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

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.


Eligibility Criteria:
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