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| ID | Type | Description | Link |
|---|---|---|---|
| 0314/05 | Other Identifier | CEP |
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| Name | Class |
|---|---|
| Cryopraxis Criobiologia Ltda. | INDUSTRY |
| Federal University of São Paulo | OTHER |
| University of South Florida | OTHER |
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Therapeutic neovascularization is an innovative strategy for cardiac tissue recovery due to chronic, intense ischemia. Thus stem cell therapy has become a promising procedure for the large number of patients with refractory angina due to coronary disease, despite of the use of multiple anti-angina medications, remain severely symptomatic with disabling angina.
Stem cell therapy using autologous cells from the patient's bone marrow, has been shown to be safe and associated with improved myocardial perfusion, reducing the symptoms of advanced coronary artery disease and increasing the functional capacity of patients whose therapeutic armamentarium available today has been exhausted.
The study hypothesis was that the infusion of autologous mononuclear cells derived from the patient's bone marrow and delivered via intramyocardial injection in patients with refractory angina and normal or slightly depressed ventricular function, promote improvement in the anginal symptoms and myocardial perfusion by the inducing neoangiogenesis.
This was a phase II, non-controlled (single arm) and open label clinical trial. The study was approved by the Institutional Review Board (IRB) and all patients gave informed consent prior to participation.
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 viable myocardium confirmed by nuclear imaging.
Patients were evaluated according to different parameters, for a total period of 12 months, and the primary objectives were:
In the screening evaluation, individuals with the presumptive diagnosis of class IV refractory angina and who met all study criteria were approached about the possibility of participating in the study by the principal investigator. Then, the patients were submitted to a baseline evaluation with a serious of blood and image tests.
The interventions were the Bone Marrow Aspiration - For each patient, a total of 100 cc of bone marrow was aspirated from the iliac crest at the time of anesthesia for their cardiac surgery - and the Infusion - After processing the cells, the surgeon delivered it by a series of epicardial injections into the left ventricular myocardium.
The processing of bone marrow autologous cells aimed to enrich the content of the bone marrow aspirate, separating the mononuclear fraction from the cells which were already differentiated.
The postoperative stage was conducted in an identical way to that of patients who undergo to a myocardial revascularization surgery. It is important to mention that both the ICU and the ward time varied according to the patient's individual evolution.
Finally, the first follow up visit took place at 1 month after the surgery. The subsequent visits were held at 3, 6 and 12 months after the procedure.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Stem Cell Therapy | Experimental | All subjects enrolled in the study underwent: Local Sedation; Bone Marrow Aspiration; Minithoracotomy; Autologous bone marrow mononuclear cells infusion. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Local sedation | Procedure | All subjects enrolled in the study underwent local sedation for bone marrow aspiration. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Angina Class Variation | 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. | 3, 6 and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Functional Change Evaluation | Analysis of Left Ventricular Ejection Fraction (in %), by echocardiogram. | Baseline and 12 months |
| Functional Change Evaluation | Analysis of objective improvement in myocardial ischemia (in %), by stress technetium scintigraphy. |
| Measure | Description | Time Frame |
|---|---|---|
| Life Quality | 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nelson A Hossne Junior, MD, PhD | Federal University of São Paulo | Principal Investigator |
| Enio Buffolo, MD, PhD | Federal University of São Paulo | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Federal University of São Paulo | São Paulo | São Paulo | SP | Brazil |
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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cell Therapy | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Bone Marrow Aspiration | Procedure | All subjects enrolled in the study underwent bone marrow aspiration after they had been anesthetized from the posterior iliac crest. The sample was aspirated into a series of sterile syringes and brought to the cell processing room/laboratory. The processing was in accordance to the Standard Operating Procedure developed observing Good Practice Guidelines. |
|
| Minithoracotomy | Procedure | The surgical procedure used as 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 | Biological | 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. |
|
| Baseline, 6 and 12 months |
| Baseline and 12 months |
| COMPLETED |
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| NOT COMPLETED |
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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.
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| ID | Title | Description |
|---|---|---|
| BG000 | Cell Therapy | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Angina Class Variation | 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. | Posted | Median | Standard Deviation | Angina Classification | 3, 6 and 12 months |
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| Secondary | Functional Change Evaluation | Analysis of Left Ventricular Ejection Fraction (in %), by echocardiogram. | Posted | Median | Standard Deviation | percentage of Left Ventrical Ejection | Baseline and 12 months |
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| Other Pre-specified | Life Quality | 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. | Posted | Median | Standard Deviation | units on a scale | Baseline and 12 months |
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| Secondary | Functional Change Evaluation | Analysis of objective improvement in myocardial ischemia (in %), by stress technetium scintigraphy. | Posted | Median | Standard Deviation | percentage of area change | Baseline, 6 and 12 months |
|
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6 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cell Therapy | 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. | 2 | 13 | 2 | 13 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Inferior myocardial infarction | Cardiac disorders | Non-systematic Assessment | The first patient died from inferior myocardial infarction after 5 years of follow-up. |
| |
| Anterior myocardial infarction | Cardiac disorders | Non-systematic Assessment | One patient died from cardiogenic shock due to anterior myocardial infarction after 5 months of follow-up. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Angina | Cardiac disorders | Non-systematic Assessment |
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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.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nelson Americo Hossne Junior | Federal University of Sao Paulo (UNIFESP) | +55 11 5571-2719 | nelson.hossne@gmail.com |
| ID | Term |
|---|---|
| D000787 | Angina Pectoris |
| ID | Term |
|---|---|
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
| D002637 | Chest Pain |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| Title | Measurements |
|---|---|
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| Angina Class at Baseline |
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