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出境医 / 临床实验 / Randomized Study of Coronary Revascularization Surgery With Injection of WJ-MSCs and Placement of an Epicardial Extracellular Matrix (scorem-cells)

Randomized Study of Coronary Revascularization Surgery With Injection of WJ-MSCs and Placement of an Epicardial Extracellular Matrix (scorem-cells)

Study Description
Brief 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.


Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Heart Failure Coronary Artery Disease Mesenchymal Stem Cell Transplantation Regenerative Medicine Biological: Wharton's jelly-derived mesenchymal cells Phase 1 Phase 2

Detailed 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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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
Primary Purpose: Treatment
Official Title: Randomized Study as Proof of Concept of Coronary Revascularization Surgery With Injection of Wharton's Jelly-derived Mesenchymal Cells and Placement of an Epicardial Extracellular Matrix Patch Seeded With WJ-MSCs in Patients With Ischemic Cardiomyopathy
Estimated Study Start Date : July 2, 2019
Estimated Primary Completion Date : January 30, 2022
Estimated Study Completion Date : June 30, 2023
Arms and Interventions
Arm Intervention/treatment
Placebo Comparator: Comparison/control group
Revascularization surgery, placement of an extracellular matrix patch without WJ-MSCs and injection of culture medium without WJ-MSCs will be performed.
 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.
Active Comparator: Experimental group
Revascularization surgery, placement of an extracellular matrix patch with WJ-MSCs cultured on the epicardial surface and injection of WJ-MSCs around the infarcted zone will be performed.
 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.
Outcome Measures
Primary Outcome Measures :
  1. Left ventricular ejection fraction (LVEF) [ Time Frame: 12 months ]
    Percentage of improvement in left ventricular ejection fraction (LVEF) on transthoracic echocardiography and cardiac magnetic resonance imaging (MRI)

  2. Final diastolic and systolic volumes [ Time Frame: 12 months ]
    Percentage of improvement of the final diastolic and systolic volumes on transthoracic echocardiography and cardiac MRI

  3. Left ventricule viability [ Time Frame: 12 months ]
    Effect on viability, defined as a percentage of wall involvement, and improvement in segment-to-segment contractility measured with MRI

  4. Ventricular arrhythmias [ Time Frame: 12 months ]
    Incidence of ventricular arrhythmias defined as nonsustained ventricular tachycardia (NSTV) or high- or low-grade ventricular extrasystoles


Secondary Outcome Measures :
  1. Estimated functional status [ Time Frame: 12 months ]
    Recovery of the estimated functional status according to the New York Heart Association (NYHA) classification

  2. Change in the median score of Quality of life [ Time Frame: 12 months ]
    Change in the median score for quality of life of the Minnesota Living with Heart Failure Questionnaire (MLHFQ)

  3. Delayed enhancement of the left ventricle [ Time Frame: 12 months ]
    Changes in the delayed enhancement of the left ventricle on MRI, defined as percentage of the wall thickness involved when adding each segment visually

  4. Improvement in the 6-minute walk test [ Time Frame: 12 months ]
    Improvement in the 6-minute walk test, defined as the percentage of change of the distance traveled

  5. Mortality at 3 and 12 months due to cardiovascular causes [ Time Frame: 12 months ]
    Mortality at 3 and 12 months due to cardiovascular causes

  6. Mortality at 3 and 12 months due to all causes [ Time Frame: 12 months ]
    Mortality at 3 and 12 months due to all causes


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   30 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Luis H Atehortua Lopez, MSc +57 4441333 ext 3138 horacio.atehortua@sanvicentefundacion.com
Contact: Segio Estrada Mira, MSc +57 3014297223 sergio.estrada@udea.edu.co

Locations
Layout table for location information
Colombia
Hospital San Vicente Fundación
Medellín, Antioquia, Colombia
Contact: Luis H Atehortua, MSc    +57 4441333 ext 3138    horacio.atehortua@sanvicentefundacion.com   
Contact: Sergio Estrada Mira, MSc    +57 3014297223    sergio.estrada@udea.edu.co   
Sponsors and Collaborators
Hospital San Vicente Fundación
Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS)
IPS Universitaria Servicios de Salud Universidad de Antioquia
Hospital San Vicente Fundación - Rionegro
Tracking Information
First Submitted Date  ICMJE June 15, 2019
First Posted Date  ICMJE July 8, 2019
Last Update Posted Date July 9, 2019
Estimated Study Start Date  ICMJE July 2, 2019
Estimated Primary Completion Date January 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 4, 2019)
  • Left ventricular ejection fraction (LVEF) [ Time Frame: 12 months ]
    Percentage of improvement in left ventricular ejection fraction (LVEF) on transthoracic echocardiography and cardiac magnetic resonance imaging (MRI)
  • Final diastolic and systolic volumes [ Time Frame: 12 months ]
    Percentage of improvement of the final diastolic and systolic volumes on transthoracic echocardiography and cardiac MRI
  • Left ventricule viability [ Time Frame: 12 months ]
    Effect on viability, defined as a percentage of wall involvement, and improvement in segment-to-segment contractility measured with MRI
  • Ventricular arrhythmias [ Time Frame: 12 months ]
    Incidence of ventricular arrhythmias defined as nonsustained ventricular tachycardia (NSTV) or high- or low-grade ventricular extrasystoles
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 4, 2019)
  • Estimated functional status [ Time Frame: 12 months ]
    Recovery of the estimated functional status according to the New York Heart Association (NYHA) classification
  • Change in the median score of Quality of life [ Time Frame: 12 months ]
    Change in the median score for quality of life of the Minnesota Living with Heart Failure Questionnaire (MLHFQ)
  • Delayed enhancement of the left ventricle [ Time Frame: 12 months ]
    Changes in the delayed enhancement of the left ventricle on MRI, defined as percentage of the wall thickness involved when adding each segment visually
  • Improvement in the 6-minute walk test [ Time Frame: 12 months ]
    Improvement in the 6-minute walk test, defined as the percentage of change of the distance traveled
  • Mortality at 3 and 12 months due to cardiovascular causes [ Time Frame: 12 months ]
    Mortality at 3 and 12 months due to cardiovascular causes
  • Mortality at 3 and 12 months due to all causes [ Time Frame: 12 months ]
    Mortality at 3 and 12 months due to all causes
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Study of Coronary Revascularization Surgery With Injection of WJ-MSCs and Placement of an Epicardial Extracellular Matrix
Official Title  ICMJE Randomized Study as Proof of Concept of Coronary Revascularization Surgery With Injection of Wharton's Jelly-derived Mesenchymal Cells and Placement of an Epicardial Extracellular Matrix Patch Seeded With WJ-MSCs in Patients With Ischemic Cardiomyopathy
Brief 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.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model 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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
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
Primary Purpose: Treatment
Condition  ICMJE
  • Cardiovascular Diseases
  • Heart Failure
  • Coronary Artery Disease
  • Mesenchymal Stem Cell Transplantation
  • Regenerative Medicine
Intervention  ICMJE 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.
Study Arms  ICMJE
  • Placebo Comparator: Comparison/control group
    Revascularization surgery, placement of an extracellular matrix patch without WJ-MSCs and injection of culture medium without WJ-MSCs will be performed.
    Intervention: Biological: Wharton's jelly-derived mesenchymal cells
  • Active Comparator: Experimental group
    Revascularization surgery, placement of an extracellular matrix patch with WJ-MSCs cultured on the epicardial surface and injection of WJ-MSCs around the infarcted zone will be performed.
    Intervention: Biological: Wharton's jelly-derived mesenchymal cells
Publications *
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  • Balbi C, Bollini S. Fetal and perinatal stem cells in cardiac regeneration: Moving forward to the paracrine era. Placenta. 2017 Nov;59:96-106. doi: 10.1016/j.placenta.2017.04.008. Epub 2017 Apr 12. Review.
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 4, 2019) 		40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2023
Estimated Primary Completion Date January 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Luis H Atehortua Lopez, MSc +57 4441333 ext 3138 horacio.atehortua@sanvicentefundacion.com
Contact: Segio Estrada Mira, MSc +57 3014297223 sergio.estrada@udea.edu.co
Listed Location Countries  ICMJE Colombia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04011059
Other Study ID Numbers  ICMJE 001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Luis Horacio Atehortua Lopez, Hospital San Vicente Fundación
Study Sponsor  ICMJE Hospital San Vicente Fundación
Collaborators  ICMJE
  • Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS)
  • IPS Universitaria Servicios de Salud Universidad de Antioquia
  • Hospital San Vicente Fundación - Rionegro
Investigators  ICMJE Not Provided
PRS Account Hospital San Vicente Fundación
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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