An Efficacy and Safety Study of Ixmyelocel-T in Patients With Critical Limb Ischemia (CLI) (REVIVE)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study To Evaluate The Efficacy, Safety, And Tolerability Of Ixmyelocel-T In Subjects With Critical Limb Ischemia And No Options For Revascularization

This study is designed to evaluate the efficacy and safety of ixmyelocel-T, a patient-specific expanded multicellular therapy, for the treatment of patients with critical limb ischemia (CLI). The study is a randomized, vehicle controlled (placebo)study in CLI patients who have no option for revascularization procedures. All patients randomized will undergo a small volume bone marrow aspiration in a 15-minute outpatient or in-office procedure. All patients will receive injections of either ixmyelocel-T or vehicle-control into their pre-identified index leg. Patients will be followed for 18 months.

Study Overview

• Status: Completed
• Conditions: Critical Limb Ischemia
• Intervention / Treatment: Biological: Ixmyelocel-T; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35211
      • Cardiology PC
    • Birmingham, Alabama, United States, 35243
      • Cardio-Thoracic Surgeons, P.C.
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Arizona Heart Institute
    • Phoenix, Arizona, United States, 85012
      • Carl T. Hayden VA Medical Center
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Central Arkansas Veteran's Healthcare System
    • Little Rock, Arkansas, United States, 72204
      • Arkansas Primary Care Clinic, P.A.
  • California
    • Concord, California, United States, 94520
      • John Muir Medical Center - Concord Campus
    • Loma Linda, California, United States, 92357
      • VA Loma Linda Healthcare
    • Los Angeles, California, United States, 90095
      • UCLA Gonda Venous Center & Ambulatory Procedure Unit
    • Sacramento, California, United States, 95819
      • Sutter Medical Group - Cardiology
    • San Diego, California, United States, 92103
      • University of California San Diego Medical Center
    • San Diego, California, United States, 92120
      • Kaiser Permanente Medical Center
    • San Francisco, California, United States, 94143-0222
      • University of California San Francisco - Division of Vascular and Endovascular Surgery
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver - Anschutz Medical Campus
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale School of Medicine
  • Florida
    • Boynton Beach, Florida, United States, 33435
      • Bethesda Memorial Hospital - Clinical Research Center
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Gainesville, Florida, United States, 32605
      • Florida Research Network, LLC
    • Gainesville, Florida, United States, 32608
      • Malcom Randall Veterans Affairs Medical Center
    • Jacksonville, Florida, United States, 32216
      • First Coast Cardiovascular Institute, P.A.
    • Miami, Florida, United States, 33136
      • University of Miami Hospital
    • Orlando, Florida, United States, 32806
      • Orlando Health
    • Pensacola, Florida, United States, 32501
      • Baptist Hospital
    • Pensacola, Florida, United States, 32501
      • Cardiology Consultants
    • Vero Beach, Florida, United States, 32960
      • Grove Place Surgery Center
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Vascular Surgical Associates, P.C.
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago - Clinical Sciences North
    • Springfield, Illinois, United States, 62702
      • Memorial Medical Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Indiana/Ohio Heart
    • Indianapolis, Indiana, United States, 46290
      • St. Vincent Medical Group, Inc.
  • Iowa
    • Windsor Heights, Iowa, United States, 50324
      • Heartland Vascular Medicine and Surgery
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
    • Baltimore, Maryland, United States, 21218
      • Union Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Health Care
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • VA Ann Arbor Healthcare System
    • Berkley, Michigan, United States, 48072
      • Cardiology and Vascular Associates, P.C.
    • Dearborn, Michigan, United States, 48124
      • Oakwood Hospital and Medical Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201
      • John D. Dingell VA Medical Center
    • Flint, Michigan, United States, 48507
      • Michigan Vascular Research Center
    • Grand Blanc, Michigan, United States, 48439
      • Integrated Vascular Vein Center of Michigan
    • Saginaw, Michigan, United States, 48602
      • Michigan CardioVascular Institutue at Covenant Medical Center
    • Ypsilanti, Michigan, United States, 48197
      • Saint Joseph Mercy Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Minneapolis VA Health Care System
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical School
    • Minneapolis, Minnesota, United States, 55407
      • Abbott Northwestern Hospital / Minneapolis Heart Institute-Vascular Clinic
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic, P.A.
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • Omaha VAMC
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • West Orange, New Jersey, United States, 07052
      • Vascular Access Center of West Orange
  • New York
    • Buffalo, New York, United States, 14203
      • University of Buffalo Surgeons Inc.
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospital
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Toledo, Ohio, United States, 43614
      • University of Toledo Medical Center
    • Toledo, Ohio, United States, 43606
      • Jobst Vascular Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Science Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System
    • Pittsburgh, Pennsylvania, United States, 15232
      • Veterans' Administration Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75208
      • DFW Vascular Group, LLP
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
    • Houston, Texas, United States, 77030
      • Texas Heart Institute at St. Luke's Episcopal Hospital
    • San Antonio, Texas, United States, 78229
      • Audie L Murphy VA Hospital - Pathology Laboratory
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center
    • Tacoma, Washington, United States, 98405
      • Cascade Vascular Associates, P.S.
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • Charleston Area Medical Center - Memorial Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53211
      • Columbia Saint Mary's
    • Milwaukee, Wisconsin, United States, 53203
      • Medical College of Wisconsin
    • Milwaukee, Wisconsin, United States, 53217
      • Wheaton Franciscan Medical Group, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and nonpregnant, nonlactating females
• Ages 35 to 90 years of age

