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

Primary Purpose

Critical Limb Ischemia

Status

Completed

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

rivaroxaban plus aspirin

clopidogrel plus aspirin

About this trial

This is an interventional prevention trial for Critical Limb Ischemia focused on measuring Restenosis, Critical Limb Ischemia, Infrainguinal Percutaneous Transluminal Angioplasty, Rivaroxaban, Clopidogrel

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Written informed consent.
Infra-inguinal PAD presenting as CLI defined as a Rutherford category of 3, 4, or 5
More than 50% stenosis in the target infrainguinal vessel
Good candidates for PTA using POBA (plain old balloon angioplasty) with or without stenting defined as TASC a and b lesions.

Exclusion Criteria:

Rutherford scale of 0,1,2 or 6
Acute limb-threatening ischemia (e.g. embolic disease)
Previous infrainguinal bypass or PTA procedures of the affected leg
Hybrid procedures
Creatinine clearance <30 mL/min
Platelet count <100x109/L
INR >1.5; Hbg <100 g/L
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
Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit
Aspirin in combination with thienopyridines within 5 days before randomization
Intravenous antiplatelets within 5 days before randomization
Fibrinolytics within 10 days before randomization
Known HIV infection at time of screening
Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis or ALT >3ULN)
Childbearing potential without proper contraceptive measures, pregnancy or breast feeding
Drug addiction or alcohol abuse within 12 months before the randomization visit
Systemic treatment with strong CYP 3A4 and P-glycoprotein inhibitors : such as ketoconazole, itraconazole, posaconazole, or ritonavir
Known allergy or hypersensitivity to any component of rivaroxaban, ASA or clopidogrel
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
Anticipated need for chronic (> 4 weeks) therapy with non-steroidal anti-inflammatory drugs.
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.
Inability to adhere to protocol.
Severe concomitant condition or disease (e.g. life expectancy <6 months secondary to cancer, advanced liver disease or dementia)

Sites / Locations

The Ottawa Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

clopidogrel plus aspirin

rivaroxaban plus aspirin

Arm Description

Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily

Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Event-free Survival

Event-free survival How long a patient is alive without the need for any further intervention or vascular events.

Overall Survival

Overall survival. How long a patient is alive following the intervention.

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

TVR

Target vessel revascularization (TVR between day 1 and final visit)

Peri-procedure Death

The number of patients that die within 30 days of the revascularization procedure.

MACE

Cumulative rate of major adverse cardiovascular events between day 1 and final visit

Major Bleeding

Cumulative rate of major bleeding between day 1 and day 90

Minor Bleeding

Cumulative clinically relevant or minor bleeding between day 1 and day 90

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

Full Information

NCT ID

NCT02260622

First Posted

October 6, 2014

Last Updated

November 25, 2019

Sponsor

Ottawa Hospital Research Institute

Collaborators

The Ottawa Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02260622

Brief Title

Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia

Acronym

RIVAL-PAD

Official 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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2019

Overall Recruitment Status

Completed

Study Start Date

October 2014 (undefined)

Primary Completion Date

June 2017 (Actual)

Study Completion Date

March 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ottawa Hospital Research Institute

Collaborators

The Ottawa Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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: 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Critical Limb Ischemia

Keywords

Restenosis, Critical Limb Ischemia, Infrainguinal Percutaneous Transluminal Angioplasty, Rivaroxaban, Clopidogrel

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

clopidogrel plus aspirin

Arm Type

Active Comparator

Arm Description

Clopidogrel 75 mg daily X 90 days plus ASA 81 mg daily

Arm Title

rivaroxaban plus aspirin

Arm Type

Experimental

Arm Description

Rivaroxaban 2.5 mg BID X 90 days plus ASA 81 mg daily

Intervention Type

Drug

Intervention Name(s)

rivaroxaban plus aspirin

Other Intervention Name(s)

treatment arm

Intervention Description

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 Type

Drug

Intervention Name(s)

clopidogrel plus aspirin

Other Intervention Name(s)

Plavix plus ASA, Standard Care

Intervention Description

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

Primary Outcome Measure Information:

Title

Reintervention, Above Ankle Amputation and Restenosis (RAS)

Description

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Number of Participants With 2 Class Improvement on the Rutherford Scale

Description

Time Frame

1 year

Title

Event-free Survival

Description

Event-free survival How long a patient is alive without the need for any further intervention or vascular events.

Time Frame

1 year

Title

Overall Survival

Description

Overall survival. How long a patient is alive following the intervention.

Time Frame

1 year

Title

The Number of Patients Requiring Target Lesions Revascularization Between Day 1 and the Final Visit (TLR)

Description

Target lesion revascularization (TLR) between day 1 and final visit

Time Frame

1 year

Title

TVR

Description

Target vessel revascularization (TVR between day 1 and final visit)

Time Frame

1 year

Title

Peri-procedure Death

Description

The number of patients that die within 30 days of the revascularization procedure.

Time Frame

30 days

Title

MACE

Description

Cumulative rate of major adverse cardiovascular events between day 1 and final visit

Time Frame

1 year

Title

Major Bleeding

Description

Cumulative rate of major bleeding between day 1 and day 90

Time Frame

90 days

Title

Minor Bleeding

Description

Cumulative clinically relevant or minor bleeding between day 1 and day 90

Time Frame

90 days

Title

Biomarkers

Description

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

Time Frame

90 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Written informed consent. Infra-inguinal PAD presenting as CLI defined as a Rutherford category of 3, 4, or 5 More than 50% stenosis in the target infrainguinal vessel Good candidates for PTA using POBA (plain old balloon angioplasty) with or without stenting defined as TASC a and b lesions. Exclusion Criteria: Rutherford scale of 0,1,2 or 6 Acute limb-threatening ischemia (e.g. embolic disease) Previous infrainguinal bypass or PTA procedures of the affected leg Hybrid procedures Creatinine clearance <30 mL/min Platelet count <100x109/L INR >1.5; Hbg <100 g/L History of or condition associated with increased bleeding risk including, but not limited to: Major surgical procedure or trauma within 30 days before the randomization visit Clinically significant gastrointestinal bleeding within 6 months before the randomization visit History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding Chronic hemorrhagic disorder Known intracranial neoplasm, arteriovenous malformation, or aneurysm Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within 3 months or any stroke within 14 days before the randomization visit Aspirin in combination with thienopyridines within 5 days before randomization Intravenous antiplatelets within 5 days before randomization Fibrinolytics within 10 days before randomization Known HIV infection at time of screening Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis or ALT >3ULN) Childbearing potential without proper contraceptive measures, pregnancy or breast feeding Drug addiction or alcohol abuse within 12 months before the randomization visit Systemic treatment with strong CYP 3A4 and P-glycoprotein inhibitors : such as ketoconazole, itraconazole, posaconazole, or ritonavir Known allergy or hypersensitivity to any component of rivaroxaban, ASA or clopidogrel 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 Anticipated need for chronic (> 4 weeks) therapy with non-steroidal anti-inflammatory drugs. 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. Inability to adhere to protocol. Severe concomitant condition or disease (e.g. life expectancy <6 months secondary to cancer, advanced liver disease or dementia)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Esteban Gandara, MD

Organizational Affiliation

Ottawa Hospital Research Institute

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Prasad Jetty, MD

Organizational Affiliation

Ottawa Hospital Research Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Ottawa Hospital

City

Ottawa

State/Province

Ontario

ZIP/Postal Code

K1Y4E9

Country

Canada

12. IPD Sharing Statement

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Pilot Study to Examine the Use of Rivaroxaban After Angioplasty for Critical Limb Ischemia

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