Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease

A randomized clinical trial

Joseph Poole, Kreton Mavromatis, José N. Binongo, Ali Khan, Qunna Li, Mohamed Khayata, Elizabeth Rocco, Matthew Topel, Xin Zhang, Charlene Brown, Matthew A. Corriere, Jonathan Murrow, Salman Sher, Stephanie Clement, Khuram Ashraf, Amr Rashed, Tarek Kabbany, Robert Neuman, Alanna Morris, Arshad Ali & 5 others Salim Hayek, John Oshinski, Youngsup Yoon, Edmund K. Waller, Arshed A. Quyyumi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

IMPORTANCE: Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE: To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS: Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES: The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS: Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE: Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01041417

Original languageEnglish
Pages (from-to)2631-2639
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume310
Issue number24
DOIs
Publication statusPublished - 2013 Dec 30

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Peripheral Arterial Disease
Granulocyte-Macrophage Colony-Stimulating Factor
Walking
Stem Cells
Randomized Controlled Trials
Placebos
Ankle Brachial Index
Intermittent Claudication
Subcutaneous Injections
Health Surveys
Bone Marrow Cells
Therapeutics
Extremities
Perfusion
Exercise
Surveys and Questionnaires

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Poole, Joseph ; Mavromatis, Kreton ; Binongo, José N. ; Khan, Ali ; Li, Qunna ; Khayata, Mohamed ; Rocco, Elizabeth ; Topel, Matthew ; Zhang, Xin ; Brown, Charlene ; Corriere, Matthew A. ; Murrow, Jonathan ; Sher, Salman ; Clement, Stephanie ; Ashraf, Khuram ; Rashed, Amr ; Kabbany, Tarek ; Neuman, Robert ; Morris, Alanna ; Ali, Arshad ; Hayek, Salim ; Oshinski, John ; Yoon, Youngsup ; Waller, Edmund K. ; Quyyumi, Arshed A. / Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease : A randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2013 ; Vol. 310, No. 24. pp. 2631-2639.
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abstract = "IMPORTANCE: Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE: To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87{\%} male, 37{\%} with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS: Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES: The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS: Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95{\%} CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95{\%} CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95{\%} CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95{\%} CI, 6.7 to 16.1) vs 4.8 (95{\%} CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95{\%} CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95{\%} CI, 6.4 to 18.7) vs 4.8 (95{\%} CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95{\%} CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE: Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01041417",
author = "Joseph Poole and Kreton Mavromatis and Binongo, {Jos{\'e} N.} and Ali Khan and Qunna Li and Mohamed Khayata and Elizabeth Rocco and Matthew Topel and Xin Zhang and Charlene Brown and Corriere, {Matthew A.} and Jonathan Murrow and Salman Sher and Stephanie Clement and Khuram Ashraf and Amr Rashed and Tarek Kabbany and Robert Neuman and Alanna Morris and Arshad Ali and Salim Hayek and John Oshinski and Youngsup Yoon and Waller, {Edmund K.} and Quyyumi, {Arshed A.}",
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Poole, J, Mavromatis, K, Binongo, JN, Khan, A, Li, Q, Khayata, M, Rocco, E, Topel, M, Zhang, X, Brown, C, Corriere, MA, Murrow, J, Sher, S, Clement, S, Ashraf, K, Rashed, A, Kabbany, T, Neuman, R, Morris, A, Ali, A, Hayek, S, Oshinski, J, Yoon, Y, Waller, EK & Quyyumi, AA 2013, 'Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 310, no. 24, pp. 2631-2639. https://doi.org/10.1001/jama.2013.282540

Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease : A randomized clinical trial. / Poole, Joseph; Mavromatis, Kreton; Binongo, José N.; Khan, Ali; Li, Qunna; Khayata, Mohamed; Rocco, Elizabeth; Topel, Matthew; Zhang, Xin; Brown, Charlene; Corriere, Matthew A.; Murrow, Jonathan; Sher, Salman; Clement, Stephanie; Ashraf, Khuram; Rashed, Amr; Kabbany, Tarek; Neuman, Robert; Morris, Alanna; Ali, Arshad; Hayek, Salim; Oshinski, John; Yoon, Youngsup; Waller, Edmund K.; Quyyumi, Arshed A.

In: JAMA - Journal of the American Medical Association, Vol. 310, No. 24, 30.12.2013, p. 2631-2639.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease

T2 - A randomized clinical trial

AU - Poole, Joseph

AU - Mavromatis, Kreton

AU - Binongo, José N.

AU - Khan, Ali

AU - Li, Qunna

AU - Khayata, Mohamed

AU - Rocco, Elizabeth

AU - Topel, Matthew

AU - Zhang, Xin

AU - Brown, Charlene

AU - Corriere, Matthew A.

AU - Murrow, Jonathan

AU - Sher, Salman

AU - Clement, Stephanie

AU - Ashraf, Khuram

AU - Rashed, Amr

AU - Kabbany, Tarek

AU - Neuman, Robert

AU - Morris, Alanna

AU - Ali, Arshad

AU - Hayek, Salim

AU - Oshinski, John

AU - Yoon, Youngsup

AU - Waller, Edmund K.

AU - Quyyumi, Arshed A.

PY - 2013/12/30

Y1 - 2013/12/30

N2 - IMPORTANCE: Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE: To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS: Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES: The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS: Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE: Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01041417

AB - IMPORTANCE: Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE: To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS: Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES: The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS: Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE: Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01041417

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DO - 10.1001/jama.2013.282540

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JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

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