Clinical Trial

. 2017 Apr 11;135(15):1417-1428.

doi: 10.1161/CIRCULATIONAHA.116.025707. Epub 2017 Feb 16.

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)

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; Cardiovascular Cell Therapy Research Network (CCTRN)

Affiliations

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.

PMID: 28209728
PMCID: PMC5388585
DOI: 10.1161/CIRCULATIONAHA.116.025707

Clinical Trial

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)

Emerson C Perin et al. Circulation. 2017.

. 2017 Apr 11;135(15):1417-1428.

doi: 10.1161/CIRCULATIONAHA.116.025707. Epub 2017 Feb 16.

Authors

Affiliations

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.

PMID: 28209728
PMCID: PMC5388585
DOI: 10.1161/CIRCULATIONAHA.116.025707

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 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.

Keywords: magnetic resonance imaging; peripheral artery disease; stem cells.

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Figures

**Figure 1. CONSORT diagram**
Individual outcome data are not available due to unusable test per quality control issue (*) or adverse event (†).

See this image and copyright information in PMC

Comment in

Every PACE Counts: Learning About Blood Cells and Blood Flow in Peripheral Artery Disease.
Bretón-Romero R, Hamburg NM. Bretón-Romero R, et al. Circulation. 2017 Apr 11;135(15):1429-1431. doi: 10.1161/CIRCULATIONAHA.117.025894. Circulation. 2017. PMID: 28396378 Free PMC article. No abstract available.

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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)

Affiliations

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)

Authors

Affiliations

Abstract

Figures

Comment in

References

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Associated data

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Full Text Sources

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Medical