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

• 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: CellPraxis Bioengenharia Ltda.
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Cell Therapy
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
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

Outcome Measures

1. Primary Outcome

Title	Angina Class Variation
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cell Therapy
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)

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
Description	Analysis of Left Ventricular Ejection Fraction (in %), by echocardiogram.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cell Therapy
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
Description	Analysis of objective improvement in myocardial ischemia (in %), by stress technetium scintigraphy.
Time Frame	Baseline, 6 and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cell Therapy
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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cell Therapy
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)

Adverse Events

Time Frame	6 years
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Cell Therapy
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	--/--
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.
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

Limitations and Caveats

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.

More Information

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

• Name/Title: Dr. Nelson Americo Hossne Junior
• Organization: Federal University of Sao Paulo (UNIFESP)
• Phone: +55 11 5571-2719
• EMail: nelson.hossne@gmail.com

• 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