Autologous Bone Marrow Mononuclear Cells in the Combined Treatment of Coronary Heart Disease

Ischemic Heart Disease Clinical Trial

— TAMIS  

Official title:

Influence of the Administration of Autologous Bone Marrow Mononuclear Cells for the Duration of Functioning Aorto-coronary Bypass Grafts in the Surgical Treatment of Coronary Heart Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02059512
• Other study ID #: NBK-2901-AMNKM
• Status: Completed
• Phase: N/A
• Start date: February 2013
• Est. completion date: January 2018

Study information

• Verified date: May 2021
• Source: St. Petersburg State Pavlov Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study evaluate the effect of the method of administration of autologous bone marrow mononuclear cells for the duration of of functioning aorto-coronary bypass grafts in the surgical treatment of coronary heart disease, to assess the degree of effectiveness depending on the method of transplantation (intramyocardial, intracoronary, combined).

Description:

Additional estimation of safety:

1. Assessment of EuroScore II.

2. Hospital Stay.

3. The duration of stay in the intensive care unit.

4. Restoration of cardiac rhythm at the end of the main stage of operation (defibrillation/ self-recovery).

5. The time of extracorporeal circulation.

6. Time of anoxia.

7. Volume abjointed (drainage) postoperative day 1, day 3

8. Troponin I, CPK-MB, Myoglobin at 1, 3 postoperative days.

9. Hb/ HCT/K+ at the end of cardiopulmonary bypass (CPB) and Hb/ HCT/K+/ ABC at the end of the operation.

10. Assessment of the degree of manifestation of a systemic inflammatory reaction in the postoperative period - leukocytes (Leu), CRP

11. Postoperative complications (hydrothorax, hydropericardium, arrhythmias, resternotomy).

12. Echocardiography at 7-14 days after surgery.

Estimation of efficiency:

1. Evaluation of systolic and diastolic myocardial function. Assessment of myocardial perfusion and metabolism (before and after treatment) - Speckle tracking echocardiography.

2. Patency of grafts within a specified time of treatment (angiography).

3. Dependence and duration of positive clinical effect on the amount of injected cell material.

4. Evaluation of the quality of life (Minnesota questionnaire, Seattle questionnaire, SF- 36 questionnaire).

5. All-cause Mortality Associated With the Progression of Basic

6. Disease.Dynamics of the functional class of angina.

7. Dynamics of the functional class of heart failure.

8. Dynamics of test data with a 6-minute walk.

Predicting the results of treatment (the effect of a number of parameters):

1. Age.

2. Gender.

3. The body mass index.

4. Diabetes.

5. Smoking.

6. Family history of cardiovascular events.

7. Duration of ischemic heart disease.

8. Serum total cholesterol (+ fractions).

9. Leukocytosis and CRP level (initial level and rate of decrease in the postoperative period).

10. The level of creatinine.

11. The presence / absence of extracardiac arteriopathy.

12. The intramyocardial or intracoronary injection of BM-MNCs.

13. Assessment of the bone marrow: the number of nucleated cells, CD34 +, CD133 +.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 117
• Est. completion date: January 2018
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Men and women from 18 to 80 years

• Patients with angina pectoris III-IV functional class

• According to angiographic examination, the presence of 3 or more stenotic coronary arteries

• Aorto-coronary bypass surgery under cardiopulmonary bypass

• Patients signed informed consent

Exclusion Criteria:

• Intolerance of heparin and HES.

• Hypothyroidism and hyperthyroidism.

• Associated pathology with a projected lifespan limitation to 3 years.

• infection diseases

• Simultaneous participation in another study.

• Pregnancy.

• Severe mental disorder.

• Refusal of a patient to participate in the study.

Related Conditions & MeSH terms

• Bone Marrow Cells
• Coronary Artery Bypass Grafting (CABG)
• Coronary Artery Disease
• Coronary Disease
• Heart Diseases
• Heart Failure
• Heart Failure, Diastolic
• Ischemic Heart Disease
• Myocardial Ischemia

Intervention

Procedure:
• Group 1
Coronary artery bypass grafting with intramyocardial administration of autologous bone marrow mononuclear cells 0.2 ml - 10 injection in the zone of blood supply LAD.
• Group 0
Coronary artery bypass grafting with intramyocardial administration of 0.9 % NaCl (sodium chloride) 0.2 ml - 10 injection in the zone of blood supply LAD.
• Group 2
Coronary artery bypass grafting with intramyocardial and intracoronary administration of autologous bone marrow mononuclear cells intramyocardial administration 0.2 ml - 10 injection in the zone of blood supply LAD.

