Intravenous MSC Therapy on Ischemia-Reperfusion Injury in Patients With Myocardial Infarction

Study Overview
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Brief Summary
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The investigators scheduled to assess the value of intravenous injection of WJ-MSC in patients with ST-segment elevation myocardial infarction (STEMI).

Detailed Description
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Ischemia/reperfusion injury in myocardial infarction can induce mass release of oxygen free radicals, trigger inflammatory reaction, and ultimately lead to myocardial remodeling and irreversible cardiac function decline. Microvascular obstruction (MVO) and haemorrhage are common pathological alternations in myocardium post primary PCI, which provide strong prognostic information for STEMI patients. Till now, there is no treatment to be used in clinical practice to reduce myocardium MVO and haemorrhage. With the deep research on stem cells, it is found that the benefits of MSC transplants for myocardium infarction may be achieved by its paracrine effect. Meanwhile, the immunoregulatory effect of MSC has been widely reported in multiply immune disease. Therefore, the applicant proposed the hypothesis that MSC can play an effective role in reducing oxidative stress and inflammatory response, inhibiting microvascular obstruction and haemorrhage. Intravenous injection of MSC will be used in patients with STEMI within 12 hours post primary PCI. The primary endpoint and safety endpoint are recorded in the one year follow up to assess the clinical outcome of intravenous MSC treatment.

Official Title
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Clinical Study on Ischemia-Reperfusion Injury Using Intravenous Administration of MSC in Patients With Myocardial Infarction Intended to Improve MVO and Prognosis After Surgery

Conditions
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Myocardial Infarction

