The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design

Abstract

BackgroundAutologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature.MethodsCells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss.ResultsFifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain.ConclusionsBMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.

Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia ― Results of a Randomized, Double-Blind, Placebo-Controlled Trial ―

“…1 However, recent data suggest that this rate is now much lower, especially in the setting of the specialized centers in which clinical trials are performed. 17 Indeed, in these centers, patients enrolled in clinical trials are previously treated according to the standard of care. In the BALI trial the 6-month amputation rate was 26% in the placebo group.…”

Avoidance of Lower-Limb Amputation by Surgical Implantation of Autologous Stem Cells

“…Th is clinical research trial demonstrated a statistically signifi cant 50% reduction in the need for amputation in patients with CLI and tissue loss (7). Th is patient continues to have some exercise-induced claudication, but he is able to perform the functions required of his daily life.…”

“…He was enrolled in a pilot trial using bone marrow-derived stem cells, which were collected, processed, and immediately returned to the patient in the same procedure (2,7). In this procedure, a nonspecifi c mononuclear cell mix was implanted with minimal time spent outside the patient's body.…”

Clinical Trials of Adult Stem Cell Therapy for Peripheral Artery Disease

“…[22][23][24][25][26][27][28][29][30][31][32][33] Procedures associated with cell therapy, such as bone marrow aspiration and injection, were generally well-tolerated by the patients, with few adverse events reported. hence, current data is promising, and safety concerns do not outweigh the promise of potential benefit, which must now be tested in definitive clinical trials.…”

“…since that time, numerous other studies have examined the efficacy and safety of cell therapy for Pad, with varying results (tables 1 and 2). [22][23][24][25][26][27][28][29][30][31][32][33] Most clinical trials of cell therapy for Pad have consisted of uncontrolled patient series, with few randomized, properly controlled studies. sample sizes have been relatively small, with most studies enrolling fewer than 50 patients.…”