Emerson C Perin1, Michael P Murphy1, Keith L March1, Roberto Bolli1, John Loughran1, Phillip C Yang1, Nicholas J Leeper1, Ronald L Dalman1, Jason Alexander1, Timothy D Henry1, Jay H Traverse1, Carl J Pepine1, R David Anderson1, Scott Berceli1, James T Willerson1, Raja Muthupillai1, Amir Gahremanpour1, Ganesh Raveendran1, Omaida Velasquez1, Joshua M Hare1, Ivonne Hernandez Schulman1, Vijaykumar S Kasi1, William R Hiatt1, Bharath Ambale-Venkatesh1, João A Lima1, Doris A Taylor1, Micheline Resende1, Adrian P Gee1, April G Durett1, Jeanette Bloom1, Sara Richman1, Patricia G'Sell1, Shari Williams1, Fouzia Khan1, Elsie Gyang Ross1, Michelle R Santoso1, JoAnne Goldman1, Dana Leach1, Eileen Handberg1, Benjamin Cheong1, Nichole Piece1, Darcy DiFede1, Barb Bruhn-Ding1, Emily Caldwell1, Judy Bettencourt1, Dejian Lai1, Linda Piller1, Lara Simpson1, Michelle Cohen1, Shelly L Sayre1, Rachel W Vojvodic1, Lem Moyé2, Ray F Ebert1, Robert D Simari1, Alan T Hirsch1. 1. From Texas Heart Institute (E.C.P., J.T.W., A.G., D.A.T., M.R., B.C., N.P.), CHI St. Luke's Health (R.M.), Houston; Indiana University School of Medicine, Indianapolis (M.P.M., K.L.M., P.G.); University of Louisville, KY (R.B., J.L., S.W.); Stanford University School of Medicine, CA (P.C.Y., N.J.L., R.L.D., F.K., E.G.R., M.R.S.); Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.A., J.H.T., J.G.); Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); University of Florida School of Medicine, Gainesville (C.J.P., R.D.A., S.B., D.L., E.H.); University of Minnesota Medical School, Minneapolis (G.R., B.B.-D., E.C., A.T.H.); University of Miami Miller School of Medicine, FL (O.V., J.M.H., I.H.S., D.D.); Orlando Health, FL (V.S.K.); University of Colorado School of Medicine and CPC Clinical Research, Aurora (W.R.H.); Johns Hopkins University, Baltimore, MD (B.A.- V., J.A.L.); Baylor College of Medicine, Houston, TX (A.P.G., A.G.D., J. Bloom, S.R.); University of Texas School of Public Health, Houston (J. Bettencourt, D.L., L.P., L.S., M.C., S.L.S., R.W.V., L.M.); National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD (R.F.E.); and University of Kansas School of Medicine, Kansas City (R.D.S.). 2. From Texas Heart Institute (E.C.P., J.T.W., A.G., D.A.T., M.R., B.C., N.P.), CHI St. Luke's Health (R.M.), Houston; Indiana University School of Medicine, Indianapolis (M.P.M., K.L.M., P.G.); University of Louisville, KY (R.B., J.L., S.W.); Stanford University School of Medicine, CA (P.C.Y., N.J.L., R.L.D., F.K., E.G.R., M.R.S.); Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.A., J.H.T., J.G.); Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); University of Florida School of Medicine, Gainesville (C.J.P., R.D.A., S.B., D.L., E.H.); University of Minnesota Medical School, Minneapolis (G.R., B.B.-D., E.C., A.T.H.); University of Miami Miller School of Medicine, FL (O.V., J.M.H., I.H.S., D.D.); Orlando Health, FL (V.S.K.); University of Colorado School of Medicine and CPC Clinical Research, Aurora (W.R.H.); Johns Hopkins University, Baltimore, MD (B.A.- V., J.A.L.); Baylor College of Medicine, Houston, TX (A.P.G., A.G.D., J. Bloom, S.R.); University of Texas School of Public Health, Houston (J. Bettencourt, D.L., L.P., L.S., M.C., S.L.S., R.W.V., L.M.); National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD (R.F.E.); and University of Kansas School of Medicine, Kansas City (R.D.S.). lemmoye@msn.com.
Abstract
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 diseasecell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.
RCT Entities:
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.
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