ReACT: Study Protocol of Intramyocardial Injection of Autologous Bone Marrow Stem Cells for Refractory Angina
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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:
-
Improvement in functional class and angina symptoms (CCSAC) of the patients with refractory angina pectoris after the infusion of autologous bone marrow mononuclear cells after the intervention;
-
Improvement in myocardial perfusion before and after cell delivery;
-
Evaluate the safety of the delivery of autologous bone marrow mononuclear cells route in individuals with refractory angina.
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Stem Cell Therapy All subjects enrolled in the study underwent: Local Sedation; Bone Marrow Aspiration; Minithoracotomy; Autologous bone marrow mononuclear cells infusion. |
Procedure: Local sedation
All subjects enrolled in the study underwent local sedation for bone marrow aspiration.
Procedure: Bone Marrow Aspiration
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.
Procedure: Minithoracotomy
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.
Biological: 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.
|
Outcome Measures
Primary Outcome Measures
- Angina Class Variation [3, 6 and 12 months]
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.
Secondary Outcome Measures
- Functional Change Evaluation [Baseline and 12 months]
Analysis of Left Ventricular Ejection Fraction (in %), by echocardiogram.
- Functional Change Evaluation [Baseline, 6 and 12 months]
Analysis of objective improvement in myocardial ischemia (in %), by stress technetium scintigraphy.
Other Outcome Measures
- Life Quality [Baseline and 12 months]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Aged above 21 years old;
-
Documented coronary artery disease by angiography and confirmed ischemia by myocardial perfusion scintigraphy with physical or pharmacological stress;
-
Class IV angina pectoris (CCSAC) that is unresponsive to optimized dose of at least two anti-anginal medications including nitrates, beta blocker, calcium channel blocker or Ranolazine) as well as aspirin or other anti-platelet agent plus statin therapy;
-
Considered to not be a candidate for either percutaneous catheter or surgical myocardial revascularization due to either anatomical type, extent of coronary disease in the target vessel, or caliber of the distal vessels;
-
Ejection fraction of > 45% by Transthoracic echocardiogram with Doppler by the Simpson method;
-
Myocardial perfusion scintigraphy showing that the areas of myocardial ischemia supply viable tissue.
Exclusion Criteria:
-
Significant Valvular Heart Disease;
-
Chronic kidney disease requiring renal replacement therapy;
-
Severe comorbidities associated with the reduction of life expectancy in less than 5 years;
-
Ongoing abusive use of alcohol or illegal drugs (Based on the Diagnostic and Statistical Manual (DSM) IV - CAGE questionnaire);
-
Positive Serologic test for HIV, Human T-cell lymphotrophic virus (HTLV), Hepatitis A, B and C;
-
History of Malignant neoplasia in the last 2 years;
-
Participation into other studies of cell therapy in the last year;
-
Pregnancy or Breast-feeding.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Federal University of São Paulo | São Paulo | Brazil | SP |
Sponsors and Collaborators
- CellPraxis Bioengenharia Ltda.
- Cryopraxis Criobiologia Ltda.
- Federal University of São Paulo
- University of South Florida
Investigators
- Principal Investigator: Nelson A Hossne Junior, MD, PhD, Federal University of São Paulo
- Study Director: Enio Buffolo, MD, PhD, Federal University of São Paulo
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Cell 0314/05
- 0314/05
Study Results
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 Detail | 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 |
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 Participants | 13 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
64
(8)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
3
23.1%
|
| Male |
10
76.9%
|
| Region of Enrollment (participants) [Number] | |
| Brazil |
13
100%
|
Outcome Measures
| 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. |
| Measure Participants | 13 |
| 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 | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | < 0.001 |
| Comments | ||
| Method | Friedman test (n=13) | |
| Comments | ||
| 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. |
| Measure Participants | 11 |
| LVEF at baseline |
59.2
(8.9)
|
| LVEF at 12 months |
61.6
(6.3)
|
| 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. |
| Measure Participants | 10 |
| 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)
|
| 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. |
| Measure Participants | 11 |
| Myocardium Ischemic Area change after 6 months |
-15
(48)
|
| Myocardium Ischemic Area change after 12 months |
-100
(37.1)
|
Adverse Events
| Time Frame | 6 years | |
|---|---|---|
| Adverse Event Reporting Description | ||
| 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 (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Cell Therapy | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/13 (15.4%) | |
| Cardiac disorders | ||
| Inferior myocardial infarction | 1/13 (7.7%) | 1 |
| Anterior myocardial infarction | 1/13 (7.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Cell Therapy | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/13 (15.4%) | |
| Cardiac disorders | ||
| Angina | 2/13 (15.4%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Dr. Nelson Americo Hossne Junior |
|---|---|
| Organization | Federal University of Sao Paulo (UNIFESP) |
| Phone | +55 11 5571-2719 |
| nelson.hossne@gmail.com |
- Cell 0314/05
- 0314/05