Best Endovascular vs. Best Surgical Therapy in Patients With Critical Limb Ischemia

Critical Limb Ischemia Clinical Trial

— BEST-CLI  

Official title:

Best Endovascular Versus Best Surgical Therapy in Patients With Critical Limb Ischemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02060630
• Other study ID #: BEST-CLI Trial
• Secondary ID: 1U01HL107407
• Status: Completed
• Phase: N/A
• Start date: August 2014
• Est. completion date: March 1, 2022

Study information

• Verified date: March 2022
• Source: HealthCore-NERI
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will compare the effectiveness of best available surgical treatment with best available endovascular treatment in adults with critical limb ischemia (CLI) who are eligible for both treatment options.

Description:

Male and female subjects aged 18 years or older will be randomized to receive either open surgical treatment or endovascular treatment. They will be followed for at least 2 years and up to 4 years and 2 months after treatment to primarily assess survival and major adverse limb events in the index or treated limb, and secondarily, to determine clinical and cost effectiveness outcomes after treatment. These outcomes (survival-free of major limb events and clinical, functional and cost effectiveness) will be compared within two cohorts of subjects: those with an available single-segment great saphenous vein, and those with an alternative conduit. The null hypotheses for both cohorts is that there will be no difference in MALE-free survival between best endovascular therapy and best surgical therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1843
• Est. completion date: March 1, 2022
• Est. primary completion date: March 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male or female, age 18 years or older.

2. Infrainguinal PAOD (occlusive disease of the arteries below the inguinal ligament).

3. CLI, defined as arterial insufficiency with gangrene, non-healing ischemic ulcer, or rest pain consistent with Rutherford categories 4-6.

4. Candidate for both endovascular and open infrainguinal revascularization as judged by the treating investigators

5. Adequate aortoiliac inflow.

6. Adequate popliteal, tibial or pedal revascularization target defined as an infrainguinal arterial segment distal to the area of stenosis/occlusion which can support a distal anastomosis of a surgical bypass.

7. Willingness to comply with protocol, attend follow-up appointments, complete all study assessments, and provide written informed consent.

Exclusion Criteria:

1. Presence of a popliteal aneurysm (>2 cm) in the index limb.

2. Life expectancy of less than 2 years due to reasons other than PAOD.

3. Excessive risk for surgical bypass (as determined by the operating surgeon and the CLI Team)

4. Planned above ankle amputation on ipsilateral limb within 4 weeks of index procedure.

5. Active vasculitis, Buerger's disease, or acute limb-threatening ischemia

6. Any prior index limb infrainguinal stenting or stent grafting associated with significant restenosis within 1 cm of stent or stent-graft, unless the occlusion/restenosis site is outside the intended treatment zone (i.e.,. a tibial vessel that is not currently intended to be revascularized as a part of the treatment for CLI).

7. Any of the following procedures performed on the index limb within 3 months prior to enrollment:

1. Infrainguinal balloon angioplasty, atherectomy, stent, or stentgraft;

2. Infrainguinal bypass with either venous or prosthetic conduit

8. Open surgical inflow procedure (aortofemoral, axillofemoral, iliofemoral, thoracofemoral or femorofemoral bypass) within 6 weeks prior to enrollment

9. Current chemotherapy or radiation therapy.

10. Absolute contraindication to iodinated contrast due to prior near-fatal anaphylactoid reaction (laryngospasm, bronchospasm, cardiorespiratory collapse, or equivalent) which would preclude patient participation in angiographic procedures.

11. Pregnancy or lactation.

12. Administration of an investigational drug for PAD within 30 days of randomization.

13. Participation in a clinical trial (except observational studies) within the previous 30 days.

14. Prior enrollment or randomization into BEST-CLI.

Related Conditions & MeSH terms

• Critical Limb Ischemia
• Ischemia

Intervention

Procedure:
• Open surgical revascularization

Device:
• Endovascular revascularization
A variety of FDA approved devices will be used within this treatment arm. The trial will submit a proof-of-concept IDE application to the FDA to cover all devices.

Locations

Country	Name	City	State
Canada	Queen Elizabeth II Health Science Center	Halifax	Nova Scotia
Canada	University of Western Ontario	London	Ontario
Canada	Jewish General Hostpital	Montreal	Quebec
Canada	McGill	Montreal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Chu de Quebec	Quebec City	Quebec
Canada	Regina Qu'Appelle	Regina	Saskatchewan
Canada	St. Paul's Hospital	Saskatoon	Saskatchewan
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	St. Boniface General Hospital	Winnipeg	Manitoba
Finland	Helsinki University Hospital	Helsinki
Italy	San Giovanni di Dio Hospital	Florence
New Zealand	Auckland City Hospital	Grafton	Auckland
New Zealand	Waikato Hospital	Hamilton	Waikato
New Zealand	Wellington Hospital	Newtown	Wellington
United States	Albany Medical Center	Albany	New York
United States	New Mexico Heart Institute	Albuquerque	New Mexico
United States	New Mexico VA Medical Center	Albuquerque	New Mexico
United States	Michigan Heart/St. Joseph Mercy Ann Arbor Hospital	Ann Arbor	Michigan
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	VA Ann Arbor Healthcare System	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Loyola University Medical Center	Baltimore	Maryland
United States	MedStar Union Memorial Hospital	Baltimore	Maryland
United States	University of Maryland Medical System	Baltimore	Maryland
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	VA Boston Healthcare System	Boston	Massachusetts
United States	Steward St. Elizabeth's Medical Center	Brighton	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Deborah Heart and Lung Center	Browns Mills	New Jersey
United States	VA Western NY Healthcare System	Buffalo	New York
United States	University of Vermont Medical Center	Burlington	Vermont
United States	University of North Carolina	Chapel Hill	North Carolina
United States	CAMC Clinical Trials Center	Charleston	West Virginia
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Central DuPage Hospital (Cadence)	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Medicine	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	University Hospitals of Cleveland/Case Western Reserve University	Cleveland	Ohio
United States	University of Missouri	Columbia	Missouri
United States	Ohio Health Research Institute	Columbus	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	Dallas VA Medical Center	Dallas	Texas
United States	Atlanta VA Medical Center	Decatur	Georgia
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Denver Health	Denver	Colorado
United States	Rocky Mountain Regional VA	Denver	Colorado
United States	Vascular Institute of the Rockies	Denver	Colorado
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	Durham VAMC	Durham	North Carolina
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Michigan Vascular Center	Flint	Michigan
United States	University of Florida (Gainesville)	Gainesville	Florida
United States	Spectrum Health	Grand Rapids	Michigan
United States	Prisma Health-Upstate (Formerly Greenville Memorial Hospital)	Greenville	South Carolina
United States	Dartmouth Hitchcock Medical Center	Hanover	New Hampshire
United States	St. Francis Hospital and Medical Center	Hartford	Connecticut
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Kaiser Foundation Hospital	Honolulu	Hawaii
United States	Memorial Hermann Hospital TMC	Houston	Texas
United States	Michael E. DeBakey VA Medical Center	Houston	Texas
United States	Indiana University Medical School	Indianapolis	Indiana
United States	University of California - Irvine	Irvine	California
United States	Midwest Aortic Vascular Institute	Kansas City	Missouri
United States	Wellmont Holston Valley Medical Center	Kingsport	Tennessee
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Gundersen Health System	La Crosse	Wisconsin
United States	San Diego VAMC	La Jolla	California
United States	UC San Diego Sulpizio Cardiovascular Center	La Jolla	California
United States	University of Arkansas for Medical Services	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Loma Linda VA Medical Center	Loma Linda	California
