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

Eric Benoit, Thomas F O'Donnell Jr, Mark D Iafrati, Enrico Asher, Dennis F Bandyk, John W Hallett, Alan B Lumsden, Gregory J Pearl, Sean P Roddy, Krishnaswami Vijayaraghavan, Amit N Patel, Eric Benoit, Thomas F O'Donnell Jr, Mark D Iafrati, Enrico Asher, Dennis F Bandyk, John W Hallett, Alan B Lumsden, Gregory J Pearl, Sean P Roddy, Krishnaswami Vijayaraghavan, Amit N Patel

Abstract

Background: Autologous 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.

Methods: Cells 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.

Results: Fifteen 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.

Conclusions: BMAC 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.

Figures

Figure 1
Figure 1
Time to Amputation over 1 year BMAC vs. Control (All study patients). The Kaplan-Meier curve demonstrates the time to amputation over 1 year between BMAC and control patients in all study subjects.
Figure 2
Figure 2
Time to Amputation over 1 year BMAC vs. Control (Rutherford 5 patients only). There were no amputations in the Rutherford 4 group, removing these patients results in separation of the BMAC and control curves and demonstrates a trend towards a positive treatment effect on amputation. (p = 0.067)
Figures 3
Figures 3
Amputation Free Survival over 1 year BMAC vs. Control (All study patients). The Kaplan-Meier curve demonstrates Amputation Free Survival (AFS) over 1 year in all study subjects with a negligible difference between BMAC and control.
Figure 4
Figure 4
Amputation Free Survival over 1 year BMAC vs. Control (Rutherford 5 patients only) displays. The separation of AFS curves demonstrates a tread towards a positive effect of BMAC on AFS (p = 0.123). As in Figure 1, the event rate in Rutherford 4 patients was low, diluting any apparent treatment effect.

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