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.

Tracking Information

• First Submitted Date: October 14, 2013
• First Posted Date: October 21, 2013
• Results First Submitted Date: December 27, 2013
• Results First Posted Date: June 3, 2014
• Last Update Posted Date: June 3, 2014
• Study Start Date: July 2005
• Actual Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 5, 2014)

Angina Class Variation [ Time Frame: 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.

Original Primary Outcome Measures (submitted: October 16, 2013)

Angina class variation [ Time Frame: 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), 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.

Current Secondary Outcome Measures (submitted: May 5, 2014)

• Functional Change Evaluation [ Time Frame: Baseline and 12 months ]
  Analysis of Left Ventricular Ejection Fraction (in %), by echocardiogram.
• Functional Change Evaluation [ Time Frame: Baseline, 6 and 12 months ]
  Analysis of objective improvement in myocardial ischemia (in %), by stress technetium scintigraphy.

Original Secondary Outcome Measures (submitted: October 16, 2013)

Functional changes evaluation [ Time Frame: Baseline, 6 and 12 months ]

This measure was a composite outcome measure, comprising analysis of echocardiogram, arrhythmia, electrocardiogram changes and allergic or other adverse events. An Echocardiogram was performed at baseline (prior to patient inclusion) and 12 months after surgery, to assess functional changes in wall motion. And safety was evaluated by documented arrhythmia, electrocardiogram changes of ischemia or infarction, or allergic or other adverse events.

Current Other Pre-specified Outcome Measures (submitted: May 5, 2014)

Life Quality [ Time Frame: 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.

Original Other Pre-specified Outcome Measures (submitted: October 16, 2013)

Life quality [ Time Frame: Baseline and 12 months ]

Analysis of the variation in life quality questionnaire (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.

Descriptive Information

• Brief Title: Study Protocol of Intramyocardial Injection of Autologous Bone Marrow Stem Cells for Refractory Angina
• Official Title: Phase II Study of Intramyocardial Injection of Autologous Bone Marrow Stem Cells for Refractory Angina in Patients With Normal or Slightly Reduced Left Ventricular Function.

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.

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:

1. 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;
2. Improvement in myocardial perfusion before and after cell delivery;
3. 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Refractory Angina

Intervention

• 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.

Study Arms

Experimental: Stem Cell Therapy

All subjects enrolled in the study underwent:

Local Sedation; Bone Marrow Aspiration; Minithoracotomy; Autologous bone marrow mononuclear cells infusion.

Interventions:

• Procedure: Local sedation
• Procedure: Bone Marrow Aspiration
• Procedure: Minithoracotomy
• Biological: Autologous bone marrow mononuclear cells infusion

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 5, 2014): 13
• Original Actual Enrollment (submitted: October 16, 2013): 14
• Actual Study Completion Date: December 2012
• Actual Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT01966042
• Other Study ID Numbers: Cell 0314/05; 0314/05 ( Other Identifier: CEP )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: CellPraxis Bioengenharia Ltda.
• Original Responsible Party: Same as current
• Current Study Sponsor: CellPraxis Bioengenharia Ltda.
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: CellPraxis Bioengenharia Ltda.
• Verification Date: May 2014