A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia

Abstract

Background: Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI).

Methods and results: Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1 × 10(5) (low-dose) and 9 to 1 × 10(6) (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration.

Conclusions: This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00616980.

Figure 1. Study Design and Subject Disposition

Figure 2. Probability of Amputation Free Survival

Probability of amputation free survival in low-dose, high-dose and control groups (A) and in combined cell-treated and control groups (B). Probability of major amputation free survival in low-dose, high-dose and control groups (C) and in combined cell-treated and control groups (D).

Figure 3. Functional Improvement and Wound Healing at 6 and 12 Months

3A: Total distance walked on 6 minute walk test at baseline and 6 and 12 months post-injection in subjects that completed the test at 6 and/or 12 months post-injection. 3B: Total wound area in the treated leg in subjects with ulcers reported at 6 and/or 12 months post-injection. Zero (0) indicates no leg ulcer present. C=control, L=low-dose, H=high-dose, WD=withdrawal, A=amputation, M=missing.

Figure 4. Summary of Mean Change from Baseline in SF-36 Health Domains

Mean (±SD) change from baseline in SF-36 health domains at 6 months and 12 months post-injection. PF=physical functioning, RP=role physical, BP=bodily pain, GH=general health, V=vitality, SF=social functioning, RE=role emotional, MH=mental health, HT=health transition.