Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

BACKGROUND: Atherosclerotic peripheral artery disease (PAD) affects 8–12% of Americans over 65 and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE is an NHLBI-sponsored, randomized, double-blind, placebo-controlled phase 2, exploratory clinical trial designed to assess safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in PAD patients and to explore associated claudication physiologic mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by ten injections into the thigh and calf of the index leg. The co-primary endpoints were: change from baseline to six months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging (MRI); as well as safety. RESULTS: A total of 82 patients with claudication and infra-inguinal PAD were randomized at nine sites, of which 78 had analyzable data (57 male, 21 female; mean age 66±9 years). The mean differences in the change over six months between study groups for PWT (mean ± standard error of the mean [SEM]) (0.9±0.8 minutes; 95% CI −0.6 to 2.5; p=0.238), collateral count (0.9±0.6 arteries; 95% CI −0.2 to 2.1; p=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/sec; 95% CI −0.8 to 0.8; p=0.978), and capillary perfusion (−0.2±0.6%; 95% CI −1.3 to 0.9; p=0.752) were not significant. Additionally, there were no significant differences for the secondary endpoints, including quality of life measures. There were no adverse safety outcomes. Correlative relationships between MRI measures and PWT were not significant. A post-hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI 0.1 to 2.9; p=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or MR outcomes, and the changes in PWT were not associated with the anatomic or physiologic MRI endpoints. Future PAD cell therapy investigational trial design may be informed by new anatomic and perfusion insights