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

• Percent of patients with adverse events [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  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.
• Percent of patients with complete wound closure by Month 12 [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  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.
• Percent of patients experiencing a major cardiac event (MACE) by Months 6, 12, and 18 [ Time Frame: 6, 12 and 18 months ] [ Designated as safety issue: No ]
  % of patients experiencing a MACE event defined as cardiovascular mortality, myocardial infarction, chest pain requiring hospitalization, or stroke.

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.

• Biological: Ixmyelocel-T
  On Day 14, 20 intramuscular injections of either ixmyelocel-T or vehicle control on pre-identified index leg.
• Other: Vehicle Control
  On Day 14, 20 intramuscular injections of either ixmyelocel-T or vehicle control on pre-identified index leg.

• Experimental: ixmyelocel-T
  Intervention: Biological: Ixmyelocel-T
• Placebo Comparator: Vehicle Control
  Intervention: Other: Vehicle Control

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