
Enrollment will be conducted at the Vascular Surgery Outpatient Clinic and on the wards at the 
Ottawa Hospital Civic Campus.  To increase our screening for eligible participants, all scheduled 
PTAs will be screened daily for eligibility and a screening log will be maintained. 
9.2.3 Participant Information and Consent  
All relevant study information will be summarized in an informed consent form. The investigator or 
delegate will explain all relevant aspects of the study to the patients prior to entry into the study 
(i.e. before any examinations and procedures associated with the selection for the study are 
performed or any study-specific data is recorded on study-specific forms). The patient will have 
ample time and opportunity to ask questions and will be informed about the right to withdraw 
from the study at any time without any disadvantage and without having to provide reasons for 
their decision. 
9.3 STEERING COMMITTEE  
A Steering Committee comprised of the trial’s co-investigators will manage the overall conduct of 
the trial. Drs. Gandara, Jetty and Ramsay 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.  
9.4 DATA MANAGEMENT  
Data will be recorded on a paper case report form (CRF) by the research personnel according to the 
protocol. CRFs will be verified for completeness and accuracy by a research team member not 
involved in the data collection.  Any changes to the CRF will be tracked.  Upon completion of data 
collection and verification of the CRF by the Investigator or designee, data will be entered in an 
data analysis software. Data will be cleaned and coded prior to analysis by a statistician. Missing 
data will be queried. Data still missing after queries will be coded appropriately by the statistician.  
Reports will be prepared prior to Data Safety Monitoring Board (DSMB) meetings including: 
enrollment per treatment arm, descriptive statistics for demographic data (and other relevant 
characteristic) to assess that randomization was effective, and a tabulated summary of AEs and 
SAEs per treatment arm.  
9.5 DATA QUALITY   
9.5.1 Role of the Data Safety Monitoring Board  
This study will be monitored by an independent Data Safety Monitoring Board (DSMB), consisting 
of an independent physician, and two other members not involved in this study. The DSMB will be 
immediately informed of any serious adverse events (SAEs), which are potentially related to study 
drug. If at any point the DSMB considers continuance of the study unacceptable, the steering 
committee will be immediately notified.  
 
The DSMB will have a scheduled meeting midway through the trial (after ~20 participants have 
completed the first 90 days of the trial or after 6-months of active recruitment).  An interim report 
will be prepared by the data management team for the study.    The report will include data on 
recruitment, compliance, adverse events, baseline comparability and treatment comparisons.  



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 24                                             



If at any point the DSMB considers continuance of the study unacceptable, the steering committee 
will be immediately notified.  
 
9.5.2 Monitoring  
The investigator (or his/her delegate) agrees to cooperate with the OHRI monitor to schedule at 
least one monitoring visit during the course of the study and to ensure that any problems detected 
in the course of this monitoring visit are resolved. This monitoring by OHRI does not replace the 
routine quality control to be performed by the Qualified  Investigator or his delegate. 
Routine quality control will be completed by the Qualified Investigator or his delegate to ensure 
that the study is being run according to the protocol. The routine monitoring of the study will 
include: 

Verification of all inclusion and exclusion criteria to confirm that only eligible participants  
are participating in the trial 

Verification of source data to ensure accuracy of study data as per the monitoring plan  

Verification that adverse events are recorded, assessed and reported according to the 
protocol 

Verification of the case report forms to ensure that they are being completed according to 
the protocol 
9.5.3 Audits  
The Investigator should understand that OHRI or its delegates, after appropriate notification may 
audit the study for Quality Assurance purposes.  
 
9.5.4 Adjudication of outcomes  
The primary outcome, bleeding events and major adverse cardiovascular events will be adjudicated 
by a blinded expert adjudication committee.    
 
