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Co-transplantation of Mesenchymal Stem Cell Derived Exosomes and Autologous Mitochondria for Patients Candidate for CABG Surgery

Primary Purpose

Myocardial Infarction, Myocardial Ischemia, Myocardial Stunning

Status
Recruiting
Phase
Phase 1
Locations
Iran, Islamic Republic of
Study Type
Interventional
Intervention
mitochondria and MSC-derived exosomes
Sponsored by
Tehran University of Medical Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myocardial Infarction

Eligibility Criteria

35 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: • Patients who are candidate for CABG due to CAD±MR History of Q-wave MI, less than one month Age: 35-80 LVEF <=25% (by any imaging modality: echocardiography/SPECT/LV angiography and Cardiac MRI) Viability study as evidenced by low-dose dobutamine stress echocardiogram and/or or thallium redistribution nuclear study (at least four viable segments). Exclusion Criteria: Severe co-morbidities (e.g., renal failure, liver failure, etc.) Inability to provide informed consent Cerebral Damage

Sites / Locations

  • Tehran University of Medical SciencesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

exosome therapy

mitochondria therapy

co-transplantation of mitochondria and exosome therapy

placebo

Arm Description

a) Intracoronary and intra-myocardial injection of exosomes (5 patients) 1 mL of exosomes containing 100 micrograms of exosomes

b) Intracoronary and intra-myocardial injection of mitochondria (5 patients) 1 mL of exosomes containing 10 million mitochondria

c) co-transplantation Intracoronary and intra-myocardial injection of exosomes and mitochondria (5 patients) 1 mL of exosomes containing 100 micrograms of exosomes 1 mL of exosomes containing 10 million mitochondria

1 mL of placebo solution

Outcomes

Primary Outcome Measures

ejection fraction
left ventricle ejection fraction
allergic reactions
reactions including angioedema, hypotention, acute allergic reaction

Secondary Outcome Measures

CK-MB
Creatine kinase (CK)
cTnT
cardiac troponin T
on pump duration
on pump duration
ECMO duration
extracorporeal membrane oxygenation duration
SPECT
defect size analysis
NYHA
cardiac function class
CMR
cardiac function

