Perin Emerson C, Murphy Michael P, March Keith L, Bolli Roberto, Loughran John, Yang Phillip C, Leeper Nicholas J, Dalman Ronald L, Alexander Jason, Henry Timothy D, Traverse Jay H, Pepine Carl J, Anderson R David, Berceli Scott, Willerson James T, Muthupillai Raja, Gahremanpour Amir, Raveendran Ganesh, Velasquez Omaida, Hare Joshua M, Hernandez Schulman Ivonne, Kasi Vijaykumar S, Hiatt William R, Ambale-Venkatesh Bharath, Lima João A, Taylor Doris A, Resende Micheline, Gee Adrian P, Durett April G, Bloom Jeanette, Richman Sara, G'Sell Patricia, Williams Shari, Khan Fouzia, Gyang Ross Elsie, Santoso Michelle R, Goldman JoAnne, Leach Dana, Handberg Eileen, Cheong Benjamin, Piece Nichole, DiFede Darcy, Bruhn-Ding Barb, Caldwell Emily, Bettencourt Judy, Lai Dejian, Piller Linda, Simpson Lara, Cohen Michelle, Sayre Shelly L, Vojvodic Rachel W, Moyé Lem, Ebert Ray F, Simari Robert D, Hirsch Alan T
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.).
Circulation. 2017 Apr 11;135(15):1417-1428. doi: 10.1161/CIRCULATIONAHA.116.025707. Epub 2017 Feb 16.
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.
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.
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; =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; =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; =0.047) in participants with completely occluded femoral arteries.
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.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.
动脉粥样硬化性外周动脉疾病影响8%至12%的65岁以上美国人，与功能状态的显著下降、心肌梗死和中风发生率增加以及缺血性截肢风险增加相关。目前间歇性跛行的治疗策略存在局限性。PACE（注射醛脱氢酶亮细胞的间歇性跛行患者）是一项由美国国立心肺血液研究所资助的随机、双盲、安慰剂对照的2期探索性临床试验，旨在评估自体骨髓来源的醛脱氢酶亮（ALDHbr）细胞在周围动脉疾病患者中的安全性和有效性，并探索相关的间歇性跛行生理机制。
所有参与者按1:1随机分组接受ALDHbr细胞或安慰剂，进行骨髓抽吸并分离ALDHbr细胞，随后在患侧大腿和小腿进行10次注射。共同主要终点是从基线到6个月时，通过磁共振成像测量的峰值步行时间（PWT）、侧支计数、腘动脉充血峰值血流和毛细血管灌注的变化，以及安全性。
共有82例间歇性跛行和股下外周动脉疾病患者在9个地点进行了随机分组，其中78例有可分析数据（57例男性，21例女性患者；平均年龄66±9岁）。研究组之间在6个月内PWT（0.9±0.8分钟；95%置信区间[CI] -0.6至2.5；P=0.238）、侧支计数（0.9±0.6条动脉；95% CI，-0.2至2.1；P=0.116）、腘动脉充血峰值血流（0.0±0.4 mL/s；95% CI，-0.8至0.8；P=0.978）和毛细血管灌注（-0.2±0.6%；95% CI，-1.3至0.9；P=0.752）的变化的平均±标准误差异不显著。此外，包括生活质量指标在内的次要终点也没有显著差异。没有不良安全结果。磁共振成像测量与PWT之间不存在显著的相关关系。一项事后探索性分析表明，在股动脉完全闭塞的参与者中，给予ALDHbr细胞可能与侧支动脉数量增加（1.5±0.7；95% CI，0.1 - 2.9；P=0.047）有关。
给予ALDHbr细胞并未改善PWT或磁共振成像结果，且PWT的变化与磁共振成像的解剖学或生理学终点无关。未来外周动脉疾病细胞治疗研究试验设计可能会受益于新的解剖学和灌注见解。