10RECORD RETENTION 
To comply with Health Canada regulations, the trial related records will be retained for 25 years.  
Records will be kept to enable linkage of participants’ identity to CRF data (master log).  This 
includes sufficient information from hospital and clinic records such as all original signed informed 
consent forms, source records, and detailed records of cell manufacturing. After 25 years, all study 
records will be destroyed by shredding or incineration 
11ANTICIPATED RESULTS- DISSEMINATION PLAN  
The results of our trial will be used by the investigators to evaluate the need for further studies 
evaluating the role of the addition of rivaroxaban to reduce clinically relevant outcomes in patients 
with CLI requiring PTA and 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 make every effort to publish and present our data and 
conclusions about feasibility such that future researchers might benefit from this work.  



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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 QI to register this trial in an acceptable registry on 
or before patient enrollment. 
 
12CONFIDENTIALITY 
All subject related information including Case Report Forms, evaluation forms, reports, etc. will be 
kept strictly confidential.  All records will be kept in a secure, locked location and only research 
staff will have access to the records.  Subjects will be identified only by means of a coded number 
specific to each subject. All computerized databases will identify subjects by numeric codes only, 
and will be password protected or encrypted. 
 
Upon request, subject records will be made available to the study sponsor, monitoring groups’ 
representative of the study sponsor, and applicable regulatory agencies such as Health Canada. 
 

 



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APPENDIX I: REFERENCES  
Reference List 
 
 
(1)  Gray BH, Conte MS, Dake MD et al. Atherosclerotic Peripheral Vascular Disease Symposium II: 
Lower-Extremity Revascularization: State of the Art. Circulation 2008;118:2864-2872. 
 
(2)  Conte MS, Geraghty PJ, Bradbury AW et al. Suggested objective performance goals and clinical 
trial design for evaluating catheter-based treatment of critical limb ischemia. Journal of Vascular 
Surgery 2009;50:1462-1473. 
 
(3)  Jensen SA, Vatten LJ, Myhre HO. The Prevalence of Chronic Critical Lower Limb Ischaemia in a 
Population of 20,000 Subjects 40GÇô69 Years of Age. European Journal of Vascular and 
Endovascular Surgery 2006;32:60-65. 
 
(4)  Sigvant B, Wiberg-Hedman K, Bergqvist D et al. A population-based study of peripheral arterial 
disease prevalence with special focus on critical limb ischemia and sex differences. Journal of 
Vascular Surgery 2007;45:1185-1191. 
 
(5)  Criqui MH, Langer RD, Fronek A, Feigelson HS. Coronary disease and stroke in patients with 
large-vessel peripheral arterial disease. Drugs 1991;42 Suppl 5:16-21. 
 
(6)  Criqui MH, Langer RD, Fronek A et al. Mortality over a period of 10 years in patients with 
peripheral arterial disease. N Engl J Med 1992;326:381-386. 
 
(7)  Tendera M, Aboyans V, Bartelink ML et al. ESC Guidelines on the diagnosis and treatment of 
peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid 
and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the 
Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology 
(ESC). Eur Heart J 2011;32:2851-2906. 
 
(8)  Rooke TW, Hirsch AT, Misra S et al. 2011 ACCF/AHA Focused Update of the Guideline for the 
Management of Patients With Peripheral Artery Disease (Updating the 2005 Guideline): A 
Report of the American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. Circulation 2011;124:2020-2045. 
 
(9)  Goodney PP, Beck AW, Nagle J, Welch HG, Zwolak RM. National trends in lower extremity 
bypass surgery, endovascular interventions, and major amputations. Journal of Vascular Surgery 
2009;50:54-60. 
 (10)  Fuster V, Falk E, Fallon JT, Badimon L, Chesebro JH, Badimon JJ. The three processes leading to 
post PTCA restenosis: dependence on the lesion substrate. Thromb Haemost 1995;74:552-559. 
 (11)  Tschopl M, Tsakiris DA, Marbet GA, Labs KH, Jager K. Role of hemostatic risk factors for 
restenosis in peripheral arterial occlusive disease after transluminal angioplasty. Arterioscler 
Thromb Vasc Biol 1997;17:3208-3214. 
 (12)  Alonso-Coello P, Bellmunt S, McGorrian C et al. Antithrombotic therapy in peripheral artery 
disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of 
chest physicians evidence-based clinical practice guidelines. CHEST Journal 2012;141:e669S-
e690S. 
 (13)  Bhatt DL, Fox KAA, Hacke W et al. Clopidogrel and Aspirin versus Aspirin Alone for the 
Prevention of Atherothrombotic Events. N Engl J Med 2006;354:1706-1717. 
 (14)  Bellemain-Appaix A. Association of clopidogrel pretreatment with mortality, cardiovascular 
events, and major bleeding among patients undergoing percutaneous coronary intervention: A 
systematic review and meta-analysis. JAMA 2012;308:2507-2516. 
 (15)  Schror K, Bretschneider E, Fischer K et al. Thrombin receptors in vascular smooth muscle cells - 
function and regulation by vasodilatory prostaglandins. Thromb Haemost 2010;103:884-890. 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 27                                             



