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

NCT ID: NCT01966042

Last Updated: 2014-06-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-07-31
• Study Completion Date: 2012-12-31

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.

Conditions

Refractory Angina

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Stem Cell Therapy

All subjects enrolled in the study underwent:

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

Group Type: EXPERIMENTAL

Local sedation

Intervention Type: PROCEDURE

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

Bone Marrow Aspiration

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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.

Interventions

Local sedation

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

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: PROCEDURE

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.

Intervention Type: BIOLOGICAL

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.

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cryopraxis Criobiologia Ltda.

INDUSTRY

Sponsor Role: collaborator

Federal University of São Paulo

OTHER

Sponsor Role: collaborator

University of South Florida

OTHER

Sponsor Role: collaborator

CellPraxis Bioengenharia Ltda.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nelson A Hossne Junior, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Federal University of São Paulo

Enio Buffolo, MD, PhD

Role: STUDY_DIRECTOR

Federal University of São Paulo

Locations

Federal University of São Paulo

São Paulo, São Paulo, Brazil

Countries

Brazil

Other Identifiers

0314/05

Identifier Type: OTHER

Identifier Source: secondary_id

Cell 0314/05

Identifier Type: -

Identifier Source: org_study_id