Intervention / Treatment
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* Biological: WJ-MSC cells implantation
* Drug: CTSTMD PBS without WJ-MSC
* Drug: Conventional drug therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 75; First performance of anterior acute ST-segment elevation myocardial infarction (STEMI), Killip grade 2 or below on admission; Completing emergency percutaneous coronary intervention within 12h, with TIMI flow grade 0 or 1 (before stent implantation) and 3 (after stent implantation); LVEF in echocardiography is 45% or below primary PCI. Exclusion Criteria: Medical history of Q wave myocardial infarction, significant valve disease, pericarditis, pericardial tamponade, myocardiopathy, chronic heart failure or cardio embolism; Non ST-segment elevation myocardial infarction; Chronic occlusion in LCX or RCA besides LAD; Diagnosed with severe coronary artery disease but not yet causing a loss of heart function; Hemodynamic disorders, shock or respiratory failure on admission; Atrial fibrillation with warfarin treatment only or at high risk of bleeding; Constant tachycardia, malignant arrhythmia, complete atrioventricular block, new-onset complete left bundle branch block (LBBB) or pacemaker implantation; Mechanical complications of acute myocardial infarction (interventricular septal defect, rupture of papillary muscle, etc.) or huge left ventricular aneurysm could only be corrected through surgical procedures; Chronic pulmonary heart disease (COPD, bronchial asthma, chronic bronchitis, emphysema or pulmonary heart disease), autoimmune disease or patients on immunosuppressive therapy; Acute infective disease; Hepatitis B/C virus or HIV; Blood system diseases (thrombocytopenia, severe anemia, leukemia, etc.); Severe renal insufficiency, with creatinine clearance (CCr) <33 ml/min or serum creatinine >133 μmol/L; Obvious abnormalities in liver function (ALT and AST 3 times higher than the upper limit of normal value); Medical history of cerebral hemorrhage; Medical history of the malignant tumor; Cognitive impairment, dementia or severe mental illness (SMI); Substantial disability negatively influenced regular follow-up research; Systematic diseases not been effectively controlled or life expectancy < 1 year; Pregnant or lactating women; Not suitable for MRI examination, or could not stick to treatment plans; Could not or not willing to give written informed consent. Exit Criteria: Intolerable infaust events or changed treatment strategy leading to serious violations of trial conduct; Requiring to exit the clinical trial; Research scheme violations, severely disrupted safety and effectiveness of the trail; Lost to follow-up cases; Conceiving children or want to do that during the treatment period; Candidates not fit to carry on the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WJ-MSC cells implantation group<br>MSC cells (allogeneic transplantation from WJ-MSC primary cells); the frequency: for one time within12h after emergency coronary artery revascularization; dose levels: 1X10^8; method of administration: intravenous injection. Other kinds of treatment are in accordance with the treatment guidelines for MI patients, listed in the column Conventional drug therapy. | Biological: WJ-MSC cells implantation<br>* Laboratory of Stem Cell of Drum Tower Hospital, Nanjing University Medical School, is able to provide types of Good Manufacture Practice (GMP) level stem cells and stem cell-based medicinal products. Clinical-grade WJ-MSC primary cells are cultured to 4  8 passages, and the surface markers (CD90+, CD105+, CD45-, CD31-, CD117-) are identified by flow cytometry. WJ-MSC cells are trypsinized and resuspended in the wash buffer of CTSTMD PBS (+Ca2+, +Mg2+). Within 2 hours after enzyme digestion, WJ-MSC cells are shipped to coronary care unit (CCU) and injected into the body.<br>* Other names: WJ-MSC;Drug: Conventional drug therapy<br>* All patients undergo guideline-recommended treatment for STEMI, including aspirin (loading dose of 300mg before maintenance dose of 100 mg/d), clopidogrel (loading dose of 300mg before maintenance dose of 75 mg/d) or Ticagrelor (loading dose of 300mg before maintenance dose of 90 mg/d), angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), β-receptor blockers, statins and nitrate esters.<br>* Other names: Conventional;|
| Placebo Comparator: CTSTMD PBS without WJ-MSC group<br>Saline only was injected in the control group. The frequency: for one time 2-12h after emergency coronary artery revascularization. Dose levels: the same dosage given to MSC group. Method of administration: intravenous injection. Other kinds of treatment are in accordance with the treatment guidelines for MI patients, listed in the column Conventional drug therapy. | Drug: CTSTMD PBS without WJ-MSC<br>* For Case-control study only.<br>* Other names: CTSTMD PBS;Drug: Conventional drug therapy<br>* All patients undergo guideline-recommended treatment for STEMI, including aspirin (loading dose of 300mg before maintenance dose of 100 mg/d), clopidogrel (loading dose of 300mg before maintenance dose of 75 mg/d) or Ticagrelor (loading dose of 300mg before maintenance dose of 90 mg/d), angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), β-receptor blockers, statins and nitrate esters.<br>* Other names: Conventional;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IS | The primary endpoint is based on patients' myocardial infarction size (IS) as a result of CMR examination. The detection is recorded in the follow up at Month 3. | at Month 3 after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACCE | Follow up main adverse cardiovascular and cerebrovascular events (MACCE) such as death, myocardial infarction, stroke and heart failure within 1 year after treatment. | within 1 year after PCI. | 
| MVO and Hemorrhage | Patients underwent cardiac magnetic resonance imaging (CMR) at Day 4 to Day 7 after presentation with STEMI on a 3.0-T scanner.The change in Microvascular obstruction (MVO) and intramyocardial hemorrhage would be followed up. MVO was defined (and quantified) as hypoenhancement within infarcted myocardium, as determined from LGE images, and was included in the total infarct size. Myocardial oedema was quantified using semi-automatic thresholding, defining AAR as enhancement within myocardium of signal intensity > 2 standard deviations (SDs) above that of a region of interest contoured in remote myocardium. Hypoenhanced areas within the AAR were regarded as intramyocardial haemorrhage (IMH). The MSI was calculated as 100 × [(AAR - infarct size)/AAR]. Infarct size, MVO, AAR and IMH were expressed as %LVM and LV volumes were indexed to body surface area. | at Day 4 to Day 7 after PCI. | 
| CMR Markers of Myocardial and Microvascular Damage | CMR markers of myocardial and microvascular damage (myocardial salvage, left ventricular end diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), microvascular obstruction (MVO), intramyocardial hemorrhage) would be followed up at Month 3 after treatment. | at Month 3 after PCI. | 
| CK-MB and Troponin | A sensitive troponin T assay for the early diagnosis and risk stratification of myocardial infarction would be evaluated. Blood samples were drawn at baseline and at Hour 6, Hour 12, Hour 24 and Hour 48 after PPCI for cardiac enzyme [creatine kinase MB isoenzyme (CK-MB) and troponin] estimation | at baseline and at Hour 6, Hour 12, Hour 24 and Hour 48 after PCI. | 
| Echocardiographic Changes | Changes in echocardiography would be tested at Hour 6, Week 1, Month 1, Month 6 and Year 1 after treatment. | at Hour 6, Week 1, Month 1, Month 6 and Year 1 after PCI. | 
| 6-min Walk Test | Changes in 6-min walk test would be tested at Hour 6, Week1, Month 1, Month 6 and Year 1 after treatment. | at Hour 6, Week1, Month 1, Month 6 and Year 1 after PCI. | 
| Serum BNP | Changes in patients' serum BNP level would be tested at Hour 7, Month 1, Month 6 and Year 1 after treatment. | at Hour 7, Month 1, Month 6 and Year 1 after PCI. | 
| MLHFQ Scale | Patients would be required to fill out the quality of life (QQL) scale Minnesota Living with Heart Failure Questionnaire (MLHFQ) at Week1, Month 1, Month 6 and Year 1 after treatment. | at Week1, Month 1, Month 6 and Year 1 after PCI. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSC