Objectives

To assess safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease (PAD) and to explore associated claudication physiologic mechanisms.

Background

Atherosclerotic 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. Claudication represents the most prevalent limb ischemic symptom, affecting 1–3 million Americans. Current treatment strategies for claudication have limitations. For example, pharmacotherapy may not achieve an ideal response rate and supervised exercise efficacy may be limited by co-morbidities. Cell therapy represents a promising approach. However, to date, there has only been one prior randomized, controlled clinical trial that evaluated the potential of these cells to improve exercise performance in claudication. The vast majority of cell therapy trials in PAD have focused on critical limb ischemia. The Cardiovascular Cell Therapy Research Network (CCTRN) noted the need for a clinical trial with both clinical and physiologically focused endpoints.

Participants

Eligible participants were adults aged 40 years and older with a diagnosis of atherosclerotic lower extremity PAD and claudication symptoms that were greater in one leg (the index leg). Claudication was characterized as no aorto-iliac (inflow) stenosis and with a significant (≥ 50%) stenosis or occlusion of at least one infrainguinal arterial segment. A total of 82 patients were enrolled at 9 sites, of which 78 had analyzable data. Of those 78 patients with analyzable data, 38 were randomized to the ALDHbr treatment group and 40 were randomized to the placebo group.

Design

PACE was a randomized, double-blind, placebo-controlled phase 2, exploratory clinical trial with participants randomized 1:1 to receive injections of either ALDHbr cells or cell-free placebo.

Participants completed questionnaires on claudication severity and quality of life at baseline. Ankle-brachial index (ABI) and Gardner-Skinner exercise treadmill testing were also performed at baseline, as well as, MRI angiography to document PAD anatomy. Participants in both treatment groups underwent bone marrow aspiration from the iliac crests. Marrow from participants in the cell treatment group were processed by enriching mononuclear cells using a Sepax device, staining the primitive stem cells for the intracellular enzyme ALDH, and aseptically sorting using a FACS Aria cell sorter. Injections of ALDHbr cells or cell-free placebo were made in the index leg at the depth of the muscular mass of the calf and lower thigh. Participants were followed for safety and efficacy for six months. Evaluations were performed on the day of injection, at one week, and one, three, and six months. Treadmill and ABI or toe-brachial index (TBI) testing were conducted at three and six months. MRI measurements were performed at six months for the primary endpoint assessment.

The co-primary endpoints were: change from baseline to six months in peak walking time (PWT), and collateral count, peak hyperemic popliteal flow, and capillary perfusion all measured by magnetic resonance imaging (MRI); as well as safety. PACE further evaluated a wide set of pre hoc defined physiological relationships that could inform PAD claudication research.

Conclusions

In patients with PAD, ALDHbr cell administration is safe but did not improve PWT, collateral count, peak hyperemic popliteal flow or capillary perfusion. Further research is needed, particularly with a larger study in order to achieve sufficient statistical power, regarding the possible increase in PWT after treatment with ALDHbr cells.

The pathophysiology of claudication is complex. The MRI techniques developed for this study may be utilized in future PAD clinical research to identify the ideal cell dose and timing of one or more cell administrations to determine if a clinically relevant therapeutic benefit might be achieved.

Perin EC, Murphy MP, March KL, et al. 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). Circulation. 2017;135(15):1417–1428. doi:10.1161/CIRCULATIONAHA.116.025707

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