United States	VA Long Beach Healthcare System	Long Beach	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Keck Medical Center of USC	Los Angeles	California
United States	UCLA-Gonda Vascular Surgery	Los Angeles	California
United States	VA Greater Los Angeles	Los Angeles	California
United States	Meriter Wisconsin Heart	Madison	Wisconsin
United States	University of Wisconsin-Madison	Madison	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Baptist Hospital of Miami	Miami	Florida
United States	Mount Sinai Miami	Miami Springs	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Milwaukee VAMC	Milwaukee	Wisconsin
United States	Minneapolis Heart Hospital/Abbott Northwestern Hosp.	Minneapolis	Minnesota
United States	Minneapolis VAMC	Minneapolis	Minnesota
United States	Yale-New Haven Hospital	New Haven	Connecticut
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Sentara Vascular Specialists	Norfolk	Virginia
United States	Florida Hospital Ocala	Ocala	Florida
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	VA Palo Alto Health Care	Palo Alto	California
United States	Temple University	Philadelphia	Pennsylvania
United States	Arizona Heart Hospital	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health and Science University	Portland	Oregon
United States	Portland VA Medical Center	Portland	Oregon
United States	Providence Heart and Vascular Institute	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	The Miriam Hospital/Brown Medical School	Providence	Rhode Island
United States	Vascular Health Partners	Queensbury	New York
United States	North Carolina Heart and Vascular Research	Raleigh	North Carolina
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	Sacramento VA Medical Center	Sacramento	California
United States	University of California Davis Medical Center	Sacramento	California
United States	St. Louis VA Medical Center	Saint Louis	Missouri
United States	The University of Utah	Salt Lake City	Utah
United States	Kaiser Permanente (San Diego)	San Diego	California
United States	Kaiser Permanente Northern California	San Francisco	California
United States	San Francisco Veterans Affairs Medical Center	San Francisco	California
United States	University of California-San Francisco Medical Center	San Francisco	California
United States	Benaroya Research Institute at Virginia Mason	Seattle	Washington
United States	Harborview Medical Center	Seattle	Washington
United States	Swedish Medical Center	Seattle	Washington
United States	University Health System: LSU Health Sciences	Shreveport	Louisiana
United States	North Central Heart Institute	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Stanford Hospital	Stanford	California
United States	Staten Island University Hospital	Staten Island	New York
United States	Stony Brook Medicine	Stony Brook	New York
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Tampa General Hospital	Tampa	Florida
United States	Tampa VAMC	Tampa	Florida
United States	Holy Name Medical Center	Teaneck	New Jersey
United States	Scott and White - Temple	Temple	Texas
United States	University of Toledo Medical Center	Toledo	Ohio
United States	Harbor - UCLA Medical Center	Torrance	California
United States	Carondelet Heart & Vascular Institute	Tucson	Arizona
United States	University of Arizona - Banner University Medical Center	Tucson	Arizona
United States	University of Oklahoma College of Medicine at Tulsa	Tulsa	Oklahoma
United States	Westchester Medical Center	Valhalla	New York
United States	GW Medical Faculty Associates, Inc.	Washington	District of Columbia
United States	Medstar Washington Hospital Center	Washington	District of Columbia
United States	Mercy Hospital Medical Center	West Des Moines	Iowa
United States	West Haven VAMC	West Haven	Connecticut
United States	South Shore Hospital	Weymouth	Massachusetts
United States	Northwestern Memorial Hospital	Winfield	Illinois
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina
United States	University of Massachusetts Medical School	Worcester	Massachusetts
United States	Pinnacle Health System	Wormleysburg	Pennsylvania

Sponsors (23)

Lead Sponsor

Collaborator

HealthCore-NERI

Abbott, Bard Ltd, Boston Medical Center, Boston Scientific Corporation, Brigham and Women's Hospital, Canadian Society for Vascular Surgery, Cardiovascular Systems Inc, Cordis Corporation, Eastern Vascular Society, Massachusetts General Hospital, Midwest Vascular Society, National Heart, Lung, and Blood Institute (NHLBI), New England Society for Vascular Surgery, Society for Clinical Vascular Surgery, Society for Interventional Radiology, Society for Vascular Medicine, Society for Vascular Surgery, Southern Vascular Society, Vascular and Endovascular Surgery Society, Vascular Interventional Advances, W.L.Gore & Associates, Western Vascular Society

Countries where clinical trial is conducted

United States,  Canada,  Finland,  Italy,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary efficacy endpoint: MALE (Major Adverse Limb Event)-free survival. MALE is defined as above ankle amputation of the index limb or major re-intervention (e.g. new bypass graft, jump/interposition graft revision, or thrombectomy/ thrombolysis)	Time to major adverse limb event or death, whichever occurs first in subjects with Single-Segment Great Saphenous Vein (SSGSV) available; Time to major adverse limb event or death, whichever occurs first in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Re-intervention and amputation-free survival (cohort 1)	Time to re-intervention of the index leg, above ankle amputation of the index leg, or death, whichever occurs first in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Re-intervention and amputation-free survival (cohort 2)	Time to re-intervention of the index leg, above ankle amputation of the index leg, or death, whichever occurs first in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from MALE-POD (POD, defined as death within 30 days of index procedure) (cohort 1)	Time to re-intervention of the index leg, amputation of the index leg, or death within 30 days of index procedure, whichever occurs first in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Clinical: Freedom from MALE-POD (POD, defined as death within 30 days of index procedure) (cohort 2)	Time to re-intervention of the index leg, amputation of the index leg, or death within 30 days of index procedure, whichever occurs first in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Amputation-free survival (cohort 1)	Time to amputation of the index leg, or death, whichever occurs first in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Amputation-free survival (cohort 2)	Time to amputation of the index leg, or death, whichever occurs first in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from POD (POD, defined as death within 30 days of index procedure) (cohort 1)	Time to death within 30 days of index procedure in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom POD (POD, defined as death within 30 days of index procedure) (cohort 2)	Time to death within 30 days of index procedure in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from Myocardial Infarction (cohort 1)	Time to myocardial infarction (MI) in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from Myocardial Infarction (cohort 2)	Time to myocardial infarction (MI) in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from Stroke (cohort 1)	Time to stroke in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from Stroke (cohort 2)	Time to stroke in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from re-intervention (major and minor) in index leg (cohort 1)	Time to re-intervention (major and minor) in index leg in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from re-intervention (major and minor) in index leg (cohort 2)	Time to re-intervention (major and minor) in index leg in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Number of re-interventions (major and minor) in per limb salvaged (cohort 1)	Number of re-interventions (major and minor) in per limb salvaged in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Number of re-interventions (major and minor) in per limb salvaged (cohort 2)	Number of re-interventions (major and minor) in per limb salvaged in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from hemodynamic failure (cohort 1)	Time to hemodynamic failure in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from hemodynamic failure (cohort 2)	Time to hemodynamic failure in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from clinical failure (cohort 1)	Time to above ankle amputation, major reintervention, MALE, degradation of WIfI stage or death, whichever occurs first in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from clinical failure (cohort 2)	Time to above ankle amputation, major reintervention, MALE, degradation of WIfI stage or death, whichever occurs first in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from Critical Limb Ischemia (CLI) (cohort 1)	Time to resolution of presenting CLI symptoms in the index limb in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from Critical Limb Ischemia (CLI) (cohort 2)	Time to resolution of presenting CLI symptoms in the index limb in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from all-cause mortality (cohort 1)	Time to all-cause mortality in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Clinical: Freedom from all-cause mortality (cohort 2)	Time to all-cause mortality in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Quality of Life assessment using VasuQoL (cohort 1)	VasuQOL measurements in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Quality of Life assessment using VasuQoL (cohort 2)	VasuQOL measurements in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Quality of Life assessment using EuroQoL (cohort 1)	EuroQOL measurements in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Quality of Life assessment using EuroQoL (cohort 2)	EuroQOL measurements in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Function assessment using SF-12, PCS (cohort 1)	Physical Component Summary (PCS) scores in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Function assessment using SF-12, PCS (cohort 2)	Physical Component Summary (PCS) scores in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Function assessment using SF-12, MCS (cohort 1)	Mental Component Summary (MCS) scores in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Function assessment using SF-12, MCS (cohort 2)	Mental Component Summary (MCS) scores in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Function assessment using SF-12, SF-6D R2 (cohort 1)	Utility Index (SF-6D R2) scores in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Function assessment using SF-12, SF-6D R2(cohort 2)	Utility Index (SF-6D R2) scores in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Pain Now (cohort 1)	Scores for Pain Now in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Pain Now (cohort 2)	Scores for Pain Now in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Usual level of Pain (cohort 1)	Scores for Usual level of Pain during the last week in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Usual level of Pain (cohort 2)	Scores for Usual level of Pain during the last week in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Best level of Pain (cohort 1)	Scores for Best level of Pain during the last week in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Best level of Pain (cohort 2)	Scores for Best level of Pain during the last week in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Worst level of Pain (cohort 1)	Scores for Worst level of Pain during the last week in subjects with SSGSV available	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Functional: Numerical rating scale for Pain, Worst level of Pain (cohort 2)	Scores for Worst level of Pain during the last week in subjects without available SSGSV	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Function: Six-minute walk test (cohort 1)	Six-minute walk test measurements in subjects with SSGSV available. The six-minute walk test was performed at a subset of clinical sites (for whom this test was standard of care) and was limited to patients for whom rest pain, wounds, or foot surgery (recent or anticipated) did not preclude weight bearing	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject
Secondary	Function: Six-minute walk test (cohort 2)	Six-minute walk test measurements in subjects without available SSGSV. The six-minute walk test was performed at a subset of clinical sites (for whom this test was standard of care) and was limited to patients for whom rest pain, wounds, or foot surgery (recent or anticipated) did not preclude weight bearing	Through each subject's last regularly scheduled study visit, up to a maximum of 84 months per subject