Full Information

First Posted
December 10, 2022
Last Updated
December 29, 2022
Sponsor
Tehran University of Medical Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT05669144
Brief Title
Co-transplantation of Mesenchymal Stem Cell Derived Exosomes and Autologous Mitochondria for Patients Candidate for CABG Surgery
Official Title
Co-transplantation of Mesenchymal Stem Cell Derived Exosomes and Autologous Mitochondria for Patients Candidate for CABG Surgery With EF< 25% (Clinical Trial Phase ])
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 20, 2022 (Actual)
Primary Completion Date
September 20, 2023 (Anticipated)
Study Completion Date
September 20, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tehran University of Medical Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Heart failure (HF) and acute myocardial infarction that often follows are among the main causes of disability and death worldwide. As such, new treatments and biological drugs are needed to protect the heart against the harmful effects of ischemia and also reperfusion injury (IRI), preserve cardiac function, reduce the zone of myocardial infarction (MI), and improve patient outcomes. In this regard, it has been shown that mitochondrial dysfunction has a key role in the pathogenesis of heart ischemia, cardiomyopathy, and reperfusion injury. in this study which includes 4 groups of intervention, we try to minimize the damage by transplantation of mitochondria and administration of MSC-derived exosomes. MSC-derived exosomes limit inflammatory damage while fresh autologous exosomes limit oxidative stress.
Detailed Description
This research will be performed as a retrospective cohort study at Tehran Heart Center. Patients will be selected from CABG candidates with severely low Ejection fraction determined by speckle echocardiography. Patients with severe co-morbidities or cerebral damage will be excluded from the study. Detailed informed consent will be taken from the patients. Patients who refuse to provide consent will receive standard treatment. Criteria Inclusion Criteria: Patients who are a candidate for CABG due to CAD±MR History of Q-wave MI, less than one month Age: 35-80 LVEF <=25% (by any imaging modality: echocardiography/SPECT/LV angiography and Cardiac MRI) Viability study as evidenced by low-dose dobutamine stress echocardiogram and/or thallium redistribution nuclear study (at least four viable segments). Exclusion Criteria: Severe co-morbidities (e.g., renal failure, liver failure, etc.) Inability to provide informed consent Cerebral Damage Study groups: The standard treatment performed for all patients is revascularisation by coronary artery bypass grafting surgery. Patients will be divided into four groups based on the treatments received, in addition to the standard treatment. Mitochondrial and exosome transplantation by intracoronary and intra-myocardial injection. Study groups: Intracoronary and intra-myocardial injection of exosomes (5 patients) Intracoronary and intra-myocardial injection of mitochondria (5 patients) Intracoronary and intra-myocardial injection of exosomes and mitochondria (5 patients) Placebo (5 patients) For the patients in groups b and c, mitochondria will be extracted from a muscle tissue specimen extracted at the beginning of the surgery from pectoralis muscles exposed after sternotomy. Mitochondria will be extracted from the muscle specimen simultaneously with the surgery. When revascularisation is achieved by the bypass grafts, The extracted mitochondria will be injected into the heart muscle. A 31-gauge insulin syringe will perform injections into ten different sites in the ischemic area of the heart muscle. Besides direct injection into the heart muscle, one-third of the extracted mitochondria will be injected into the coronary sinus. Patients in groups a and b will receive the extracted exosome from MSC cells described in step 2. The extracted exosome will be injected into the coronary sinus after the placement of the Cardiopulmonary bypass. Isolation and characterisation of mesenchymal stem cells from the human umbilical cord (UC-MSCs) Human umbilical cord mesenchymal stem cells are enzymatically isolated by collagenase in terms of a previous study and cultured in DMEM / F12 medium with 10% exosome-depleted FBS (GMP grade) with penicillin and streptomycin antibiotics and incubated at 37 ° C and 5% CO2. After the cell confluence reaches 80%, the conditioned medium is collected (for exosome isolation, the cells are used in passage 3). The phenotypic analysis is performed on the third passage. Surface antigens are analysed for CD90, CD105, CD73 and CD34 using flow cytometry. Extraction of exosomes from UC-MSCs by ultracentrifugation and characterisation. After the cell confluence reaches 80%, the conditioned medium is collected for exosome isolation by several ultracentrifuges. In brief, after 48 h, the conditioned medium (CM) of the cells is centrifuged at 400 g for 10 min to remove cells and at 2500 g for 30 min to eliminate apoptotic bodies and debris. Afterwards, CM was centrifuged twice at 100 000 g for two h, followed by the process of suspending the exosome pellet in PBS. Surface antigens are analysed for CD9, CD63 and CD81 using western blot. Furthermore, Bradford Colorimetric Assay (BCA) kit is used to measure exosome production total protein at a wavelength of 570 nm. Dynamic light scattering (DLS) determines the size distribution of exosomes. Extraction of mitochondria from US-MSCs and characterisation. Short-term evaluation of the safety of clinical trial transplant mitochondria and exosome phase I: The patient will be under close monitoring after the surgery based on clinical symptoms, signs, arrhythmia, echocardiographic evaluations and lab results. Short-term evaluations of the patient in terms of blood factors (cTnT, CK-MB) Creatine kinase (CK) and its isoenzyme CK-MB are critical tools for diagnosing acute myocardial infarction (AMI). The content of CK-MB relative to total CK in myocardial cells is variable; in normal myocardium, it is low and enhanced several-fold in hypoxic myocardium and heart stroke. SPECT scan, Cardiac MRI and Dobutamine stress Speckle Echocardiography, before and after 2 months. The evaluation of the patient's recovery will be performed one month after the surgery. This evaluation is based on patients' signs and symptoms, Function Class assessments, Speckle and Dobutamine stress Eco, SPECT Nuclear heart Scan and Cardiac MRI imaging (CMR). Evaluations will be performed before surgery and one month after the surgery. Close Comparison will be performed between evaluation results to report possible improvements in the patient's condition. The assessed variables for follow-up evaluation include: Ejection Fraction variables from Eco and CMR (LVEF, RVEF, Global EF) 16 Segment viability analysis by SPECT scan and CMR NYHA Classification assessment based on patient physical examination. Data Analysis will be performed by IBM SPSS Statistics Version 25. A p-value of less than 0.05 will be assessed as significant.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myocardial Infarction, Myocardial Ischemia, Myocardial Stunning

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Intracoronary and intra-myocardial injection of exosomes (5 patients) Intracoronary and intra-myocardial injection of mitochondria (5 patients) Intracoronary and intra-myocardial injection of exosomes and mitochondria (5 patients) Placebo (5 patients)
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
exosome therapy
Arm Type
Experimental
Arm Description
a) Intracoronary and intra-myocardial injection of exosomes (5 patients) 1 mL of exosomes containing 100 micrograms of exosomes
Arm Title
mitochondria therapy
Arm Type
Experimental
Arm Description
b) Intracoronary and intra-myocardial injection of mitochondria (5 patients) 1 mL of exosomes containing 10 million mitochondria
Arm Title
co-transplantation of mitochondria and exosome therapy
Arm Type
Experimental
Arm Description
c) co-transplantation Intracoronary and intra-myocardial injection of exosomes and mitochondria (5 patients) 1 mL of exosomes containing 100 micrograms of exosomes 1 mL of exosomes containing 10 million mitochondria
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
1 mL of placebo solution
Intervention Type
Biological
Intervention Name(s)
mitochondria and MSC-derived exosomes
Intervention Description
autologous mitochondria and MSC-derived exosomes
Primary Outcome Measure Information:
Title
ejection fraction
Description
left ventricle ejection fraction
Time Frame
3 months
Title
allergic reactions
Description
reactions including angioedema, hypotention, acute allergic reaction
Time Frame
3 months
Secondary Outcome Measure Information:
Title
CK-MB
Description
Creatine kinase (CK)
Time Frame
2 week
Title
cTnT
Description
cardiac troponin T
Time Frame
2 week
Title
on pump duration
Description
on pump duration
Time Frame
during the surgery
Title
ECMO duration
Description
extracorporeal membrane oxygenation duration
Time Frame
duration after surgery if needed
Title
SPECT
Description
defect size analysis
Time Frame
1 and 3 months post surgery
Title
NYHA
Description
cardiac function class
Time Frame
1 and 3 months post surgery
Title
CMR
Description
cardiac function
Time Frame
1 and 3 months post surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: • Patients who are candidate for CABG due to CAD±MR History of Q-wave MI, less than one month Age: 35-80 LVEF <=25% (by any imaging modality: echocardiography/SPECT/LV angiography and Cardiac MRI) Viability study as evidenced by low-dose dobutamine stress echocardiogram and/or or thallium redistribution nuclear study (at least four viable segments). Exclusion Criteria: Severe co-morbidities (e.g., renal failure, liver failure, etc.) Inability to provide informed consent Cerebral Damage
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
hossein ahmadi tafti
Phone
+989121153540
Email
hosseinahmaditafti@yahoo.com
First Name & Middle Initial & Last Name or Official Title & Degree
mohsen ahmadi tafti
Phone
+989122109773
Email
smohsenahmadi1364@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
alireza hadizadeh, M.D
Organizational Affiliation
Tehran University of Medical Sciences
Official's Role
Study Chair
Facility Information:
Facility Name
Tehran University of Medical Sciences
City
Tehran
ZIP/Postal Code
1411713138
Country
Iran, Islamic Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
farzad masoudkabir, M.D
Phone
+989124028728
Email
thc@tums.ac.ir

12. IPD Sharing Statement

Plan to Share IPD
No

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Co-transplantation of Mesenchymal Stem Cell Derived Exosomes and Autologous Mitochondria for Patients Candidate for CABG Surgery

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