Cardiovascular Cell Therapy Research Network

Cardiovascular Cell Therapy Research Network (CCTRN) is a network of physicians, scientists, and support staff dedicated to studying stem cell therapy for treating heart disease. The CCTRN is funded by the National Institutes of Health (NIH) and includes expert researchers with experience in cardiovascular care at seven stem cell centers in the United States. The goals of the Network are to complete research studies that will potentially lead to more effective treatments for patients with cardiovascular disease, and to share knowledge quickly with the healthcare community.

Mission statement

The mission of the CCTRN is to achieve public health advances for the treatment of cardiovascular diseases, through the conduct and dissemination of collaborative research leading to evidence-based treatment options and improved outcome for patients with heart disease.[1]

Components of the Network

The sponsor

The National Heart, Lung, and Blood Institute (NHLBI) is one of 27 institutes/centers of the National Institutes of Health (NIH) and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The NHLBI plans and directs research in the development and evaluation of interventions and devices related to prevention, treatment, and rehabilitation of patients with such diseases and disorders.

The Coordinating Center for Clinical Trials

Since 1971, the Coordinating Center for Clinical Trials () at The University of Texas School of Public Health has played a leading role in cardiovascular disease and vision research by serving as a coordinating center for 25 nationwide multicenter clinical trials. The CCCT's primary function is to provide and coordinate all operations, procedures, and activities of a large-scale randomized controlled clinical trial. The CCCT serves as the Data Coordinating Center for the CCTRN. The DCC was led by Lemuel Moye (2006-2019) and Barry R. Davis (2019-2021).

The clinical sites

The CCTRN includes seven stem cell centers in the United States with experience and expertise in clinical trials studying treatments for heart disease and peripheral artery disease. These sites include:

Body of work

In July 2008, the CCTRN opened enrollment in two studies in patients who had recently had heart attacks: TIME[2] ((NCT00684021)) and LateTIME[3] ((NCT00684060)). The purpose of these studies was to determine if stem cells safely taken from an individual's bone marrow could be transplanted back into the injured heart muscle of the individual and improve the heart's ability to pump following a heart attack, as well as to determine the best time for transplanting the cells following a heart attack. The results of both studies were presented at the American Heart Association (AHA) Scientific meetings in 2011 (LateTIME) and 2012 (TIME), and simultaneously published in JAMA.[4][5]

In March 2009, the CCTRN opened enrollment in a heart failure study: FOCUS [6] ((NCT00824005)). The purpose of this study was to determine the safety and effectiveness of injecting bone marrow stem cells into heart muscle in an attempt to promote blood vessel growth that could potentially improve the blood supply in hearts that are failing. This study recruited patients who had heart failure, but would no longer benefit from other forms of standard treatment such as surgery or coronary artery repair procedures such as balloon angioplasty or stent placement. The results of this study were presented at the American College of Cardiology (ACC) Annual Meeting in 2012 and simultaneously published in JAMA.[7]

In June 2013, CCTRN opened enrollment in a study in peripheral artery disease: PACE [8] ((NCT01774097)). The purpose of this study was to determine the safety and effectiveness of bone marrow-derived stem cell therapy on improving blood flow and walking ability in patients with peripheral artery disease. The results of this study were published in Circulation in 2017.[9]

In October 2015, CCTRN opened enrollment in a study in heart failure: CONCERT-HF [10] (NCT02501811). The purpose of the study was to determine whether giving autologous Mesenchymal Stem Cells (MSCs) and/or C-kit+ cells to patients with heart muscle damage is safe and to help us learn whether these treatments improve heart function for people who are not ideal candidates for other forms of standard therapy such as surgery. The results of this study were published in the European Journal of Heart Failure in 2021.[11]

In September 2016, CCTRN opened enrollment in a study in anthracycline-induced cardiomyopathy (AIC): SENECA [12] (NCT02509156). The purpose of the study was to determine whether giving allogeneic mesenchymal stem cells (MSCs) to patients with AIC is safe and whether these treatments improve heart function. The results of this study were published in JACC CardioOncology in 2020.[13]

