PACE: ALDH bright cells fail to improve functional outcomes in claudication

NEW ORLEANS — Compared with placebo, aldehyde dehydrogenase bright cells did not improve functional or MRI-based outcomes in patients with claudication, according to findings from the PACE study presented at the American Heart Association Scientific Sessions.

Claudication affects 1 million to 3 million Americans, but treatment options are limited to cilostazol, supervised exercise and revascularization, so cell therapy, which can promote arteriogenesis and angiogenesis and affect the skeletal muscles and the endothelium, may have promise in this area, Emerson C. Perin, MD, PhD, from the Texas Heart Institute in Houston, said in a presentation.

“The pathophysiology of claudication is complex, and there is little correlation between large artery flow and symptoms,” he said.

Perin and colleagues conducted a phase 2 study of aldehyde dehydrogenase (ALDH) bright cells, which showed the ability to perform ischemic repair in preclinical models and demonstrated safety and feasibility in phase 1 studies in people with critical limb ischemia or congestive HF.

The researchers randomly assigned 78 patients (mean age, 66 years; 27% women) with atherosclerotic peripheral artery disease and claudication symptoms or atypical leg pain, pre-exercise ankle-brachial index < 0.9 or pre-exercise toe-brachial index < 0.7, and significant stenosis or occlusion of infrainguinal arteries to receive ALDH bright cells or placebo. All patients received 10 injections in the leg of 1 mL of the cells or placebo.

The primary functional endpoint was change in treadmill peak walking time from baseline to 6 months. The primary MRI-based endpoints were changes in collateral artery count, capillary perfusion and peak hyperemic popliteal flow at 6 months.

“The PACE trial was designed so that these novel endpoints would inform both on intermittent new claudication, a significant new contribution to the field, as well as cell therapy,” Perin said. “It was performed to enhance the understanding of PAD and explore the underlying mechanisms of limb perfusion and the relationships with claudication in the setting of a novel cell therapy for PAD. In PACE, the physiologic exploratory goal was equal to that of measuring clinical outcomes.”

Change in peak walking time at 6 months was 2.1 minutes in the cell group and 1.2 minutes in the placebo group (difference, 0.9; 95% CI, –0.6 to 2.5), Perin said.

There were no differences between the groups in 6-month change in collateral artery count (weight-adjusted P = .081), peak hyperemic flow (weight-adjusted P = .835) or capillary perfusion (weight-adjusted P = .937), he said.

“These three MR endpoints can essentially account for all the arterial flow going down the leg,” Perin said.

In a subgroup of patients (n = 28) with baseline ankle-brachial index < 0.6, the cell therapy conferred a change in collateral artery count at 6 month compared with placebo (weight-adjusted P = .021), Perin said.

In a post hoc analysis, Perin and colleagues found among patients with an occluded femoral artery at baseline (n = 54), who had a significantly higher baseline collateral count than those with a patent femoral artery, the cell therapy was associated with a 6-month improvement in collateral artery count compared with placebo (difference, 1.5; 95% CI, 0.5-2.9).

“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” he said.

Although there was no significant improvement in outcomes associated with the cell therapy, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” Perin said. – by Erik Swain

Reference:

Perin EC, et al. CSSR.01 – Cell Therapy: Ready for Prime Time? Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Disclosure: The study was funded in part by Aldagen. Perin reports no relevant financial disclosures.