 (16)  Vidula H, Tian L, Liu K et al. Biomarkers of Inflammation and Thrombosis as Predictors of Near-
Term Mortality in Patients with Peripheral Arterial Disease: A Cohort Study. Annals of Internal 
Medicine 2008;148:85-93. 
 (17)  Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Markers of Coagulation Activation, 
Endothelial Stimulation and Inflammation in Patients with Peripheral Arterial Disease. European 
Journal of Vascular and Endovascular Surgery 2005;29:171-176. 
 (18)  Christersson C, Oldgren J, Bylock A, Siegbahn A, Wallentin L. Early decrease in coagulation 
activity after myocardial infarction is associated with lower risk of new ischaemic events: 
observations from the ESTEEM trial. European Heart Journal 2007;28:692-698. 
 (19)  CHRISTERSSON C, OLDGREN J, BYLOCK A, WALLENTIN L, SIEGBAHN A. Long-term treatment with 
ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity 
after a myocardial infarction. Journal of Thrombosis and Haemostasis 2005;3:2245-2253. 
 (20)  Eikelboom JW, Weitz JI, Budaj A et al. Clopidogrel does not suppress blood markers of 
coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary 
syndromes. European Heart Journal 2002;23:1771-1779. 
 (21)  Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. Inter-Society Consensus 
for the Management of Peripheral Arterial Disease (TASC II) [abstract]Norgren L, Hiatt WR, 
Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. J Vasc Surg 2007;45:S5-S67 
 (22)  Edmondson RA, Cohen AT, Das SK, Wagner MB, Kakkar VV. Low-molecular weight heparin 
versus aspirin and dipyridamole after femoropopliteal bypass grafting. The Lancet 
1994;344:914-918. 
 (23)  Strecker EP, G+Âttmann D, Boos I, Vetter S. Low-molecular-weight heparin (reviparin) reduces 
the incidence of femoropopliteal in-stent stenosis: Preliminary results of an ongoing study. 
Cardiovasc Intervent Radiol 1998;21:375-379. 
 (24)  Koppensteiner R, Spring S, Amann-Vesti BR et al. Low-molecular-weight heparin for prevention 
of restenosis after femoropopliteal percutaneous transluminal angioplasty: a randomized 
controlled trial. J Vasc Surg 2006;44:1247-1253. 
 (25)  Duschek N, Vafaie M, Skrinjar E et al. Comparison of enoxaparin and unfractionated heparin in 
endovascular interventions for the treatment of peripheral arterial occlusive disease: a 
randomized controlled trial. J Thromb Haemost [serial online] 2011;9:2159-2167 Available from: 
Department of Vascular and Endovascular Surgery, Wilhelminenspital, Vienna Center for Public 
Health, Department of Epidemiology, Medical University of Vienna, Vienna, Austria. 
nduschek@me.com. 
 (26)  Norgren L, Swedish EnoxaVasc Study Group. Can low molecular weight heparin replace 
unfractionated heparin during peripheral arterial reconstruction? An open label prospective 
randomized controlled trial. J Vasc Surg [serial online] 2004;39:977-984 Available from: 
University Hospital, Department of Surgery, Orebro S-70185, Sweden. lars.norgren@kir.lu.se. 
 (27)  Schweizer J, Muller A, Forkmann L, Hellner G, Kirch W. Potential use of a low-molecular-weight 
heparin to prevent restenosis in patients with extensive wall damage following peripheral 
angioplasty. Angiology [serial online] 2001;52:659-669 Available from: Clinic for Internal 
Medicine I, Kuchenwald Hospital, Chemnitz, Germany. 
 (28)  Kalani M, Apelqvist J, Blomback M, Rooke TW. Dalteparin improved chronic foot ulcers and 
reduced the number of amputations in diabetic peripheral arterial occlusive disease. Evid -Based 
Med [serial online] 2004;9:73 Available from: BMJ Publishing Group. 
 (29)  Kalani M, Apelqvist J, Blomback M et al. Effect of dalteparin on healing of chronic foot ulcers in 
diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-
blind, placebo-controlled study. Diabetes care [serial online] 2003;26:2575-2580 Available from: 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 28                                             