References
  1. Simari R.D., Moyé L.A., Skarlatos S.I,, Ellis S.G., Zhao D.X., Willerson J.T., Henry T.D., Pepine C.J. Development of a network to test strategies in cardiovascular cell delivery: the NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN). J. Cardiovasc. Transl. Res. 2010 Feb;3(1):30-6.
  2. Traverse J.H., Henry T.D., Vaughan D., Ellis S.G., Pepine C.J., Willerson J.T., Zhao D.X.M., Piller L.B., Penn M.S., Byrne B.J., Perin E.C., Gee A.P., Hatzopoulous A.K., McKenna D.H., Forder J.R., Taylor D.A., Cogle C.R., Olson R.E., Jorgenson B.C., Sayre S.L., Vojvodic R.W., Gordon D.J., Skarlatos S.I., Moyé L.A., Simari R.D. for the Cardiovascular Cell Therapy Research Network. Rationale and Design for TIME: A Phase-II, Randomized, Double-Blind, Placebo-Controlled Pilot Trial Evaluating the Safety and Effect of Timing of Administration of Bone Marrow Mononuclear Cells Following Acute Myocardial Infarction. Journal American Heart Association. 2009 Sep;158(3):356-63.
  3. Traverse J.H., Henry T.D., Vaughan D.E., Ellis S.G., Pepine C.J., Willerson J.T., Zhao D.X.M., Simpson L., Penn M.S., Byrne B.J., Perin E.C., Gee A.P., Hatzopoulous A.K., McKenna D.H., Forder J.R., Taylor D.A., Cogle C.R., Baraniuk S., Olson R.E., Jorgenson B.E., Sayre, S.L., Vojvodic, R.W., Gordon, D.J., Skarlatos, S.I., Moye, L.A., Simari, R.D. for the Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and Design for Late TIME: A Phase-II, Randomized, Placebo-Controlled, Double-Blind Pilot Trial Evaluating the Safety and Effect of Administration of Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction. Texas Heart Institute Journal 2010 Aug;37(4):412-420.
  4. Traverse J.H., Henry T.D., Ellis S.G., Pepine C.J., Willerson J.T., Zhao D.X.M., Forder J.R., Byrne B.J., Hatzopoulos A.K., Penn M.S., Perin E.C., Baran K.W., Chambers J.W., Lambert C.E., Raveendran G., Simon D.I., Vaughan D.E., Simpson L.M., Gee A.P., Taylor D.A., Cogle C.R., Thomas J.D., Silva G.V., Jorgenson B.C., Olson R.E., Bowman S.D., Francescon J.L., Geither C.L., Handberg E.M., Smith D., Baraniuk S., Piller L.B., Loghin C., Aguilar D., Richman S.J., Zierold-Fairman C., Bettencourt J., Sayre S.L., Vojvodic R.W., Skarlatos S.I., Gordon D.J., Ebert R.F., Kwak M., Moyé L.A., Simari R.D. for the Cardiovascular Cell Therapy Research Network (CCTRN). Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction on Left-Ventricular Function: The LateTIME Randomized Trial. JAMA. 2011 Nov; 306(19):2110-2119.
  5. Traverse J.H., Henry T.D., Pepine C.J., Willerson J.T., Zhao D.X.M., Ellis S.G., Forder J.R., Anderson R.D., Hatzopoulos A.K., Penn M.S., Perin E.C., Chambers J.W., Baran K.W., Raveendran G., Lambert C.E., Lerman, A, Simon D.I., Vaughan D.E., Lai D., Gee A.P., Taylor D.A., Cogle C.R., Thomas J.D., Silva G.V., Olson R.E., Bowman S.D., Francescon J.L., Geither C.L., Handberg E.M., Kappenman C., Westbrook L., Piller L.B., Simpson, L.M., Baraniuk S., Loghin C., Aguilar D., Richman S.J., Zierold-Fairman C., Spoon, D.B., Bettencourt J., Sayre S.L., Vojvodic R.W., Skarlatos S.I., Gordon D.J., Ebert R.F., Kwak M., Moyé L.A., Simari R.D. for the Cardiovascular Cell Therapy Research Network (CCTRN). Effect of Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial Infarction: The TIME Randomized Trial. JAMA. 2012 Dec; 308(22):2380-9.
  6. Willerson J.T., Perin E.C., Ellis S.G., Pepine C.J., Henry T.D., Zhao D.X.M., Lai D., Penn M.S., Byrne B.J., Silva G., Gee A., Traverse J.H., Hatzopoulos A.K., Forder J.R., Martin D., Kronenberg M., Taylor D.A., Cogle C.R., Baraniuk S., Westbrook L., Sayre S.L., Vojvodic R.W., Gordon D.J., Skarlatos S.I., Moyé L.A., Simari R.D., for the Cardiovascular Cell Therapy Research Network (CCTRN) Rationale and Design for the Intramyocardial Injection of Autologous Bone Marrow Mononuclear Cells for Patients with Chronic Ischemic Heart Disease and Left Ventricular Dysfunction Trial (FOCUS). American Heart Journal. 2010 Aug; 160(2):215-223.
  7. Perin E.C., Willerson J.T., Pepine C.J., Henry T.D., Ellis S.G., Zhao D.X.M., Silva G.V., Lai D., Thomas J.D., Kronenberg M.W., Martin A.D., Anderson R.D., Traverse J.H., Penn M.S., Anwaruddin S., Hatzopoulos A.K., Gee A.P., Taylor D.A., Cogle C.R., Smith D., Westbrook L., Handberg E.M., Olson R.E., Geither C.L., Bowman S.D., Francescon J.L., Baraniuk S., Piller L.B., Simpson, L.M., Loghin C., Aguilar D., Richman S.J., Zierold-Fairman C., Spoon, D.B., Bettencourt J., Sayre S.L., Vojvodic R.W., Skarlatos S.I., Gordon D.J., Ebert R.F., Kwak M., Moyé L.A., Simari R.D. for the Cardiovascular Cell Therapy Research Network (CCTRN). Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Ischemic Heart Failure: The FOCUS-CCTRN Trial. JAMA. 2012 April; 307(16):1717-26.
  8. Perin EC, Murphy M, Cooke JP, Moyé L, Henry TD, Bettencourt J, Gahremanpour A, Leeper N, Anderson RD, Hiatt WR, Lima JA, Venkatesh B, Sayre SL, Vojvodic RW, Taylor DA, Ebert RF, Hirsch AT; Cardiovascular Cell Therapy Research Network. Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells. Am Heart J. 2014 Nov;168(5):667-73. doi: 10.1016/j.ahj.2014.07.021. Epub 2014 Jul 30. PMID 25440794; PMCID: PMC4254580.
  9. Perin EC, Murphy MP, March KL, Bolli R, Loughran J, Yang PC, Leeper NJ, Dalman RL, Alexander J, Henry TD, Traverse JH, Pepine CJ, Anderson RD, Berceli S, Willerson JT, Muthupillai R, Gahremanpour A, Raveendran G, Velasquez O, Hare JM, Hernandez Schulman I, 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, Gyang Ross E, 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; Cardiovascular Cell Therapy Research Network (CCTRN). 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. 2017 Apr 11;135(15):1417-1428. doi: 10.1161/CIRCULATIONAHA.116.025707. Epub 2017 Feb 16.
  10. Bolli R, Hare JM, March KL, Pepine CJ, Willerson JT, Perin EC, Yang PC, Henry TD, Traverse JH, Mitrani RD, Khan A, Hernandez-Schulman I, Taylor DA, DiFede DL, Lima JAC, Chugh A, Loughran J, Vojvodic RW, Sayre SL, Bettencourt J, Cohen M, Moyé L, Ebert RF, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure). Circ Res. 2018 Jun 8;122(12):1703-1715. doi: 10.1161/CIRCRESAHA.118.312978. Epub 2018 Apr 27. PMID 29703749; PMCID: PMC5993622.
  11. Bolli R, Mitrani RD, Hare JM, Pepine CJ, Perin EC, Willerson JT, Traverse JH, Henry TD, Yang PC, Murphy MP, March KL, Schulman IH, Ikram S, Lee DP, O'Brien C, Lima JA, Ostovaneh MR, Ambale-Venkatesh B, Lewis G, Khan A, Bacallao K, Valasaki K, Longsomboon B, Gee AP, Richman S, Taylor DA, Lai D, Sayre SL, Bettencourt J, Vojvodic RW, Cohen ML, Simpson L, Aguilar D, Loghin C, Moyé L, Ebert RF, Davis BR, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail. 2021 Apr 3. doi: 10.1002/ejhf.2178. Epub ahead of print. PMID 33811444.
  12. Bolli R, Hare JM, Henry TD, Lenneman CG, March KL, Miller K, Pepine CJ, Perin EC, Traverse JH, Willerson JT, Yang PC, Gee AP, Lima JA, Moyé L, Vojvodic RW, Sayre SL, Bettencourt J, Cohen M, Ebert RF, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial. Am Heart J. 2018 Jul;201:54-62. doi: 10.1016/j.ahj.2018.02.009. Epub 2018 Apr 4. PMID 29910056; PMCID: PMC7282462.
  13. Bolli R, Perin EC, Willerson JT, Yang PC, Traverse JH, Henry TD, Pepine CJ, Mitrani RD, Hare JM, Murphy MP, March KL, Ikram S, Lee DP, O'Brien C, Durand JB, Miller K, Lima JA, Ostovaneh MR, Ambale-Venkatesh B, Gee AP, Richman S, Taylor DA, Sayre SL, Bettencourt J, Vojvodic RW, Cohen ML, Simpson LM, Lai D, Aguilar D, Loghin C, Moyé L, Ebert RF, Davis BR, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial. JACC CardioOncol. 2020 Nov;2(4):581-595. doi: 10.1016/j.jaccao.2020.09.001. Epub 2020 Dec 22. PMID 33403362; PMCID: PMC7781291.
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