Locations

Country	Name	City	State
Russian Federation	First Pavlov State Medical University of St. Petersburg	St. Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
St. Petersburg State Pavlov Medical University

Country where clinical trial is conducted

Russian Federation, 

References & Publications (2)

Komok V.V., Bunenkov N.S., Beliy S.A., Pizin V.M., Kondratev V.M., Dulaev ?.V., Lukashenko V.I., Kobak A.E., Maksimova T.S., Sergienko I.P., Parusova E.V., Smirnova L.A., Babenko E.V., Afanasev B.V., Nemkov A.S., Khubulava G.G. Assessment of safety of additional transplantation of autologous bone marrow mononuclear cells in the combined treatment of coronary heart disease. Results from a randomized, blind, placebo-controlled trial (TAMIS). Russian Journal of Transplantology and Artificial Organs. 2019;21(2):112-120. (In Russ.) https://doi.org/10.15825/1995-1191-2019-2-112-120

Komok V.V., Bunenkov N.S., Beliy S.A., Pizin V.M., Kondratev V.M., Dulaev A.V., Kobak A.E., Maksimova T.S., Sergienko I.P., Parusova E.V., Smirnova L.A., Babenko E.V., Afanasev B.V., Nemkov A.S., Khubulava G.G. Evaluation of the effectiveness of combined treatment of coronary heart disease - coronary artery bypass grafting, transplantation of autologous bone marrow mononuclear cells: a randomized, double-blind, placebo-controlled study. Russian Journal of Transplantology and Artificial Organs. 2019;21(4):54-66. https://doi.org/10.15825/1995-1191-2019-4-54-66

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The Volume of Cellular Material (Cytosis).	Dependence and Duration of Positive Clinical Effect on the Amount of Injected Cell Material (cytosis).	Initial data at the time of collection of bone marrow cells.
Other	The Amount of Cell Material (Percentage).	Dependence and duration of positive clinical effect on the amount of injected cell material (Mononuclear fraction %, CD34+ %, CD133+ %).; Assessment - mononuclear fraction, CD 34 +, CD 133+ according to flow cytometry data.	Initial data at the time of collection of bone marrow cells.
Other	Smoking as a Factor That Negatively Affects the Results of the Test With a 6-minute Walk in Dynamics.	The distance covered (in meters) was compared with the proper value depending on age (years), height (cm), weight (kg), body mass index (BMI). The due values (6MWD (i)) were calculated using the following formulas: For men: 6?WD (i) = 7.57 × height - 5.02 × age - 1.76 × weight - 309 or 6MWD (i) = 1140 - 5.61 × BMI - 6.94 × age. For women: 6?WD (i) = 2.11 × height - 2.29 × weight - 5.78 × age + 667 Or 6?WD (i) = 1017 - 6.24 × BMI - 5.83 × age. This difference at baseline is reported as distance walked for smokers minus non-smokers.	12 months after treatment.
Primary	Assessment of the Initial Risk of Surgery (EuroScore II).	EuroScoreII is intended to assess the risk of adverse outcome of coronary artery bypass grafting. Assessment factors: age, sex, serum creatinine, extracardiac artery disease, chronic lung disease, severe neurological disorders, previous cardiac surgery, previous myocardial infarction, left ventricular dysfunction, diabetes mellitus, pulmonary hypertension, IV class of angina severity, active endocarditis, unstable angina, surgery, critical condition of the patient before surgery, type of surgery. The higher the percentage, the higher the risk of surgery.	Before CABG surgery at baseline.
Primary	Length of Hospital Stay. Length of Stay in the Intensive Care Unit.	The results were obtained from the analysis of primary data.	Primary hospitalization for planned CABG.
Primary	The Severity of the Systemic Inflammatory Response in the Postoperative Period (Leukocytosis).	Assessment of the severity of the systemic inflammatory response during hospital stay after surgery. Assessment of the level of inflammation by the severity of an increase in leukocytes (leukocytosis).; Leukocytosis - an increase in the number of leukocytes per unit volume of blood. The norm of leukocytes in the blood is 5.5-8.810^9 /l. For adults, leukocytosis is considered to be an increase in the number of leukocytes in the blood of more than 9.0*10^9 / l In the statistical analysis, the grouping of indicators in the indicated intervals was used, in view of the individual characteristics of the course of the postoperative period in each case.	The parameters were evaluated initially at baseline in the postoperative period - an interval of 0-6 hours, 12-18 hours, 18-24 hours, 48 hours, 72 hours, 96 hours, 7 days and 14 days.
Primary	Assessment of the Degree of General Inflammatory Response (C-reactive Protein (CRP)),	Results of dynamic control of laboratory parameters of CRP. C-reactive protein. This fraction of plasma proteins increases in the presence of an inflammatory process in the body. It is synthesized in response to the ingestion of toxins of pathological microorganisms into the bloodstream and neutralizes them by binding them. In addition, it appears when the body's own cells are destroyed in the event of necrosis, tumor disintegration or extensive trauma, inactivating the resulting products. In addition to eliminating toxins, CRP triggers a cascade of immune responses aimed at eliminating pathologically altered structures.; Normally absent (or less than 0.4 mg / l). In the statistical analysis, the grouping of indicators in the indicated intervals was used, in view of the individual characteristics of the course of the postoperative period in each case.	Initial data, control point in the interval 4-6 days of the postoperative period, control point in the interval 12-14 days of the postoperative period.
Primary	The Volume of Discharge Through the Drains in the Early Postoperative Period.	A daily assessment of the discharge by drainage before removal was carried out. It was carried out to assess the possible development of an excessive inflammatory reaction (polyserositis phenomena) in response to the transplantation of autologous bone marrow mononuclear cells.	Evaluation of these data - for the time spent in the intensive care unit before removing the drains.
Primary	Dynamics of Markers of Myocardial Damage (Troponin I, Myoglobin).	Assessment of the severity of the period of ischemia / reperfusion. And the effect of autologous bone marrow mononuclear cells transplantation on these indicators.	1 and 3 days of the postoperative period.
Primary	Dynamics of Markers of Myocardial Damage (Creatine Phosphokinase Fraction MB (CPK-MB)).	Assessment of the severity of the period of ischemia / reperfusion. And the effect of autologous bone marrow mononuclear cells transplantation on these indicators.	1 and 3 days of the postoperative period.
Primary	Intraoperative Assessment of Homeostasis (Hemoglobin (Hb).	These parameters were evaluated at the end of the cardiopulmonary bypass and at the end of the surgery. The interval between indicators is on average from 60 to 120 minutes.	Intraoperative data.
