Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

BACKGROUND: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age 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 (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. RESULTS: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [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/s; 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. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging 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, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.

Autologous bone marrow mononuclear cell therapy for critical limb ischemia is effective and durable.

OBJECTIVE: We have previously shown that autologous bone marrow mononuclear cell (ABMNC) therapy improves measures of limb perfusion, rest pain, wound healing, and amputation-free survival (AFS) at 1 year in patients with critical limb ischemia (CLI). Long-term durability of ABMNC therapy for CLI remains unknown. The objective of the current study was to evaluate long-term clinical outcomes 5 years after treatment. METHODS: Data were retrospectively gathered from a database and via a patient survey and review of medical records of patients previously enrolled in this phase I/II trial. AFS, freedom from major amputation, and freedom from major adverse limb events (MALE) were calculated using the product-limit estimate. The incidence of cardiac, malignant, and other medical events relevant to the safety of cell therapy were tabulated during the time from treatment to follow-up. RESULTS: Twenty-one of the 24 patients (88%) who completed the initial 1-year phase I/II trial were available for the 5-year analysis; AFS was 74% (95% confidence interval [CI], 0.53-0.87), freedom from major amputation was 78% (95% CI, 0.58-0.90), and freedom from MALE was 65% (95% CI, 0.45-0.80). Three patients (14%) had major cardiac events. There were no incidences of malignancies or diagnoses of clinically significant proliferative retinopathy. Fifteen patients (71%) report continued improvement in pain-free walking. Nineteen (90%) patients believed that the study was of significant medical value and would participate again. CONCLUSIONS: ABMNC therapy provides long-term freedom from AFS, major amputation, and MALE that are comparable with other reports of patients who underwent surgical and endovascular interventions for CLI. Furthermore, no patients developed tumorigenesis or clinically significant retinopathy. Because of the limited number of patients studied, our findings will need to be followed up in a larger phase III trial.