Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia (RIVAL-PAD)

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

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.

Study Overview

• Status: Completed
• Conditions: Critical Limb Ischemia
• Intervention / Treatment: Drug: clopidogrel plus aspirin; Drug: rivaroxaban plus aspirin

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y4E9
      • The Ottawa Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent.
2. Infra-inguinal PAD presenting as CLI defined as a Rutherford category of 3, 4, or 5
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 and b lesions.

Exclusion Criteria:

1. Rutherford scale of 0,1,2 or 6
2. Acute limb-threatening ischemia (e.g. embolic disease)
3. Previous infrainguinal bypass or PTA procedures of the affected leg
4. Hybrid procedures
5. Creatinine clearance <30 mL/min
6. Platelet count <100x109/L
7. INR >1.5; Hbg <100 g/L

8. History of or condition associated with increased bleeding risk including, but not limited to:

   1. Major surgical procedure or trauma within 30 days before the randomization visit
   2. Clinically significant gastrointestinal bleeding within 6 months before the randomization visit
   3. History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding
   4. Chronic hemorrhagic disorder
   5. Known intracranial neoplasm, arteriovenous malformation, or aneurysm
   6. Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg
9. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit
10. Aspirin in combination with thienopyridines within 5 days before randomization
11. Intravenous antiplatelets within 5 days before randomization
12. Fibrinolytics within 10 days before randomization
13. Known HIV infection at time of screening
14. Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis or ALT >3ULN)
15. Childbearing potential without proper contraceptive measures, pregnancy or breast feeding
16. Drug addiction or alcohol abuse within 12 months before the randomization visit
17. Systemic treatment with strong CYP 3A4 and P-glycoprotein inhibitors : such as ketoconazole, itraconazole, posaconazole, or ritonavir
18. Known allergy or hypersensitivity to any component of rivaroxaban, ASA or clopidogrel
19. Need for long term anticoagulation or double antiplatelet agents other than PAD such as atrial fibrillation, heart valve replacement, acute coronary syndrome, stroke or venous thromboembolism
20. Anticipated need for chronic (> 4 weeks) therapy with non-steroidal anti-inflammatory drugs.
21. 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.
22. Inability to adhere to protocol.
23. Severe concomitant condition or disease (e.g. life expectancy <6 months secondary to cancer, advanced liver disease or dementia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: clopidogrel plus aspirin; Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily	Drug: clopidogrel plus aspirin; 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; Other Names: Standard Care; Plavix plus ASA
Experimental: rivaroxaban plus aspirin; Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily	Drug: rivaroxaban plus aspirin; 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; Other Names: treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reintervention, Above Ankle Amputation and Restenosis (RAS)	The primary outcome is a combined endpoint consisting of any Reintervention (surgical procedures to revascularize), Above ankle amputation and restenosis(recurrence of blockage in the vein) (RAS) at one year	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With 2 Class Improvement on the Rutherford Scale	Clinical improvement defined as cumulative improvement of 2 classes of the Rutherford scale without the need for repeated TLR in surviving patients. There are seven stages to consider. the lower the score the less severe the disease or condition. Rutherford Scale: 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	1 year
Event-free Survival	Event-free survival How long a patient is alive without the need for any further intervention or vascular events.	1 year
Overall Survival	Overall survival. How long a patient is alive following the intervention.	1 year
The Number of Patients Requiring Target Lesions Revascularization Between Day 1 and the Final Visit (TLR)	Target lesion revascularization (TLR) between day 1 and final visit	1 year
TVR	Target vessel revascularization (TVR between day 1 and final visit)	1 year
Peri-procedure Death	The number of patients that die within 30 days of the revascularization procedure.	30 days
MACE	Cumulative rate of major adverse cardiovascular events between day 1 and final visit	1 year
Major Bleeding	Cumulative rate of major bleeding between day 1 and day 90	90 days
Minor Bleeding	Cumulative clinically relevant or minor bleeding between day 1 and day 90	90 days
Biomarkers	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	90 days

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: The Ottawa Hospital
• Investigators: Principal Investigator: Esteban Gandara, MD, Ottawa Hospital Research Institute; Principal Investigator: Prasad Jetty, MD, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: October 6, 2014
• First Submitted That Met QC Criteria: October 6, 2014
• First Posted (Estimate): October 9, 2014

Study Record Updates

• Last Update Posted (Actual): December 4, 2019
• Last Update Submitted That Met QC Criteria: November 25, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Rivaroxaban; Restenosis; Clopidogrel; Critical Limb Ischemia; Infrainguinal Percutaneous Transluminal Angioplasty
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Rivaroxaban
• Other Study ID Numbers: 20130484-01H