Primary	Intraoperative Assessment of Homeostasis (Hematocrit (HCT)).	These parameters were evaluated at the end of the cardiopulmonary bypass and at the end of the surgery. The interval between indicators is on average from 60 to 120 minutes.	Intraoperative data.
Primary	Intraoperative Assessment of Homeostasis (?+).	These parameters were evaluated at the end of the cardiopulmonary bypass and at the end of the surgery. The interval between indicators is on average from 60 to 120 minutes.	Intraoperative data.
Primary	Cardiopulmonary Bypass Time.		Intraoperative data.
Primary	Time of Aortic Clamping (Anoxia).	Estimation of the time from the moment the clamp is applied to the aorta (complete clamping of the aorta) to the removal of the clamp from the aorta.	Intraoperative data.
Primary	Assessment of Complications in the Postoperative Period. Additional Estimation of Safety.	The presence of complications in the postoperative period (Hydrothorax, Hydropericardium, Cardiac arrhythmias - atrial fibrillation / atrial flutter).	Postoperative period.
Primary	Left Ventricular Ejection Fraction - Echocardiography - Assessment of Myocardial Contractility on Days 7-14 After Surgical Treatment. Additional Estimation of Safety.	Evaluation of myocardial contractility according to echocardiography, in particular the left ventricular ejection fraction, was carried out within 7-14 days of the postoperative period, depending on the patient's clinical condition, as well as the maximum degree of information content of this study. The lower the indicator, the worse the prognosis of an unfavorable outcome.	7-14 days of the postoperative period
Primary	Assessment of Myocardial Contractility on Days 7-14 After Surgical Treatment - Echocardiography (Size of the Left Ventricle - Index). Additional Estimation of Safety.	Assessment of myocardial contractility according to echocardiography, in particular the size of the left ventricle - its index, was carried out within 7-14 days of the postoperative period, depending on the clinical condition of the patient, as well as on the maximum information content of this study. The higher the indicator (left ventricular size - index), the worse the prognosis of an unfavorable outcome.; The index is used as an indicator of payment to obtain a more reliable result (taking into account the individual characteristics of each patient).; index - left ventricular size (mm.)/ body mass index (kg/m^2).	7-14 days after surgery
Primary	Volume of the Left Ventricle - Index - Echocardiography. Assessment of Myocardial Contractility on Days 7-14 After Surgical Treatment. Additional Estimation of Safety.	Evaluation of myocardial contractility according to echocardiography, in particular volume of the left ventricle - index was carried out within 7-14 days of the postoperative period, depending on the patient's clinical condition, as well as the maximum degree of information content of this study. The greater the figure (volume of the left ventricle - index), the worse the prognosis of adverse outcome.; The index is used as an indicator of the payment to obtain a more reliable result (taking into account individual characteristics of each patient).; index - volume of the left ventricle (ml.)/ body mass index (kg / m^2).	7-14 days after surgery
Primary	Restoration of the Heart Rate After the Completion of the Main Stage of the Surgical Intervention. Additional Estimation of Safety.	The need to perform defibrillation to restore sinus rhythm, at the end of the main stage of surgery.	Upon completion of the main stage of surgery.
Secondary	All-cause Mortality Associated With the Progression of Basic Disease.	The total number of deaths - in the primary hospitalization and during the observation period of 12 months after surgical treatment - deaths associated with the progression of the initial disease.; The complication rate for CABG operations is 30±10%. According to n1=kn2; n1 sample size, in the control. In group 0, k=2/3 times more than in group 1 and group 2. The difference between the test and control frequencies is e=p1-p2. Accordingly, with p1 = 0.2; p2=0.4, d= 0.1; n1=49.5, n2=33. The result is group 0 - 36, group 1 and 2 - 25+25 = 50. The null hypothesis of complication rate d.All patients included in the study.	12 months after surgery
Secondary	Quality of Life. Evaluation of the Quality of Life (Minnesota Questionnaire (MHFLQ), Seattle Questionnaire (SAQ), SF-36 Questionnaire). Estimation of Efficiency.	The SF-36 questionnaire. The indicators of each scale vary between 0 and 100, where 100 represents total health. The results are presented in the form of scores on 8 scales, compiled in such a way that a higher score indicates a higher level of quality of life.MHFLQ - for patients with heart failure.The specified questionnaire consists of 21 questions. To answer each question, a scale of 6 points from the minimum intensity of certain symptoms to the maximum is used. The assessment is based on the sum of points, where the maximum number of points - 105 corresponds to the patient's worst condition. The lowest score 0 points is the best clinical condition of the patient. SAQ consists of 19 questions about the patient's condition, which are divided into the following 5 scales. The quality of life for each of the five scales under consideration is measured in percent, with 0% corresponding to the worst quality of life, and 100% to the best.	At baseline and after one year.
