Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

Victoria Florea, Angela C. Rieger, Darcy L. DiFede, Jill El-Khorazaty, Makoto Natsumeda, Monisha N. Banerjee, Bryon A. Tompkins, Aisha Khan, Ivonne H Schulman, Ana Marie Landin, Muzammil Mushtaq, Samuel Golpanian, Maureen Lowery, John Byrnes, Robert Hendel, Mauricio G Cohen, Krystalenia Valasaki, Marietsy V. Pujol, Eduard Ghersin, Roberto MikiCindy Delgado, Fouad Abuzeid, Mayra Vidro-Casiano, Russell G. Saltzman, Daniel DaFonseca, Lina V. Caceres, Kevin N. Ramdas, Adam Mendizabal, Alan W. Heldman, Raul Mitrani, Joshua Hare

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.

OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy.

METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07).

CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

Original languageEnglish (US)
Pages (from-to)1279-1290
Number of pages12
JournalCirculation Research
Volume121
Issue number11
DOIs
StatePublished - Nov 10 2017

Fingerprint

Mesenchymal Stromal Cells
Cardiomyopathies
Confidence Intervals
Cell- and Tissue-Based Therapy
Injections
Cicatrix
Heart Failure
Safety
Brain Natriuretic Peptide
Bone Marrow
Clinical Trials
Therapeutics

Keywords

  • bone marrow
  • cell-based therapy
  • heart failure
  • hospitalization
  • stem cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study). / Florea, Victoria; Rieger, Angela C.; DiFede, Darcy L.; El-Khorazaty, Jill; Natsumeda, Makoto; Banerjee, Monisha N.; Tompkins, Bryon A.; Khan, Aisha; Schulman, Ivonne H; Landin, Ana Marie; Mushtaq, Muzammil; Golpanian, Samuel; Lowery, Maureen; Byrnes, John; Hendel, Robert; Cohen, Mauricio G; Valasaki, Krystalenia; Pujol, Marietsy V.; Ghersin, Eduard; Miki, Roberto; Delgado, Cindy; Abuzeid, Fouad; Vidro-Casiano, Mayra; Saltzman, Russell G.; DaFonseca, Daniel; Caceres, Lina V.; Ramdas, Kevin N.; Mendizabal, Adam; Heldman, Alan W.; Mitrani, Raul; Hare, Joshua.

In: Circulation Research, Vol. 121, No. 11, 10.11.2017, p. 1279-1290.

Research output: Contribution to journalArticle

Florea, V, Rieger, AC, DiFede, DL, El-Khorazaty, J, Natsumeda, M, Banerjee, MN, Tompkins, BA, Khan, A, Schulman, IH, Landin, AM, Mushtaq, M, Golpanian, S, Lowery, M, Byrnes, J, Hendel, R, Cohen, MG, Valasaki, K, Pujol, MV, Ghersin, E, Miki, R, Delgado, C, Abuzeid, F, Vidro-Casiano, M, Saltzman, RG, DaFonseca, D, Caceres, LV, Ramdas, KN, Mendizabal, A, Heldman, AW, Mitrani, R & Hare, J 2017, 'Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)', Circulation Research, vol. 121, no. 11, pp. 1279-1290. https://doi.org/10.1161/CIRCRESAHA.117.311827
Florea, Victoria ; Rieger, Angela C. ; DiFede, Darcy L. ; El-Khorazaty, Jill ; Natsumeda, Makoto ; Banerjee, Monisha N. ; Tompkins, Bryon A. ; Khan, Aisha ; Schulman, Ivonne H ; Landin, Ana Marie ; Mushtaq, Muzammil ; Golpanian, Samuel ; Lowery, Maureen ; Byrnes, John ; Hendel, Robert ; Cohen, Mauricio G ; Valasaki, Krystalenia ; Pujol, Marietsy V. ; Ghersin, Eduard ; Miki, Roberto ; Delgado, Cindy ; Abuzeid, Fouad ; Vidro-Casiano, Mayra ; Saltzman, Russell G. ; DaFonseca, Daniel ; Caceres, Lina V. ; Ramdas, Kevin N. ; Mendizabal, Adam ; Heldman, Alan W. ; Mitrani, Raul ; Hare, Joshua. / Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study). In: Circulation Research. 2017 ; Vol. 121, No. 11. pp. 1279-1290.
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title = "Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)",
abstract = "RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy.METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0{\%} (95{\%} confidence interval [CI], 6.9{\%} to 50.0{\%}) in 20 million and 13.3{\%} (95{\%} CI, 3.5{\%} to 43.6{\%}) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0{\%} (95{\%} CI, 6.9{\%} to 50.0{\%}) in 20 million and 7.1{\%} (95{\%} CI, 1.0{\%} to 40.9{\%}) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7{\%} (95{\%} CI, 12.7{\%} to 64.9{\%}) in 20 million and 42.9{\%} (95{\%} CI, 17.7{\%} to 71.1{\%}) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95{\%} CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95{\%} CI, -0.36 to 0.23; P=0.65; between group P=0.07).CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.",
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author = "Victoria Florea and Rieger, {Angela C.} and DiFede, {Darcy L.} and Jill El-Khorazaty and Makoto Natsumeda and Banerjee, {Monisha N.} and Tompkins, {Bryon A.} and Aisha Khan and Schulman, {Ivonne H} and Landin, {Ana Marie} and Muzammil Mushtaq and Samuel Golpanian and Maureen Lowery and John Byrnes and Robert Hendel and Cohen, {Mauricio G} and Krystalenia Valasaki and Pujol, {Marietsy V.} and Eduard Ghersin and Roberto Miki and Cindy Delgado and Fouad Abuzeid and Mayra Vidro-Casiano and Saltzman, {Russell G.} and Daniel DaFonseca and Caceres, {Lina V.} and Ramdas, {Kevin N.} and Adam Mendizabal and Heldman, {Alan W.} and Raul Mitrani and Joshua Hare",
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TY - JOUR

T1 - Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

AU - Florea, Victoria

AU - Rieger, Angela C.

AU - DiFede, Darcy L.

AU - El-Khorazaty, Jill

AU - Natsumeda, Makoto

AU - Banerjee, Monisha N.

AU - Tompkins, Bryon A.

AU - Khan, Aisha

AU - Schulman, Ivonne H

AU - Landin, Ana Marie

AU - Mushtaq, Muzammil

AU - Golpanian, Samuel

AU - Lowery, Maureen

AU - Byrnes, John

AU - Hendel, Robert

AU - Cohen, Mauricio G

AU - Valasaki, Krystalenia

AU - Pujol, Marietsy V.

AU - Ghersin, Eduard

AU - Miki, Roberto

AU - Delgado, Cindy

AU - Abuzeid, Fouad

AU - Vidro-Casiano, Mayra

AU - Saltzman, Russell G.

AU - DaFonseca, Daniel

AU - Caceres, Lina V.

AU - Ramdas, Kevin N.

AU - Mendizabal, Adam

AU - Heldman, Alan W.

AU - Mitrani, Raul

AU - Hare, Joshua

PY - 2017/11/10

Y1 - 2017/11/10

N2 - RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy.METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07).CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

AB - RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy.METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07).CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

KW - bone marrow

KW - cell-based therapy

KW - heart failure

KW - hospitalization

KW - stem cells

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