Department of Cardiology, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden. 
majid.kalani@ks.se. 
 (30)  Wilson AM, Brittenden J, Bachoo P, Ford I, Nixon GF. Randomized controlled trial of aspirin and 
clopidogrel versus aspirin and placebo on markers of smooth muscle proliferation before and 
after peripheral angioplasty. J Vasc Surg [serial online] 2009;50:861-869 Available from: 
Department of Surgery, University of Aberdeen, Aberdeen, United Kingdom. 
awilson78@doctors.net.uk. 
 (31)  Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Clopidogrel has no effect on D-dimer and 
thrombin-antithrombin III levels in patients with peripheral arterial disease undergoing 
peripheral percutaneous transluminal angioplasty. J Vasc Surg [serial online] 2005;42:252-258 
Available from: Department of Vascular Surgery, University of Aberdeen, Scotland, United 
Kingdom. k.cassar@abdn.ac.uk. 
 (32)  Zhao G, Shaik RS, Zhao H, Beagle J, Kuo S, Hales CA. Low molecular weight (LMW) heparin 
inhibits injury-induced femoral artery remodeling in mouse via upregulating CD44 expression. 
Journal of Vascular Surgery 2011;53:1359-1367. 
 (33)  Kothapalli D, Flowers J, Xu T, Pur+® E, Assoian RK. Differential Activation of ERK and Rac 
Mediates the Proliferative and Anti-proliferative Effects of Hyaluronan and CD44. Journal of 
Biological Chemistry 2008;283:31823-31829. 
 (34)  Samama MM. The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--
compared with other anticoagulants. Thromb Res 2011;127:497-504. 
 (35)  Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial 
Fibrillation. N Engl J Med 2011;365:883-891. 
 (36)  Granger CB, Alexander JH, McMurray JJV et al. Apixaban versus Warfarin in Patients with Atrial 
Fibrillation. N Engl J Med 2011;365:981-992. 
 (37)  Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis 
after Total Knee Arthroplasty. N Engl J Med 2008;358:2776-2786. 
 (38)  Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis 
after Hip Arthroplasty. N Engl J Med 2008;358:2765-2775. 
 (39)  Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or Enoxaparin for 
Thromboprophylaxis after Knee Replacement. N Engl J Med 2009;361:594-604. 
 (40)  Bauersachs R, Berkowitz SD, Brenner B et al. Oral rivaroxaban for symptomatic venous 
thromboembolism. N Engl J Med 2010;363:2499-2510. 
 (41)  Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 
2012;366:1287-1297. 
 (42)  Agnelli G, Buller HR, Cohen A et al. Apixaban for Extended Treatment of Venous 
Thromboembolism. N Engl J Med 2012;368:699-708. 
 (43)  Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in Patients with a Recent Acute Coronary 
Syndrome. N Engl J Med 2011;366:9-19. 
 (44)  ANSELL J. Factor Xa or thrombin: is factor Xa a better target? Journal of Thrombosis and 
Haemostasis 2007;5:60-64. 
 (45)  Borissoff JI, Spronk HMH, ten Cate H. The Hemostatic System as a Modulator of Atherosclerosis. 
N Engl J Med 2011;364:1746-1760. 
 (46)  Mann KG, Brummel K, Butenas S. What is all that thrombin for? Journal of Thrombosis and 
Haemostasis 2003;1:1504-1514. 
 (47)  Borensztajn K, Peppelenbosch MP, Spek CA. Factor Xa: at the crossroads between coagulation 
and signaling in physiology and disease. Trends in Molecular Medicine 2008;14:429-440. 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 29                                             



