ORLANDO – A large trial of a novel cellular expansion therapy will soon get underway in patients with critical limb ischemia patients and no revascularization options.
Based upon favorable results in initial safety and efficacy studies, the REVIVE-CLI trial of ixmyelocel-T will involve 80 U.S. centers and 594 no-option critical limb ischemia patients with tissue loss at baseline. The primary efficacy end point will be amputation-free survival at 12 months, Dr. William Marston said at the annual scientific sessions of the American Heart Association.
Ixmyelocel-T relies on a 50 mL aspirate of a patient’s bone marrow cells obtained from the ischial tuberosity during a 15-minute office procedure. Over the next 12 days, an automated process is used to expand the cell types believed to be beneficial in critical limb ischemia. The cells are then reintroduced into the patient via 20 intramuscular injections, 0.5 mL each, into the foot, calf, and lower thigh. The procedure takes 20 minutes and is performed in an office setting, explained Dr. Marston, professor of surgery and chief of the division of vascular surgery at the University of North Carolina, Chapel Hill.
The benefits of the process were noted in a double-blind, placebo-controlled, multicenter study involving 72 subjects with infrainguinal occlusive arterial disease deemed not amenable to revascularization. Half of the patients had diabetes. Participants were randomized 2:1 to ixmyelocel-T or to placebo injections. The primary end point was death, major amputation on the treated limb, doubling of wound size from baseline, or new gangrene. During 12 months of follow-up, the primary end point occurred in 67% of controls and in 40% of the ixmyelocel-T group, for a 62% relative reduction in risk.
The major driver of the significant difference in the end point was the change in the wound size. Baseline wounds were present in 45 subjects. Total wound surface area doubled in 5 of 29 ixmyelocel-T–treated patients with baseline wounds, as compared to 7 of 16 controls.
The secondary efficacy end point was amputation-free survival. One-third of controls and one-quarter of ixmyelocel-T–treated patients had an amputation during the study period. The study wasn’t powered to draw conclusions regarding amputation-free survival, according to the surgeon.
The treatment and control groups did not differ in terms of adverse events or study withdrawals due to adverse events.
The laboratory process reduces RBCs, T and B lymphocytes, and CD45+ granulocytes while achieving a 200-fold expansion of monocytes into activated macrophages and a 50-fold increase in mesenchymal stem cells. The mechanism of benefit of ixmyelocel-T, based upon preclinical data, is believed to involve remodeling of ischemic tissue, modulation of inflammation, and promotion of angiogenesis.
"There’s quite a bit of upregulation of tumor necrosis factor-alpha, interleukins, and other proinflammatory cytokines in these patients. We think that this combination of cells that are reintroduced may have benefits other than angiogenesis that may be very important in wound patients," Dr. Marston said.
Other approaches to cellular therapy in critical limb ischemia are being pursued by other groups. Some involve harvesting large quantities of bone marrow under general anesthesia, which Dr. Marston sees as less practical than the ixmyelocel-T strategy.
Dr. Marston declared that he serves as a scientific advisor to Aastrom Biosciences, which is developing ixmyelocel-T.