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

Critical Limb Ischemia Clinical Trial

— REVIVE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01483898
• Other study ID #: ABI 55-1009-1
• Status: Completed
• Phase: Phase 3
• Start date: February 2012
• Est. completion date: March 25, 2014

Study information

• Verified date: May 2021
• Source: Vericel Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: March 25, 2014
• Est. primary completion date: March 25, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Critical Limb Ischemia
• Ischemia

Intervention

Biological:
• Ixmyelocel-T
On Day 14, 20 intramuscular injections of ixmyelocel-T on pre-identified index leg.

Other:
• Placebo
On Day 14, 20 intramuscular injections of vehicle control on pre-identified index leg.

Locations

Country	Name	City	State
United States	VA Ann Arbor Healthcare System	Ann Arbor	Michigan
United States	University of Colorado Denver - Anschutz Medical Campus	Aurora	Colorado
United States	Union Memorial Hospital	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Cardiology and Vascular Associates, P.C.	Berkley	Michigan
United States	Cardio-Thoracic Surgeons, P.C.	Birmingham	Alabama
United States	Cardiology PC	Birmingham	Alabama
United States	University Of Alabama At Birmingham	Birmingham	Alabama
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Bethesda Memorial Hospital - Clinical Research Center	Boynton Beach	Florida
United States	University of Buffalo Surgeons Inc.	Buffalo	New York
United States	University of North Carolina Hospital	Chapel Hill	North Carolina
United States	Charleston Area Medical Center - Memorial Hospital	Charleston	West Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois at Chicago - Clinical Sciences North	Chicago	Illinois
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	John Muir Medical Center - Concord Campus	Concord	California
United States	DFW Vascular Group, LLP	Dallas	Texas
United States	Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	John D. Dingell VA Medical Center	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan Vascular Research Center	Flint	Michigan
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Indiana/Ohio Heart	Fort Wayne	Indiana
United States	Florida Research Network, LLC	Gainesville	Florida
United States	Malcom Randall Veterans Affairs Medical Center	Gainesville	Florida
United States	Integrated Vascular Vein Center of Michigan	Grand Blanc	Michigan
United States	Hattiesburg Clinic, P.A.	Hattiesburg	Mississippi
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Heart Institute at St. Luke's Episcopal Hospital	Houston	Texas
United States	The Methodist Hospital	Houston	Texas
United States	St. Vincent Medical Group, Inc.	Indianapolis	Indiana
United States	First Coast Cardiovascular Institute, P.A.	Jacksonville	Florida
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Arkansas Primary Care Clinic, P.A.	Little Rock	Arkansas
United States	Central Arkansas Veteran's Healthcare System	Little Rock	Arkansas
United States	VA Loma Linda Healthcare	Loma Linda	California
United States	UCLA Gonda Venous Center & Ambulatory Procedure Unit	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Vascular Surgical Associates, P.C.	Marietta	Georgia
United States	University of Miami Hospital	Miami	Florida
United States	Columbia Saint Mary's	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Wheaton Franciscan Medical Group, Inc.	Milwaukee	Wisconsin
United States	Abbott Northwestern Hospital / Minneapolis Heart Institute-Vascular Clinic	Minneapolis	Minnesota
United States	Minneapolis VA Health Care System	Minneapolis	Minnesota
United States	University of Minnesota Medical School	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Ochsner Clinic foundation	New Orleans	Louisiana
United States	Mount Sinai Medical Center	New York	New York
United States	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma
United States	Omaha VAMC	Omaha	Nebraska
United States	Orlando Health	Orlando	Florida
United States	Baptist Hospital	Pensacola	Florida
United States	Cardiology Consultants	Pensacola	Florida
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Arizona Heart Institute	Phoenix	Arizona
United States	Carl T. Hayden VA Medical Center	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	VA Pittsburgh Healthcare System	Pittsburgh	Pennsylvania
United States	Veterans' Administration Medical Center	Pittsburgh	Pennsylvania
United States	Sutter Medical Group - Cardiology	Sacramento	California
United States	Michigan CardioVascular Institutue at Covenant Medical Center	Saginaw	Michigan
United States	University of Utah	Salt Lake City	Utah
United States	Audie L Murphy VA Hospital - Pathology Laboratory	San Antonio	Texas
United States	Kaiser Permanente Medical Center	San Diego	California
United States	University of California San Diego Medical Center	San Diego	California
United States	University of California San Francisco - Division of Vascular and Endovascular Surgery	San Francisco	California
United States	Swedish Medical Center	Seattle	Washington
United States	University of Washington	Seattle	Washington
United States	Memorial Medical Center	Springfield	Illinois
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Cascade Vascular Associates, P.S.	Tacoma	Washington
United States	Jobst Vascular Institute	Toledo	Ohio
United States	University of Toledo Medical Center	Toledo	Ohio
United States	University of Arizona	Tucson	Arizona
United States	Grove Place Surgery Center	Vero Beach	Florida
United States	Vascular Access Center of West Orange	West Orange	New Jersey
United States	Heartland Vascular Medicine and Surgery	Windsor Heights	Iowa
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina
United States	UMASS Memorial Health Care	Worcester	Massachusetts
United States	Saint Joseph Mercy Hospital	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Vericel Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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

External Links

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