Secondary	Assessment of the Functional Class of Exertional Angina at 12 Months After Surgical Treatment.	functional class - The usual load does not cause changes in the state of health. Painful attacks occur against the background of excessive loads - after climbing several flights of stairs, while walking fast.; functional class - Pain attacks when walking more than 500 meters, when climbing stairs more than one floor.; functional class - The patient does not tolerate minimal physical activity. An attack occurs when walking a distance of 50-100 meters. Climbing stairs is difficult.; functional class - Activity is significantly limited. Angina pectoris manifests itself when performing minimal actions, including at rest.	up to 12 months
Secondary	Dynamics of the Functional Class of Heart Failure (NYHA). Estimation of Efficiency.	functional class - There is no limitation of a person's physical activity, shortness of breath manifests itself when going above the third floor.; functional class - slight limitation of activity, palpitations, shortness of breath, fatigue occur during normal physical activity and more.; functional class - Symptoms occur with the smallest physical activity, resulting in a significant decrease in activity. At rest, clinical manifestations are not observed.; The smaller the functional class, the better the quality of human life.	Assessment of the dynamics at 12 months after treatment.
Secondary	Evaluation of the Left Ventricular Ejection Fraction 12 Months After Treatment.	According to echocardiography.	12 months after treatment.
Secondary	Estimation of the Index of Linear Parameters of the Left Ventricle 12 Months After the Treatment. Estimation of Efficiency.	Evaluation of myocardial contractility according to echocardiography, in particular the size of the left ventricle - the index was carried out 12 months after CABG. The higher the indicator (left ventricular size - index), the worse the prognosis of an unfavorable outcome.; The index is used as an indicator of the payment to obtain a more reliable result (taking into account individual characteristics of each patient).; index - size of the left ventricle (mm.)/ body mass index (kg/m^2).	12 months after the treatment.
Secondary	Estimation of the Index of Volumetric Parameters of the Left Ventricle 12 Months After the Treatment. Estimation of Efficiency.	Evaluation of myocardial contractility according to echocardiography, in particular the volume of the left ventricle - the index was carried out 12 months after CABG. The higher the indicator (left ventricular volume - index), the worse the prognosis of an unfavorable outcome.; The index is used as an indicator of the payment to obtain a more reliable result (taking into account individual characteristics of each patient).; index - volume of the left ventricle (mm.)/ body mass index (kg/m^2).	12 Months After the Treatment
Secondary	Assessment of Left Ventricular Diastolic Function - Peak E of Transmitral Flow and Peak ? of Transmitral Flow 12 Months After Treatment.	Evaluation of left ventricular diastolic function (echocardiography). The peak velocity E reflects the pressure gradient between the LA and LV in early diastole, and it is affected by preload and disturbance LV relaxation The speed of peak A, which forms at the end diastole, influences LV compliance and contractility left atrium.	12 months after treatment.
Secondary	Assessment of Left Ventricular Diastolic Function E/A - 12 Months After Treatment.	The ratio of the transmitral flow, wave E (ejection wave / left ventricular contraction) to wave A (ejection wave / left atrial contraction). The norm is 0.75-1.5 Less than 0.75 violation of relaxation, more than 1.5 restrictive type of diastolic dysfunction.	12 months after treatment
Secondary	Assessment of Left Ventricular Diastolic Function - DT and IVRT 12 Months After Treatment.	Echocardiographic data ( DT (Half-time of wave E), time of isovolumic relaxation of the left ventricle (IVRT).; DT (Half-time of wave E). The DT time index reflects the relaxation process LV, LV diastolic pressure after mitral valve opening, and LV compliance. 150-200 ms - normal; > 200 ms - violation of relaxation; 150-200 ms - pseudonormal type of left ventricular filling; <150 ms - restrictive type of diastolic dysfunction IVRT (time of isovolumic relaxation of the left ventricl.) <100 ms - normal; > 100 ms - violation of relaxation	12 Months After Treatment.
Secondary	Distance Traveled in the 6-minute Walk Test. Test Results With 6 Minute Walk	The dynamic of the number of meters walked according to the 6-minutes walk test (6MWD) in the observation groups.	initially and after 12 months
Secondary	The Number of Functioning Grafts 12 Months After CABG. Patency of Grafts Within a Specified Time of Treatment (Angiography).	According to the angiographic study.	up to 12 months
Secondary	Analysis of the Effect of Left Ventricular Diastolic Dysfunction on the Patency of the Grafts.	Echocardiographic data.	up to 12 months

External Links

•   Assessment of safety of additional transplantation of autologous bone marrow mononuclear cells in the combined treatment of coronary heart disease. Results from a randomized, blind, placebo-controlled trial (TAMIS).
•   Evaluation of the effectiveness of combined treatment of coronary heart disease - coronary artery bypass grafting, transplantation of autologous bone marrow mononuclear cells: a randomized, double-blind, placebo-controlled study.