Transepicardial With Transseptal Autologous CD 133+ Bone Marrow Cell Implantation in Patient Following CABG Surgery

• Sponsor: National Cardiovascular Center Harapan Kita Hospital Indonesia (Other)
• Overall Status: Completed
• CT.gov ID: NCT02870933
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 39
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Heart Failure has several etiologies and one of them is coronary artery disease. Coronary artery bypass grafting (CABG) is one of revascularizations method which has been used for decades in coronary artery disease theraphy. However, data about coronary artery bypass grafting shows that post-CABG patients still have low ejection fraction. For the last decade, there have been a lot of studies about the using of stem cells to increase heart contractility and reverse the heart remodelling process. In this study, we use CD 133+ bone marrow stem cells which has been proved to have higher angiogenesis potential. The stem cells is given during CABG by injection transepicardial and transseptal. The purpose of this study is to determine whether transpicardial and transseptal injection of CD 133+ bone marrow stem cells can improve myocardial perfusion in patient with low ejection fraction following CABG surgery.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Biological: Transepicardial with Transseptal CD 133+ Implantation	Phase 4

Detailed Description

Study sample : patient with low ejection fraction indicated for CABG surgery in NCCHK who fulfill inclusion and exclusion criteria

Sampling method : first we use consecutive method to find subject with male sex and age 40-70. After that, we use simple random sampling to allocate each subject to each group.

Total samples is 13 for each group. To anticipated drop out rate 10%, total sample is 15 for each group.

Intervention and measurement :

Control group will only receive CABG surgery. Study group will receive CBAG surgery and stem cell implantation. Stem cell aspiration will be performed 1 day before CABG procedure. Before aspiration, patients will be given local anesthetic and light sedation. Stem cell will be collected from posterior iliac crest. Total aspirate 190 cc. Stem cell CD133+ will be separated using CliniMACS® Magnetic Separation Device after labelled with Magnetic microbeads

• anti CD133 labelling.

Myocardial perfusion reserve index will be measure using MRI. MPRI value will be obtained globally and segmentally in each 16 ventricle segments VEGF plasma level will be measured using sandwich Enzyme-linked Immunosorbent Assay method.

Ejection fraction, left ventricle dimension, and scar size will be measured using MRI.

Quality of life will be measured using Minnesota Living With Heart Failure Questionnaire.

Statistical analysis is done using IBM SPSS Statistics version 21.0 (SPSS inc, Chicago, IL, USA). Numerical data will be presented in either mean/standard deviation or median/min-max depend on distribution of data. Hypothesis test for numeric variable is done using paired/non-paired T test or Mann-Whitney/Wilcoxon depend on normality of data. Normality test is done using Shapiro-Wilk test. Hypothesis test for category varible is done using chi-square or fischer test.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effect of Transepicardial Augmentation on Transseptal Autologous CD 133+ Bone Marrow Cell Implantation to Myocardial Perfusion in Patient Following Coronary Artery Bypass Grafting
• Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Apr 1, 2018
• Actual Study Completion Date: Apr 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: subject this arm will receive Transepicardial with Transseptal CD 133+ Implantation	Biological: Transepicardial with Transseptal CD 133+ Implantation; Transepicardial with Transseptal CD 133+ Implantation
No Intervention: control this arm will not receive Transepicardial with Transseptal CD 133+ Implantation

Outcome Measures

Primary Outcome Measures

1. Myocardial Defect Perfusion [Baseline, 6 months]

   Number of heart wall segments with perfusion defect measured by MRI.

2. Left Ventricular Ejection Fraction [Baseline, 6 months]

   Left ventricular ejection fraction (LVEF) measured by MRI. Normal range of LVEF ranges from 50% to 70%. Borderline LVEF ranges from 41% to 49% Reduced LVEF ranges < 41%

Secondary Outcome Measures

1. Six Minutes Walking Test [Baseline, 6 months]

   Quality of life will be assessed using Six minutes walking test, to see the changes of six minutes walking test before and after intervention Distances reported for healthy individuals ages 40 yo 85 years range from 400 to 700 m..