• Diagnosis of CLI with tissue loss (corresponding to Rutherford Category 5; see Appendix B) having an ulcer size of at least 0.5 cm2, a smaller sized ulcer penetrating into the subcutaneous tissue, and/or gangrene (dry). In addition, the subject must have ONE of the following documented at screening:

  • Ankle systolic pressure < 70 mm Hg
  • Toe systolic pressure < 50 mm Hg
  • TcPO2 < 30 mm Hg (in a supine position)
• Subjects must have no reasonable standard-of-care options for surgical or endovascular revascularization interventions

• Subjects must have the following:

  • A narrative documenting the reasons why the site vascular specialist considers the subject "no option". A vascular specialist will be the principal investigator (PI) or subinvestigator and is defined as: vascular surgeon, interventional cardiologist, certified vascular medicine specialist, or interventional radiologist; AND
  • Secondary confirmation by an independent Eligibility Review Committee (ERC; see Section 8.1) after review of appropriate documents including, but not limited to: imaging results, medical records, surgical history, site vascular specialist narrative documenting reasons for "no option," and/or lab reports.
• Major amputation in the index leg or death is not anticipated within 3 months of screening in the opinion of the vascular specialist (who must be the PI or subinvestigator)
• In the opinion of the investigator, the subject is controlled on medical therapy indicated for CLI (unless there is a documented contraindication or intolerance)
• Subject is current with all age-appropriate American Cancer Society (ACS) or similar (e.g., United States Preventative Service Task Force) screening guidelines
• Given medical history and concurrent medication, the subject is an acceptable candidate for bone marrow aspiration and intramuscular injection procedures in the opinion of the Investigator
• Subject is willing and able to comply with the scheduled visits, aspiration/injection procedure, wound care instructions treatment plan, and other study procedures for the duration of the study
• Provide a personally-signed and dated informed consent document indicating that the subject (or a legally-acceptable representative, if permitted by the site's Investigational Review Board [IRB]) has been informed of all pertinent aspects of the study

Exclusion Criteria:

Patients presenting with any of the following will not be randomized:

Disease-specific:

