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Study Protocol of Intramyocardial Injection of Autologous Bone Marrow Stem Cells for Refractory Angina (ReACT)

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ClinicalTrials.gov Identifier: NCT01966042
Recruitment Status : Completed
First Posted : October 21, 2013
Results First Posted : June 3, 2014
Last Update Posted : June 3, 2014
Sponsor:
Collaborators:
Cryopraxis Criobiologia Ltda.
Federal University of São Paulo
University of South Florida
Information provided by (Responsible Party):
CellPraxis Bioengenharia Ltda.

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Refractory Angina
Interventions Procedure: Local sedation
Procedure: Bone Marrow Aspiration
Procedure: Minithoracotomy
Biological: Autologous bone marrow mononuclear cells infusion
Enrollment 13
Recruitment Details Refractory angina patients routinely undergoing treatment at the São Paulo Hospital, in São Paulo, Brazil, a referral tertiary Federal University Hospital for coronary heart disease, were included in the study. The study protocol (ReACT™) was approved by the local and national ethical committee and all patients provided written informed consent.
Pre-assignment Details Refractory angina patients were defined as those with functional class IV (angina at rest) according to the Canadian Cardiovascular Society Angina Classification (CCSAC) despite maximum medical therapy, not suitable for conventional myocardial revascularization and with viable myocardium identification.
Arm/Group Title Cell Therapy
Hide Arm/Group Description

All subjects enrolled in the study underwent bone marrow aspiration and autologous bone marrow mononuclear cells infusion.

Local sedation: All subjects enrolled underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled underwent bone marrow aspiration after anesthesia from the posterior iliac crest. The sample was aspirated into sterile syringes and brought to the cell processing laboratory. The processing was in accordance to the Standard Operating Procedure developed observing Good Practice Guidelines.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened, the surgeon drew up the cells into syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

Period Title: Overall Study
Started 13
Completed 11
Not Completed 2
Reason Not Completed
Death             2
Arm/Group Title Cell Therapy
Hide Arm/Group Description

All subjects enrolled in the study underwent bone marrow aspiration and infusion of autologous bone marrow mononuclear cells.

Local sedation: All subjects enrolled in the study underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled in the study underwent bone marrow aspiration after anesthesia.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated, allowing the good access to the viable myocardial areas.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened and the coronary anatomy reviewed by examination of the pre-operatory nuclear scan to define the area of ischemia, the surgeon drew up the cells into a series of syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

Overall Number of Baseline Participants 13
Hide Baseline Analysis Population Description
One patient died from cardiogenic shock due to anterior myocardial infarction after 5 months of follow-up. One patient, after 47.3 months of ReACT's procedure, migrated to CCSAC 4 and met inclusion criteria again. This patient was submitted to a new ReACT's procedure.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 13 participants
64  (8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
Female
3
  23.1%
Male
10
  76.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Brazil Number Analyzed 13 participants
13
1.Primary Outcome
Title Angina Class Variation
Hide Description

It was evaluated in accordance with the percentage of participants that change the functional class of angina according to CCSAC (Canadian Cardiovascular Society Angina Classification - description below), after treatment. The functional class of angina was also analyzed as an ordinal variable and the median of the functional class was calculated before and after the procedure, at the time of interest (3, 6 and 12 months post treatment), in comparison to baseline, ie. value at 3 months minus value at baseline.

Screening of Functional Graduation of Stable Angina:

I - Angina only occurs after a fast or prolonged and strenuous effort during work or recreation.

II - Slight limitation to everyday activities. III - Considerable limitation of common physical activity. IV - Inability to perform any physical activity without discomfort, the symptoms can be present at rest.

Time Frame 3, 6 and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cell Therapy
Hide Arm/Group Description:

All subjects enrolled in the study underwent bone marrow aspiration and infusion of autologous bone marrow mononuclear cells.

Local sedation: All subjects enrolled in the study underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled in the study underwent bone marrow aspiration after anesthesia.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated, allowing the good access to the viable myocardial areas.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened and the coronary anatomy reviewed by examination of the pre-operatory nuclear scan to define the area of ischemia, the surgeon drew up the cells into a series of syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

Overall Number of Participants Analyzed 13
Median (Standard Deviation)
Unit of Measure: Angina Classification
Angina Class at 3 Months -2.0  (1.1)
Angina Class at 6 Months -1.0  (1.3)
Angina Class at 12 Months -0.5  (0.9)
Angina Class at Baseline 4.0  (0.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cell Therapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Friedman test (n=13)
Comments [Not Specified]
2.Secondary Outcome
Title Functional Change Evaluation
Hide Description Analysis of Left Ventricular Ejection Fraction (in %), by echocardiogram.
Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cell Therapy
Hide Arm/Group Description:

All subjects enrolled in the study underwent bone marrow aspiration and infusion of autologous bone marrow mononuclear cells.

Local sedation: All subjects enrolled in the study underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled in the study underwent bone marrow aspiration after anesthesia.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated, allowing the good access to the viable myocardial areas.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened and the coronary anatomy reviewed by examination of the pre-operatory nuclear scan to define the area of ischemia, the surgeon drew up the cells into a series of syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

Overall Number of Participants Analyzed 11
Median (Standard Deviation)
Unit of Measure: percentage of Left Ventrical Ejection
LVEF at baseline 59.2  (8.9)
LVEF at 12 months 61.6  (6.3)
3.Secondary Outcome
Title Functional Change Evaluation
Hide Description Analysis of objective improvement in myocardial ischemia (in %), by stress technetium scintigraphy.
Time Frame Baseline, 6 and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cell Therapy
Hide Arm/Group Description:

All subjects enrolled in the study underwent bone marrow aspiration and infusion of autologous bone marrow mononuclear cells.