2. Wall Motion Score Index [Baseline, 6 months]

   Cardiac wall motion abnormality will be measured using Wall Motion Score Index with MRI. Each myocardial segment is assigned a score from 1 to 4. The 16 segment model of myocardial segmentation is recommended. A WMSI of 1.0 is considered normokinetic. A WMSI of 1.5 is considered mild hypokinesia A WMSI of 2.0 is considered hypokinesia A WMSI of 2.5 is considered severe hypokinesia A WMSI of 3.0 is considered akinetic.

3. Myocardial Scar Size [Baseline, 6 months]

   Percentage of myocardial scar size proportion measured by MRI to quantify and define the extent/transmurality of scar tissue, the following definitions were used spatial (circumferential) extent, the number of affected segments nontransmurality, the number of segmments with a segmental scar score of 1 or 2, and transmurality, the number of segments with a segmental scar score of 3 or 4 total score, summed segmental scar scores per patient divided by 17 (which reflects the damage per patient)

4. Vascular Endothelial Growth Factor [Baseline, 6 months]

   Cytokine that has important role for angiogenesis. Normal range for plasma VEGF is 0-115 pg/ml

5. Left Ventricle End Systolic Volume [Baseline, 6 months]

   Left ventricle end-systolic volume is the volume of blood in a left ventricle at the end of contraction, or systole, and the beginning of filling, or diastole. Normal LVESV ranges is 37 - 57 mililiters.

6. Minnesota Living With Heart Failure Questionnaire [Baseline, 6 months]

   Quality of life assessed using Minnesota Living With Heart Failure Questionnaire consist of 21 questions, to see the changes before and after intervention. Minimum score = 0, Maximum score = 105 Higher values represent a worse outcome

7. Left Ventricle End Diastolic Volume [Baseline, 6 months]

   Left ventricle end-diastolic volume is the volume of blood in the left ventricle at end load or filling in (diastole) or the amount of blood in the ventricle just before systole. Normal ranges of LVEDV is 121 - 163 mililiters

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• patients with coronary artery disease 3 vessels disease indicated for CABG

• LVEF < 35% which has been confirmed by MRI

• Patients with akinetic or hypokineic segment, and left ventricle myocardial hypoperfusion confirmed in MRI

• has signed informed consent

Exclusion Criteria:

Emergency CABG Ungraftable coronary artery Acute myocardial Infarct (<14 days) Valve disease which need surgery repair Contraindicated for MRI High degree ventricular arrhytmia Coagulation disorder HIV positive patient, Hepatitis B + patients, HCV + patients AST/ALT > 1,5 upper normal value Creatinine > 2 g/dl. Malignancy

Drop out criteria :

Aortic cross clamp >120 minutes and CABG total time >180

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cardiovascular Center Harapan Kita	Jakarta	DKI Jakarta	Indonesia	11420

Sponsors and Collaborators

• National Cardiovascular Center Harapan Kita Hospital Indonesia

Investigators

• Principal Investigator: Tri Wisesa Soetisna, MD, MHA, National Cardiovascular Center Harapan Kita

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 25, 2020
• Informed Consent Form - Feb 25, 2020

More Information

Publications

None provided.

• Responsible Party: Tri Wisesa Soetisna, MD, MHA, Director of Human Capital and General Affairs of National Cardiac Center, National Cardiovascular Center Harapan Kita Hospital Indonesia
• ClinicalTrials.gov Identifier: NCT02870933
• Other Study ID Numbers: LB.02.01/VII/086/KEP.007.EV
• First Posted: Aug 17, 2016
• Last Update Posted: Apr 2, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Tri Wisesa Soetisna, MD, MHA, Director of Human Capital and General Affairs of National Cardiac Center, National Cardiovascular Center Harapan Kita Hospital Indonesia: CD 133+; Transepicardial with Transseptal Implantation; CABG
• Additional relevant MeSH terms: Coronary Artery Disease

Study Results

Participant Flow

Arm/Group Title	CABG + Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Period Title: Overall Study
STARTED	15	15
COMPLETED	13	13
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	CABG + Transepicardial With Transseptal CD 133+ Implantation	Control	Total
Arm/Group Description	this arm will receive Transepicardial with Transseptal CD 133+ Implantation	this arm will not receive Transepicardial with Transseptal CD 133+ Implantation	Total of all reporting groups
Overall Participants	13	13	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.92 (8.95)	57.46 (6.33)	56.69 (7.63)
Sex: Female, Male (Count of Participants)
Female	1 7.7%	1 7.7%	2 7.7%
Male	12 92.3%	12 92.3%	24 92.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Indonesia	13 100%	13 100%	26 100%
Systolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	121.92 (14.37)	126.5 (19.60)	123.38 (17.51)
Diastolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	78.00 (12.03)	72.46 (15.36)	75.04 (13.52)
Smoking (Count of Participants)
Count of Participants [Participants]	11 84.6%	9 69.2%	20 76.9%
Dyslipidemia (Count of Participants)
Count of Participants [Participants]	6 46.2%	11 84.6%	17 65.4%
Hypertension (Count of Participants)
Count of Participants [Participants]	9 69.2%	7 53.8%	16 61.5%
Menopause (Count of Participants)
Count of Participants [Participants]	1 7.7%	1 7.7%	2 7.7%
Diabetes (Count of Participants)
Count of Participants [Participants]	5 38.5%	9 69.2%	14 53.8%
Random blood sugar level (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	126.85 (38.89)	136.85 (39.0)	131.85 (38.50)
NYHA grade III-IV (Count of Participants)
Count of Participants [Participants]	3 23.1%	4 30.8%	7 26.9%
CCS grade III-IV (Count of Participants)
Count of Participants [Participants]	1 7.7%	2 15.4%	3 11.5%
Six minutes walk test (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	297.08 (72.56)	308.92 (79.37)	303.0 (74.75)
Left Ventricle Ejection Fraction (Percentage of Ejection Fraction) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Ejection Fraction]	25.88 (5.66)	30.18 (3.85)	28.03 (5.23)
Left Ventricle End-Systolic Volume (mililiters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mililiters]	115.87 (35.94)	141.05 (27.77)	128.46 (33.99)
Left Ventricle End-Diastolic Volume (mililiters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mililiters]	156.10 (47.46)	200.89 (37.10)	178.5 (47.58)
Myocardial Scar Size (Percentage of Scar Area) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Scar Area]	27.76 (15.76)	24.45 (13.73)	26.11 (14.58)
Myocardial perfusion defect (Percentage of Myocardial Perfusion) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of Myocardial Perfusion]	15.76 (4.38)	15.38 (4.87)	15.57 (4.62)
Wall motion score index (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.32 (0.17)	2.07 (0.31)	2.2 (0.28)
Minnesotta Living with Heart Failure Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	30.3 (13.73)	21.46 (8.76)	25.88 (12.16)
Vascular Endothelial Growth Factor (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	46.86 (141.20)	40.46 (40.08)	43.66 (101.75)

Outcome Measures

1. Primary Outcome

Title	Myocardial Defect Perfusion
Description	Number of heart wall segments with perfusion defect measured by MRI.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op	15.76 (4.38)	15.38 (4.87)
Post-op	2.08 (2.13)	3.85 (5.20)

2. Primary Outcome

Title	Left Ventricular Ejection Fraction
Description	Left ventricular ejection fraction (LVEF) measured by MRI. Normal range of LVEF ranges from 50% to 70%. Borderline LVEF ranges from 41% to 49% Reduced LVEF ranges < 41%
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op	25.88 (5.66)	30.18 (3.85)
Post-op	34.58 (11.32)	31.62 (7.89)

3. Secondary Outcome

Title	Six Minutes Walking Test
Description	Quality of life will be assessed using Six minutes walking test, to see the changes of six minutes walking test before and after intervention Distances reported for healthy individuals ages 40 yo 85 years range from 400 to 700 m..
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op	299	298
Post-op	420	378

4. Secondary Outcome

Title	Wall Motion Score Index
Description	Cardiac wall motion abnormality will be measured using Wall Motion Score Index with MRI. Each myocardial segment is assigned a score from 1 to 4. The 16 segment model of myocardial segmentation is recommended. A WMSI of 1.0 is considered normokinetic. A WMSI of 1.5 is considered mild hypokinesia A WMSI of 2.0 is considered hypokinesia A WMSI of 2.5 is considered severe hypokinesia A WMSI of 3.0 is considered akinetic.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op	2.32 (0.17)	2.07 (0.31)
Post-op	1.82 (0.43)	2.08 (0.28)

5. Secondary Outcome

Title	Myocardial Scar Size
Description	Percentage of myocardial scar size proportion measured by MRI to quantify and define the extent/transmurality of scar tissue, the following definitions were used spatial (circumferential) extent, the number of affected segments nontransmurality, the number of segmments with a segmental scar score of 1 or 2, and transmurality, the number of segments with a segmental scar score of 3 or 4 total score, summed segmental scar scores per patient divided by 17 (which reflects the damage per patient)
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	subjectTransepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre op	27.76 (15.76)	24.45 (13.73)
Post op	25.46 (12.91)	27.32 (12.92)

6. Secondary Outcome

Title	Vascular Endothelial Growth Factor
Description	Cytokine that has important role for angiogenesis. Normal range for plasma VEGF is 0-115 pg/ml
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op	46.86 (141.20)	40.46 (40.08)
Post-op	61.05 (63.01)	19.88 (33.78)

7. Secondary Outcome

Title	Left Ventricle End Systolic Volume
Description	Left ventricle end-systolic volume is the volume of blood in a left ventricle at the end of contraction, or systole, and the beginning of filling, or diastole. Normal LVESV ranges is 37 - 57 mililiters.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op LVESV	115.87 (35.94)	141.05 (7.77)
Post-op LVESV	126.91 (86.03)	149.33 (44.96)

8. Secondary Outcome

Title	Minnesota Living With Heart Failure Questionnaire
Description	Quality of life assessed using Minnesota Living With Heart Failure Questionnaire consist of 21 questions, to see the changes before and after intervention. Minimum score = 0, Maximum score = 105 Higher values represent a worse outcome
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op	27	23
Post-op	12	14

9. Secondary Outcome

Title	Left Ventricle End Diastolic Volume
Description	Left ventricle end-diastolic volume is the volume of blood in the left ventricle at end load or filling in (diastole) or the amount of blood in the ventricle just before systole. Normal ranges of LVEDV is 121 - 163 mililiters
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Transepicardial With Transseptal CD 133+ Implantation	Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation	this arm will receive CABG only
Measure Participants	13	13
Pre-op LVEDV	156.10 (47.46)	200.89 (37.10)
Post-op LVEDV	183.68 (94.99)	219.97 (35.64)

Adverse Events

Time Frame	6 months
Arm/Group Title	Subject		Control
Arm/Group Description	this arm will receive CABG + Transepicardial with Transseptal CD 133+ Implantation		this arm will receive CABG only
All Cause Mortality
	Subject		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		1/13 (7.7%)
Serious Adverse Events
	Subject		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		1/13 (7.7%)
General disorders
Haemodynamic instability	1/13 (7.7%)		0/13 (0%)
Infections and infestations
Sepsis	1/13 (7.7%)		1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Subject		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.