 (48)  Rosenkranz AC, Schror K, Rauch BH. Direct inhibitors of thrombin and factor Xa attenuate clot-
induced mitogenesis and inflammatory gene expression in human vascular smooth muscle cells. 
Thromb Haemost 2011;106:561-562. 
 (49)  Laurent M, Varin R, Joimel U et al. A Novel Mechanism of Action of Rivaroxaban: Inhibition of 
Monocyte and Macrophage Procoagulant Activity and Consequence On Inflammatory Process. 
ASH Annual Meeting Abstracts 2009;114:3124. 
 (50)  Becker R. Factor Xa-A Pleuripotential Protease. J Thromb Thrombolysis 2003;15:5-9. 
 (51)  Kaiser B. DX-9065a, a Direct Inhibitor of Factor Xa. Cardiovascular Drug Reviews 2003;21:91-104. 
 (52)  Ragosta M, Gimple LW, Gertz SD et al. Specific factor Xa inhibition reduces restenosis after 
balloon angioplasty of atherosclerotic femoral arteries in rabbits. Circulation 1994;89:1262-
1271. 
 (53)  BECKER EM, PERZBORN E, KLIPP A et al. Effects of rivaroxaban, acetylsalicylic acid and 
clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis. Journal 
of Thrombosis and Haemostasis 2012;10:2470-2480. 
 (54)  Thabane L, Ma J, Chu R et al. A tutorial on pilot studies: the what, why and how. BMC Med Res 
Methodol 2010;10:1. 
 (55)  Rutherford RB, Baker JD, Ernst C et al. Recommended standards for reports dealing with lower 
extremity ischemia: Revised version. Journal of Vascular Surgery 1997;26:517-538. 
 (56)  Diehm N, Baumgartner I, Jaff M et al. A call for uniform reporting standards in studies assessing 
endovascular treatment for chronic ischaemia of lower limb arteries. European Heart Journal 
2007. 
 (57)  Nicola+» SPA, Kruidenier LM, Rouwet EV, Graffius K, Prins MH, Teijink JAW. The walking 
impairment questionnaire: An effective tool to assess the effect of treatment in patients with 
intermittent claudication. Journal of Vascular Surgery 2009;50:89-94. 
 (58)  Schulman S, Kearon C, the SUBCOMMITTEE ON CONTROL OF ANTICOAGULATION OF THE 
SCIENTIFIC AND STANDARDIZATION COMMITTEE OF THE INTERNATIONAL SOCIETY ON 
THROMBOSIS AND HAEMOSTASIS. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and 
Haemostasis 2005;3:692-694. 
 (59)  Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharmaceut Statist 
2005;4:287-291. 
 (60)  Stallard N. Optimal sample sizes for phase II clinical trials and pilot studies. Statist Med 
2012;31:1031-1042. 
 (61)  Palesch YY, Tilley BC, Sackett DL, Johnston KC, Woolson R. Applying a Phase II Futility Study 
Design to Therapeutic Stroke Trials. Stroke 2005;36:2410-2414. 
 (62)  Olin JW, Sealove BA. Peripheral Artery Disease: Current Insight Into the Disease and Its Diagnosis 
and Management [abstract]Olin JW, Sealove BA. Mayo Clin Proc 2010;85:678-692 
 
 



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APPENDIX 1: SCHEDULE OF EVENTS 
 
Screening 
Visit 
-30 days to 
 -1 day 
PTA 
Baseline 
Day 1 
Visit 
Day 7 
(+/- 3 days) 
Visit 
Day 30 * 
(+/- 14 days) 
 
Visit 
Day 90 
(- 14 days) 
Visit 
6 months* 
(+/-30 days) 
 
