PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial
Lars Norgren, Norbert Weiss, Sigrid Nikol, John C Lantis, Manesh R Patel, Robert J Hinchliffe, Holger Reinecke, Hans Dieter Volk, Petra Reinke, Gian Paolo Fadini, Racheli Ofir, Daniel Rothenstein, Nitsan Halevy, Mitko Karagjozov, John H Rundback- Surgery
Abstract
Background
Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization.
Methods
People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12–36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events.
Results
Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048).
Conclusion
Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).