Local sedation: All subjects enrolled in the study underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled in the study underwent bone marrow aspiration after anesthesia.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated, allowing the good access to the viable myocardial areas.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened and the coronary anatomy reviewed by examination of the pre-operatory nuclear scan to define the area of ischemia, the surgeon drew up the cells into a series of syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

Overall Number of Participants Analyzed 11
Median (Standard Deviation)
Unit of Measure: percentage of area change
Myocardium Ischemic Area change after 6 months -15  (48)
Myocardium Ischemic Area change after 12 months -100  (37.1)
4.Other Pre-specified Outcome
Title Life Quality
Hide Description

Analysis of the variation in life quality questionnaire - Short Form Health Survey (SF-36) was performed. Each domain of the questionnaire was evaluated as a quantitative variable and the medians were retrieved before and after the procedure.

The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index.

It consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e. a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

One patient was lost before answering the questionnaire post procedure.

Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cell Therapy
Hide Arm/Group Description:

All subjects enrolled in the study underwent bone marrow aspiration and infusion of autologous bone marrow mononuclear cells.

Local sedation: All subjects enrolled in the study underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled in the study underwent bone marrow aspiration after anesthesia.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated, allowing the good access to the viable myocardial areas.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened and the coronary anatomy reviewed by examination of the pre-operatory nuclear scan to define the area of ischemia, the surgeon drew up the cells into a series of syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

Overall Number of Participants Analyzed 10
Median (Standard Deviation)
Unit of Measure: units on a scale
Physical Function Pre-procedure 20.0  (27.1)
Physical Function Post-procedure 72.5  (24.5)
Role-Physical Pre-procedure 0.0  (31.6)
Role-Physical Post-procedure 100.0  (33.7)
Bodily Pain Pre-procedure 11.0  (17.3)
Bodily Pain Post-procedure 100.0  (35.1)
General Health Pre-procedure 20.0  (20.0)
General Health Post-procedure 72.0  (19.7)
Vitality Pre-procedure 40.0  (22.1)
Vitality Post-procedure 95  (31.4)
Social Function Pre-procedure 12.5  (30.3)
Social Function Post-procedure 100.0  (39.3)
Role-Emotional Pre-procedure 100.0  (31.6)
Emotional Post-procedure 100.0  (36.0)
Mental Health Pre-procedure 70.0  (33.3)
Mental Health Post-procedure 98.0  (23.9)
Time Frame 6 years
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cell Therapy
Hide Arm/Group Description

All subjects enrolled in the study underwent bone marrow aspiration and infusion of autologous bone marrow mononuclear cells.

Local sedation: All subjects enrolled in the study underwent local sedation for bone marrow aspiration.

Bone Marrow Aspiration: All subjects enrolled in the study underwent bone marrow aspiration after anesthesia.

Minithoracotomy: The cardiac access route was the left anterolateral thoracotomy or left anterior minithoracotomy, depending on the segment of the left ventricle to be treated, allowing the good access to the viable myocardial areas.

Autologous bone marrow mononuclear cells infusion: Once the subject had his or her chest opened and the coronary anatomy reviewed by examination of the pre-operatory nuclear scan to define the area of ischemia, the surgeon drew up the cells into a series of syringes and injected the entire contents of the cell preparation in a series of injections directly into the myocardium.

All-Cause Mortality
Cell Therapy
Affected / at Risk (%)
Total   --/--    
Hide Serious Adverse Events
Cell Therapy
Affected / at Risk (%) # Events
Total   2/13 (15.38%)    
Cardiac disorders   
Inferior myocardial infarction * [1]  1/13 (7.69%)  1
Anterior myocardial infarction * [2]  1/13 (7.69%)  1
*
Indicates events were collected by non-systematic assessment
[1]
The first patient died from inferior myocardial infarction after 5 years of follow-up.
[2]
One patient died from cardiogenic shock due to anterior myocardial infarction after 5 months of follow-up.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cell Therapy
Affected / at Risk (%) # Events
Total   2/13 (15.38%)    
Cardiac disorders   
Angina *  2/13 (15.38%)  2
*
Indicates events were collected by non-systematic assessment
Due to ethical aspects and the inability to justify the use of a surgical intramyocardial placebo in this population, this was non-randomized, open study.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Nelson Americo Hossne Junior
Organization: Federal University of Sao Paulo (UNIFESP)
Phone: +55 11 5571-2719
EMail: nelson.hossne@gmail.com
Layout table for additonal information
Responsible Party: CellPraxis Bioengenharia Ltda.
ClinicalTrials.gov Identifier: NCT01966042    
Other Study ID Numbers: Cell 0314/05
0314/05 ( Other Identifier: CEP )
First Submitted: October 14, 2013
First Posted: October 21, 2013
Results First Submitted: December 27, 2013
Results First Posted: June 3, 2014
Last Update Posted: June 3, 2014