Final Visit
12 months* 
(+/-30 days) 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion & Exclusion Criteria 
X 
 
 
 
 
 
 
Physical Exam1 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Dispense study medication 
 
X 
 
 
 
 
 
Study medication compliance review 
 
 
X 
X 
X 
 
 
Rutherford Score 
X 
X 
 
X 
 
X 
X 
Review of bleeding events 
X 
X 
 
X 
X 
X 
X 
Review of major cardiac events  
 
X 
 
X 
X 
X 
X 
Review of Re-interventions  
 
 
 
X 
X 
X 
X 
Review of Adverse Events 
 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests Results 2
X 
 
 
 
 
 
 
Review of Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
Collect Imaging Outcomes  
 
 
X 
 
X 
X 
Blood Work, research samples 3 
 
   X 
X 
 
X 
 
 
1 Height and weight 
2 CBC, coagulation tests, and serum creatinine 
3 Includes: Platelet activation, coagulation markers, smooth muscle activation, inflammation markers  
*Visit may be completed in person or via telephone follow-up  



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APPENDIX 2: RIFLE SAE FORM  

	

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OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 32                                                    



 !!
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OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 33                                                    



 +!
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OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 34                                                    



14  ,	
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OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 35                                                    



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OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 36                                                    



APPENDIX 3 : CYP3A4 AND P GLYCOPROTEIN INHIBITORS  
 

Amiodarone 

Boceprevir  

Clarithromycin 

Cyclosporine 

Diltiazem 

Erythromycin  

Itraconazole 

Ketoconazole 

Nicardipine 

Nifedipine 

Posaconazole  

Quinine 

Ritonavir 

Saquinavir 

Telaprevir 
 
Sources 
(1) : Pharmacology Weekly COMPREHENSIVE DRUG REFERENCE TABLE 
(http://www.pharmacologyweekly.com/content/pages/drug-reference-table-cyp-p450-ugt-enzymes-
transporters-ab)  
(2) Rivaroxaban Product Monograph – Bayer Canada  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



OHRI protocol:  20130484   Version 3.0,  04 MAY 2015                                                     Page 37                                                    



APPENDIX 4: PRODUCT INFORMATION 

6<	3?
 
Source:
Bayer Canada
Brand Name 
XARELTO
Manufacturer
Bayer 
Dosage form
Film-coated, round, biconvex, light 
red immediate release tablets of 6 
mm diameter for oral use. 
Daily dose:
2 tablets (2.50 mg twice daily every 
12 hours)   
 
Rivaxobaran will be supplied free of charge to all study participants randomized in treatment arm 1. 
Rivaxobaran tablets will be stored at the Ottawa Hospital Research Pharmacy. Each bottle will be labeled 
according to Food and Drug Regulations Division 5 Part C requirements as Rivoxabaran 2.5 mg is not a 
product currently approved in Canada.  

:;
 
Source:
Commercial 
Brand Name 
As per hospital formulary 
Manufacturer
As per Hospital formulary   
Dosage Form  
Tablets 
Daily dose:
1  tablet (ASA 81 mg) OD
 
ASA will be supplied free of charge to all study participants. Bottles will be labeled according to Food and 
Drug Regulations Division 5 Part C requirements as although ASA is standard of care for the proposed 
indication, it is an off label use according to the Product Monograph .  

@?
 
Source:
Commercial 
Brand Name 
As per Hospital Formulary   
Manufacturer
As per Hospital Formulary   
Dosage Form 
Tablets 
Daily dose:
1 tablet (Clopidogrel 75 mg )OD 
 
Clopidogrel  will be supplied free of charge to all study participants randomized in treatment arm 2.  
Proposed indication, dose and route are within the parameters of the NOC : Clopidogrel is approved in 
Canada for the secondary prevention of atherothrombotic events (myocardial infarction, stroke and 
vascular death) in patients with atherosclerosis documented by stroke, myocardial infarction, or 
established peripheral arterial disease (Plavix Product monograph) . The recommended dose of is 75 mg 
once daily with or without food.