• Failed open surgical revascularization (on index leg) within 4 weeks of screening Visit 1
• Acute limb-threatening ischemia, trauma, known non-atherosclerotic vascular disease (e.g., temporal/giant cell arteritis, Takayasu's arteritis, Raynaud's occlusive disease, Buerger's disease), embolic disease, aortoiliac disease with > 50% stenosis, or history of hypercoagulable states
• Advanced CLI (i.e., nonsalvageable) defined as Rutherford Category 6
• Clinical evidence of invasive infection in index leg (e.g., cellulitis, osteomyelitis, wet gangrene)
• At screening, non-heel wound size of > 20 cm2 (excluding toe gangrene); or wounds on the heel > 10 cm2 on the index leg as measured by the Wound Core Lab (WCL) from photographs (and/or acetates) provided by the site
• Previous amputation at or above the talus in the index leg Medical History
• Hemoglobin A1c (HbA1c) ≥ 10% at screening
• Diabetic subjects with uncontrolled or untreated proliferative retinopathy as determined by dilated eye exam (by qualified eye care professional as per American Diabetes Association guidelines)
• Blood clotting disorder not caused by medication (e.g., thrombophilia)
• Active non-basal cell cutaneous malignancy requiring surgery, chemotherapy, and/or radiation in the past 12 months
• Current documented drug or alcohol abuse that would interfere with the subject's compliance with study procedures
• Known allergies to any equine, porcine, or bovine products
• Body mass index (BMI) ≥ 50 kg/m2 at screening
• Established chronic kidney disease (CKD) requiring dialysis (Stage 5); estimated creatinine clearance < 15 mg/mL/min at screening
• Systolic blood pressure (SBP) > 200 mm Hg or diastolic blood pressure (DBP) > 120 mm Hg or papilledema noted via ophthalmoscope at screening physical exam
• Within 3 months prior to screening, a clinically significant history of cardiac disease

Laboratory Parameters:

• Abnormal laboratory values (performed at central lab) at screening:

  • Platelets < 50,000 μL
  • Aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 3 times the upper limit of normal (ULN)
  • Human immunodeficiency virus 1 (HIV 1), HIV 2, or syphilis positive (rapid plasma reagin [RPR])
  • Active hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV); Exclusionary Procedures, Devices, or Medication
• Exposure to immunosuppressive therapy for oncologic or chronic non-oncologic reasons in the prior 12 months or expected requirement over the course of the study (e.g., chemotherapy, radiation therapy, methotrexate)
• Concurrent participation in another clinical trial or receiving experimental medication within 30 days of screening or having previously been exposed to Aastrom's ixmyelocel T product [previously known as tissue repair cells (TRC), cardiac repair cells (CRC), vascular repair cells (VRC)]
• On the index leg, use of concomitant wound treatments not currently approved for ischemic wound-healing within 30 days prior to screening or plans to initiate new, nonstandard-of-care treatments to the index leg during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Other: Placebo; On Day 14, 20 intramuscular injections of vehicle control on pre-identified index leg.
EXPERIMENTAL: ixmyelocel-T	Biological: Ixmyelocel-T; On Day 14, 20 intramuscular injections of ixmyelocel-T on pre-identified index leg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amputation free survival (AFS) at 12 months post-injection	The primary objective will be to assess the efficacy of ixmyelocel-T compared to placebo (vehicle control) on AFS at 12 months post-injection in CLI patients with no options for revascularization. Amputation free survival is defined as time to the first occurrence of either major amputation (above the talus) in the index leg or all-cause mortality (death).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of patients with adverse events	A secondary objective will be to evaluate the overall safety and tolerability of ixmyelocel-T versus placebo in patients with CLI from time of aspiration through 18 months post-treatment/follow-up by % of patients with adverse events.	18 months
Percent of patients with complete wound closure by Month 12	A secondary objective is to assess the percent of patients with at least 1 ischemic wound on the index leg that is present at Visit 3 (preinjection) having complete closure by Month 12.	12 months
Percent of patients experiencing a major cardiac event (MACE) by Months 6, 12, and 18	% of patients experiencing a MACE event defined as cardiovascular mortality, myocardial infarction, chest pain requiring hospitalization, or stroke.	6, 12 and 18 months

Collaborators and Investigators

• Sponsor: Vericel Corporation

Publications and helpful links

Helpful Links

• Aastrom Biosciences Homepage
• Vascular Disease Foundation
• Peripheral Arterial Disease Coalition
• Vascular web provided by The Society for Vascular Surgery
• Legs For Life
• University of California, Davis
• Mayo Clinic

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (ACTUAL): March 25, 2014
• Study Completion (ACTUAL): March 25, 2014

Study Registration Dates

• First Submitted: November 30, 2011
• First Submitted That Met QC Criteria: December 1, 2011
• First Posted (ESTIMATE): December 2, 2011

Study Record Updates

• Last Update Posted (ACTUAL): May 27, 2021
• Last Update Submitted That Met QC Criteria: May 25, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: PAD; stem cells; cell therapy; critical limb ischemia; MSC; peripheral vascular disease; CLI; REVIVE
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: ABI 55-1009-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO