Clinical trial NCT01966042: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Refractory Angina
Keywords: Refractory angina
Cell Therapy
Bone Marrow
Mononuclear Cells
Lead sponsor: CellPraxis Bioengenharia Ltda.
Sponsor class: INDUSTRY
Collaborators: name: Cryopraxis Criobiologia Ltda.
name: Federal University of São Paulo
name: University of South Florida
First posted: 2013-10-21
Enrollment: 13
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Angina Class Variation
timeFrame: 3, 6 and 12 months
Secondary outcomes:
measure: Functional Change Evaluation
timeFrame: Baseline and 12 months
measure: Functional Change Evaluation
timeFrame: Baseline, 6 and 12 months
Other outcomes:
measure: Life Quality
timeFrame: Baseline and 12 months
Locations:
city: São Paulo
country: Brazil
facility: Federal University of São Paulo
Study officials:
affiliation: Federal University of São Paulo
name: Nelson A Hossne Junior, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Federal University of São Paulo
name: Enio Buffolo, MD, PhD
role: STUDY_DIRECTOR
References: