Use of Ixmyelocel-T (Formerly Vascular Repair Cells [VRC]) in Patients With Peripheral Arterial Disease to Treat Critical Limb Ischemia (RESTORE-CLI)

• Composite efficacy endpoint assessing time to treatment failure(failure defined as major amputation, doubling of wound size, and new gangrene) [ Time Frame: Day 7 and Months 3, 6, 9, 12 ] [ Designated as safety issue: No ]
• Percentage of patients failing treatment [ Time Frame: Day 7, and Months 3,6,9, and 12 ] [ Designated as safety issue: No ]
• Time to major amputation [ Time Frame: Day 7 and Month 3, 6, 9, and 12 ] [ Designated as safety issue: No ]
• Percentage of patients undergoing major amputation [ Time Frame: Day 7 and Months 3, 6, 9, 12 ] [ Designated as safety issue: No ]
• Incidence of revascularization interventions throughout duration of study [ Time Frame: Day 7 and Months 3,6,9,12 ] [ Designated as safety issue: No ]
• Incidence of bypass surgery for patients throughout duration of study [ Time Frame: Day 7 and Months 3,6,9,12 ] [ Designated as safety issue: No ]
• Healing of all wounds in the target limb [ Time Frame: Day 7 and Months 3,6,9,12 ] [ Designated as safety issue: No ]
• Ankle and/or toe pressure and ankle brachial pressure index and/or toe brachial index [ Time Frame: Day 7 and Months 3,6,9,12 ] [ Designated as safety issue: No ]
• Pain, as measured by visual analog scale(VAS) [ Time Frame: Day 7 and Months 3,6,9,12 ] [ Designated as safety issue: No ]
• The King's College Vascular Quality of Life Questionnaire [ Time Frame: Baseline and Months 6 and 12 ] [ Designated as safety issue: No ]
• Walking distance as measured by six-minute walk test(with or without walking device) [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
• Concurrent Meds for trends [ Time Frame: Day 7 and Months 3, 6, 9, 12 ] [ Designated as safety issue: No ]

This study is designed to evaluate the safety and efficacy of autologous Vascular Repair Cells (VRC) for patients with peripheral arterial disease as a treatment for critical limb ischemia.

The double-blind study is expected to enroll 150 patients, randomized into two patient groups. The treatment group will receive intramuscular (IM) injections of the VRCs into the affected limb; the control group will receive intramuscular injections with an electrolyte solution (without cells). Both groups will receive the standard of care appropriate for their medical condition.

The study will assess the safety and ability of Aastrom TRC autologous bone marrow cells to restore peripheral blood flow affected by critical limb ischemia.

Peripheral arterial disease (PAD), also known as Peripheral Vascular Disease (PVD), occurs when peripheral arteries are damaged by arterial hypertension and/or by the formation of atherosclerotic plaques. PAD is a chronic disease that progressively constricts arterial circulation of limbs. The term critical limb ischemia (CLI) is used for all patients with chronic ischemia rest pain, ulcers, or gangrene in limbs attributable to objectively proven PAD. These sequelae represent the end stage of PAD. PAD is associated with several other clinical conditions, i.e. hypertension, cardiovascular disease, hyperlipidemia, diabetes, tobacco use, obesity and stroke.

The double-blind study is expected to enroll 150 patients, randomized into two patient groups. The treatment group will receive intramuscular injections of the TRC product into the affected limb; the control group will receive intramuscular injections with an electrolyte solution (without cells). Both groups will receive the standard of care appropriate for their medical condition.

• Biological: autologous bone marrow cells
  IM injection
  Other Name: Vascular Repair Cells (VRCs)
• Biological: electrolyte solution (without cells)
  IM Injection

• Experimental: Treatment
  The Treatment arm of the study will receive standard of care therapy and injections of the study cellular product.
  Intervention: Biological: autologous bone marrow cells
• Placebo Comparator: Control
  The Control arm of the study will receive standard of care and placebo injections.
  Intervention: Biological: electrolyte solution (without cells)

• Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, Stern TP, Watling S, Bartel RL. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther. 2012 Jun;20(6):1280-6. doi: 10.1038/mt.2012.52. Epub 2012 Mar 27.
• Powell RJ, Comerota AJ, Berceli SA, Guzman R, Henry TD, Tzeng E, Velazquez O, Marston WA, Bartel RL, Longcore A, Stern T, Watling S. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg. 2011 Oct;54(4):1032-41. Epub 2011 Jul 31.

Inclusion Criteria:

• Males and females, 18-90 years of age
• Diagnosis of CLI
• Infrainguinal occlusive disease, without options for revascularization
• No surgical interventions planned
• Life expectancy of 2 years
• Normal organ and marrow function
• Patients with controlled blood pressure (≤ 180/110 mmHg) and established anti-hypertensive therapy
• Established anti-platelet therapy

Exclusion Criteria:

• Poorly controlled diabetes mellitus (hemoglobin A1c [HbA1c] > 10%)
• Aortoiliac disease with > 50% stenosis
• Wounds with severity greater than Grade 3 on the Wagner Scale
• Any known failed ipsilateral revascularization within 2 weeks of enrollment
• Previous amputation of the talus, or above in the target limb
• Life-threatening ventricular arrhythmia; unstable angina; or, myocardial infarction within 4 weeks of enrollment
• Severe congestive heart failure (CHF) (i.e. New York Heart Association [NYHA] Stage IV)
• Receiving treatment with hematopoietic growth factors
• Infection of the involved extremity(ies)
• Active wet gangrenous tissue
• Require uninterruptible anticoagulation therapy
• Blood clotting disorder
• Cancer
• End stage renal disease requiring dialysis for more than 6 months prior to enrollment
• Pregnant or lactating
• Having received medication for thrombolytic therapy (e.g. rTPA or other enzymatic clot busters) within 30 days prior to enrollment
• Undergoing hyperbaric oxygen treatment within 2 weeks of enrollment
• Concomitant wound treatments with growth factors or tissue engineered products
• Receiving anti-angiogenic drugs