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Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT04011059
Other study ID # 001
Secondary ID
Status Not yet recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date July 2, 2019
Est. completion date June 30, 2023

Study information

Verified date July 2019
Source Hospital San Vicente Fundación
Contact Luis H Atehortua Lopez, MSc
Phone +57 4441333
Email horacio.atehortua@sanvicentefundacion.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Ischemic heart disease is one of the most important causes of mortality and morbidity in the Western world and is a public health problem. Among ischemic heart diseases, myocardial infarction has specific significance because the cardiac muscle does not have sufficient and adequate capacity to regenerate; therefore, necrosis of a region leads to the formation of a fibrous scar. Infarction can lead to a progressive and irreversible decrease in cardiac function, resulting in heart failure (HF) syndrome, depending on the area affected by this scar, via a ventricular remodeling mechanism.

In recent years, HF has been revealed as a major public health problem due to its incidence and its social, economic and especially human impact, as it represents a serious limitation of the quality of life of individuals. The prevalence of HF in the general population of the United States and the United Kingdom is approximately 1%, and in those older than 75 years, the prevalence varies between 5 and 10%. Regarding its prognosis, recent data from the Framingham Study indicate that at 5 years, the mortality rate of HF is 75% in men and 62% in women; the mean mortality rate of all cancers is 50%.

The molecular basis of congestive HF is the absence of cardiac cells capable of regenerating the heart muscle. Despite the publication of recent studies suggesting the existence of stem cells capable of regenerating cardiomyocytes destroyed because of myocardial infarction, in humans, the capacity of these cells is insufficient to replace the cells destroyed due to necrosis secondary to ischemia.

In recent years, the accumulation of results derived from preclinical studies has allowed the development of the first clinical trials of the feasibility and safety of cardiac regeneration using cellular therapy. Several studies have shown that t cells exist in adult bone marrow, such as mesenchymal stem cells, hematopoietic stem cells and, more recently, multipotent stem cells (MAPC), with the ability to differentiate into endothelial tissue and cardiac muscle, which can contribute to the regeneration of damaged myocardial tissue and improve cardiac function in animal infarction models. However, cell therapy research has moved rapidly toward the use of more undifferentiated cells rather than hematopoietic lineages, such as mesenchymal cells. These cells can be obtained from different sources, with a tendency toward the use of characterized allogeneic cells, which are immediately available in the potential recipient. Given that this type of therapy has not been rigorously investigated in Latin America, we aim to determine the effect of therapy using Wharton's jelly-derived mesenchymal cells (WJ-MSCs) from the human umbilical cord on neomyogenesis in patients with previous myocardial infarction who are undergoing open revascularization. Our hospital has some experience with regenerative therapy, both in patients with acute myocardial infarction and chronic infarction, with encouraging results that support this new phase of inter-institutional research.

Objective: To evaluate the safety and estimate the effect of coronary revascularization accompanied by intramyocardial injection of WJ-MSCs and the placement of an extracellular matrix patch seeded with WJ-MSCs compared to coronary revascularization accompanied by injection of culture medium without the presence of WJ-MSC and placement of an extracellular matrix patch without seeding with WJ-MSC on global and regional cardiac function, myocardial viability and the incidence of adverse effects determined as ventricular arrhythmias.


Description:

A randomized clinical trial will be conducted as a proof of concept in 40 patients with previous myocardial infarction and a viable myocardial zone with indications for coronary artery bypass grafts. Twenty patients will be included in each treatment arm over 36 months. One group will undergo revascularization surgery, extracellular matrix patch placement and injection of cell culture medium; the other group will undergo revascularization surgery, extracellular matrix patch placement on the epicardial surface with cultured WJ-MSCs and injection of WJ-MSCs around the infarcted zone.

The allocation of treatments will be defined by block sizes of 2, 4 and 6, randomly determined by a random number generator (ralloc, Stata Co. 8,2). This assignment will only be known by the tissue bank that will deliver the syringes with the solution to be administered and the epicardium patches to the study participants.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 40
Est. completion date June 30, 2023
Est. primary completion date January 30, 2022
Accepts healthy volunteers No
Gender All
Age group 30 Years to 75 Years
Eligibility Inclusion Criteria:

- Patients with a diagnosis of coronary disease, performed by coronary angiography, requiring conventional coronary revascularization surgery

- History of myocardial infarction; evidence of akinesia or regional dyskinesia more than 1 week old

- Ejection fraction less than 40%

- Age between 30 and 75 years

- Negative serology for HIV, hepatitis B virus (HBV), and hepatitis C virus HCV

- Negative pregnancy test for women of childbearing age

- Patients who sign the informed consent complying with all of the provisions of current regulations in Colombia

Exclusion Criteria:

- History of myocardial infarction with ST-segment elevation within 2 weeks prior to surgery

- History of myocardial infarction without ST-segment elevation within the previous week (the decision to include these patients within the first week after suffering a non-ST elevation infarction is at the discretion of the research team)

- Previous history of tachycardia or ventricular fibrillation

- History of active neoplasia or previous chemotherapy treatment

- Severe or uncontrolled concomitant disease (i.e., poorly controlled chronic kidney or liver failure)

- Patients who, due to their place of residence, mental health or social situation, have difficulty meeting the conditions of the protocol

- Women who are pregnant or breast-feeding

- Patients or legal representatives withdrawing informed consent at any time during the study.

- Previous history of heart transplant

- Patients with functional organ impairment: liver function: total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase greater than 2 times the upper reference limit; kidney function: serum creatinine > 1.5 mg/dl or creatinine clearance < 60 ml/min.

Study Design


Intervention

Biological:
Wharton's jelly-derived mesenchymal cells
Revascularization surgery, placement of an extracellular matrix patch with WJ-MSCs cultured on the epicardial surface and injection of WJ-MSC around the infarcted zone.

Locations

Country Name City State
Colombia Hospital San Vicente Fundación Medellín Antioquia

Sponsors (4)

Lead Sponsor Collaborator
Hospital San Vicente Fundación Hospital San Vicente Fundación - Rionegro, Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS), IPS Universitaria Servicios de Salud Universidad de Antioquia

Country where clinical trial is conducted

Colombia, 

References & Publications (40)

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Chen PM, Yen ML, Liu KJ, Sytwu HK, Yen BL. Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J Biomed Sci. 2011 Jul 18;18:49. doi: 10.1186/1423-0127-18-49. Review. — View Citation

Chong JJ, Chandrakanthan V, Xaymardan M, Asli NS, Li J, Ahmed I, Heffernan C, Menon MK, Scarlett CJ, Rashidianfar A, Biben C, Zoellner H, Colvin EK, Pimanda JE, Biankin AV, Zhou B, Pu WT, Prall OW, Harvey RP. Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell. 2011 Dec 2;9(6):527-40. doi: 10.1016/j.stem.2011.10.002. — View Citation

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Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circ Res. 2015 Apr 10;116(8):1361-77. doi: 10.1161/CIRCRESAHA.116.304386. Epub 2015 Jan 28. Review. — View Citation

Gaafar T, Attia W, Mahmoud S, Sabry D, Aziz OA, Rasheed D, Hamza H. Cardioprotective Effects of Wharton Jelly Derived Mesenchymal Stem Cell Transplantation in a Rodent Model of Myocardial Injury. Int J Stem Cells. 2017 May 30;10(1):48-59. doi: 10.15283/ijsc16063. — View Citation

Garbern JC, Lee RT. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell. 2013 Jun 6;12(6):689-98. doi: 10.1016/j.stem.2013.05.008. — View Citation

Ghostine S, Carrion C, Souza LC, Richard P, Bruneval P, Vilquin JT, Pouzet B, Schwartz K, Menasché P, Hagège AA. Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation. 2002 Sep 24;106(12 Suppl 1):I131-6. — View Citation

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Menasché P, Hagège AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin M, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol. 2003 Apr 2;41(7):1078-83. — View Citation

Munir H, Luu NT, Clarke LS, Nash GB, McGettrick HM. Comparative Ability of Mesenchymal Stromal Cells from Different Tissues to Limit Neutrophil Recruitment to Inflamed Endothelium. PLoS One. 2016 May 12;11(5):e0155161. doi: 10.1371/journal.pone.0155161. eCollection 2016. — View Citation

Nimsanor N, Phetfong J, Plabplueng C, Jangpatarapongsa K, Prachayasittikul V, Supokawej A. Inhibitory effect of oxidative damage on cardiomyocyte differentiation from Wharton's jelly-derived mesenchymal stem cells. Exp Ther Med. 2017 Dec;14(6):5329-5338. doi: 10.3892/etm.2017.5249. Epub 2017 Oct 2. — View Citation

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Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells. 2004;22(7):1330-7. — View Citation

Wang WE, Li L, Xia X, Fu W, Liao Q, Lan C, Yang D, Chen H, Yue R, Zeng C, Zhou L, Zhou B, Duan DD, Chen X, Houser SR, Zeng C. Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury. Circulation. 2017 Aug 29;136(9):834-848. doi: 10.1161/CIRCULATIONAHA.116.024307. Epub 2017 Jun 22. — View Citation

Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells. 2008 Nov;26(11):2865-74. doi: 10.1634/stemcells.2007-1028. Epub 2008 Aug 14. — View Citation

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Zwetsloot PP, Végh AM, Jansen of Lorkeers SJ, van Hout GP, Currie GL, Sena ES, Gremmels H, Buikema JW, Goumans MJ, Macleod MR, Doevendans PA, Chamuleau SA, Sluijter JP. Cardiac Stem Cell Treatment in Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Studies. Circ Res. 2016 Apr 15;118(8):1223-32. doi: 10.1161/CIRCRESAHA.115.307676. Epub 2016 Feb 17. Review. — View Citation

* Note: There are 40 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Left ventricular ejection fraction (LVEF) Percentage of improvement in left ventricular ejection fraction (LVEF) on transthoracic echocardiography and cardiac magnetic resonance imaging (MRI) 12 months
Primary Final diastolic and systolic volumes Percentage of improvement of the final diastolic and systolic volumes on transthoracic echocardiography and cardiac MRI 12 months
Primary Left ventricule viability Effect on viability, defined as a percentage of wall involvement, and improvement in segment-to-segment contractility measured with MRI 12 months
Primary Ventricular arrhythmias Incidence of ventricular arrhythmias defined as nonsustained ventricular tachycardia (NSTV) or high- or low-grade ventricular extrasystoles 12 months
Secondary Estimated functional status Recovery of the estimated functional status according to the New York Heart Association (NYHA) classification 12 months
Secondary Change in the median score of Quality of life Change in the median score for quality of life of the Minnesota Living with Heart Failure Questionnaire (MLHFQ) 12 months
Secondary Delayed enhancement of the left ventricle Changes in the delayed enhancement of the left ventricle on MRI, defined as percentage of the wall thickness involved when adding each segment visually 12 months
Secondary Improvement in the 6-minute walk test Improvement in the 6-minute walk test, defined as the percentage of change of the distance traveled 12 months
Secondary Mortality at 3 and 12 months due to cardiovascular causes Mortality at 3 and 12 months due to cardiovascular causes 12 months
Secondary Mortality at 3 and 12 months due to all causes Mortality at 3 and 12 months due to all causes 12 months
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