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, Michael Murphy, Keith L. March, Roberto Bolli, John Loughran, Phillip C. Yang, Nicholas J. Leeper, Ronald L. Dalman, Jason Alexander, Timothy D. Henry, Jay H. Traverse, Carl J. Pepine, R. David Anderson, Scott Berceli, James T. Willerson, Raja Muthupillai, Amir Gahremanpour, Ganesh Raveendran, Omaida Velasquez, Joshua M. HareIvonne Hernandez Schulman, Vijaykumar S. Kasi, William R. Hiatt, Bharath Ambale-Venkatesh, João A. Lima, Doris A. Taylor, Micheline Resende, Adrian P. Gee, April G. Durett, Jeanette Bloom, Sara Richman, Patricia G'Sell, Shari Williams, Fouzia Khan, Elsie Gyang Ross, Michelle R. Santoso, Joanne Goldman, Dana Leach, Eileen Handberg, Benjamin Cheong, Nichole Piece, Darcy Difede, Barb Bruhn-Ding, Emily Caldwell, Judy Bettencourt, Dejian Lai, Linda Piller, Lara Simpson, Michelle Cohen, Shelly L. Sayre, Rachel W. Vojvodic, Lem Moyé, Ray F. Ebert, Robert D. Simari, Alan T. Hirsch

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1417-1428
Number of pages12
JournalCirculation
Volume135
Issue number15
DOIs
StatePublished - Apr 11 2017
Externally publishedYes

Fingerprint

Intermittent Claudication
Peripheral Arterial Disease
Aldehyde Dehydrogenase
Cell- and Tissue-Based Therapy
Extremities
Perfusion
Walking
Exercise
Confidence Intervals
Safety
Arteries
Bone Marrow
Placebos
Magnetic Resonance Imaging
Clinical Trials
National Heart, Lung, and Blood Institute (U.S.)
Magnetic Resonance Angiography
Femoral Artery
Thigh
Amputation

Keywords

  • magnetic resonance imaging
  • peripheral artery disease
  • stem cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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). / Perin, Emerson C.; Murphy, Michael; 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.; David Anderson, R.; Berceli, Scott; Willerson, James T.; Muthupillai, Raja; Gahremanpour, Amir; Raveendran, Ganesh; Velasquez, Omaida; Hare, Joshua M.; Schulman, Ivonne Hernandez; 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; Ross, Elsie Gyang; 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.

In: Circulation, Vol. 135, No. 15, 11.04.2017, p. 1417-1428.

Research output: Contribution to journalArticle

Perin, EC, Murphy, M, March, KL, Bolli, R, Loughran, J, Yang, PC, Leeper, NJ, Dalman, RL, Alexander, J, Henry, TD, Traverse, JH, Pepine, CJ, David Anderson, R, Berceli, S, Willerson, JT, Muthupillai, R, Gahremanpour, A, Raveendran, G, Velasquez, O, Hare, JM, Schulman, IH, Kasi, VS, Hiatt, WR, Ambale-Venkatesh, B, Lima, JA, Taylor, DA, Resende, M, Gee, AP, Durett, AG, Bloom, J, Richman, S, G'Sell, P, Williams, S, Khan, F, Ross, EG, Santoso, MR, Goldman, J, Leach, D, Handberg, E, Cheong, B, Piece, N, Difede, D, Bruhn-Ding, B, Caldwell, E, Bettencourt, J, Lai, D, Piller, L, Simpson, L, Cohen, M, Sayre, SL, Vojvodic, RW, Moyé, L, Ebert, RF, Simari, RD & Hirsch, AT 2017, '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)', Circulation, vol. 135, no. 15, pp. 1417-1428. https://doi.org/10.1161/CIRCULATIONAHA.116.025707
Perin, Emerson C. ; Murphy, Michael ; 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. ; David Anderson, R. ; Berceli, Scott ; Willerson, James T. ; Muthupillai, Raja ; Gahremanpour, Amir ; Raveendran, Ganesh ; Velasquez, Omaida ; Hare, Joshua M. ; Schulman, Ivonne Hernandez ; 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 ; Ross, Elsie Gyang ; 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. / 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). In: Circulation. 2017 ; Vol. 135, No. 15. pp. 1417-1428.
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title = "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)",
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.",
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TY - JOUR

T1 - Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

T2 - The CCTRN PACE Trial (Patients with Intermittent Claudication Injected with ALDH Bright Cells)

AU - Perin, Emerson C.

AU - Murphy, Michael

AU - March, Keith L.

AU - Bolli, Roberto

AU - Loughran, John

AU - Yang, Phillip C.

AU - Leeper, Nicholas J.

AU - Dalman, Ronald L.

AU - Alexander, Jason

AU - Henry, Timothy D.

AU - Traverse, Jay H.

AU - Pepine, Carl J.

AU - David Anderson, R.

AU - Berceli, Scott

AU - Willerson, James T.

AU - Muthupillai, Raja

AU - Gahremanpour, Amir

AU - Raveendran, Ganesh

AU - Velasquez, Omaida

AU - Hare, Joshua M.

AU - Schulman, Ivonne Hernandez

AU - Kasi, Vijaykumar S.

AU - Hiatt, William R.

AU - Ambale-Venkatesh, Bharath

AU - Lima, João A.

AU - Taylor, Doris A.

AU - Resende, Micheline

AU - Gee, Adrian P.

AU - Durett, April G.

AU - Bloom, Jeanette

AU - Richman, Sara

AU - G'Sell, Patricia

AU - Williams, Shari

AU - Khan, Fouzia

AU - Ross, Elsie Gyang

AU - Santoso, Michelle R.

AU - Goldman, Joanne

AU - Leach, Dana

AU - Handberg, Eileen

AU - Cheong, Benjamin

AU - Piece, Nichole

AU - Difede, Darcy

AU - Bruhn-Ding, Barb

AU - Caldwell, Emily

AU - Bettencourt, Judy

AU - Lai, Dejian

AU - Piller, Linda

AU - Simpson, Lara

AU - Cohen, Michelle

AU - Sayre, Shelly L.

AU - Vojvodic, Rachel W.

AU - Moyé, Lem

AU - Ebert, Ray F.

AU - Simari, Robert D.

AU - Hirsch, Alan T.

PY - 2017/4/11

Y1 - 2017/4/11

N2 - 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.

AB - 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.

KW - magnetic resonance imaging

KW - peripheral artery disease

KW - stem cells

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U2 - 10.1161/CIRCULATIONAHA.116.025707

DO - 10.1161/CIRCULATIONAHA.116.025707

M3 - Article

C2 - 28209728

AN - SCOPUS:85013817042

VL - 135

SP - 1417

EP - 1428

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 15

ER -