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

Phase 1

Not yet recruiting

• Conditions: Myocardial Infarction
• Interventions: Biological: WJ-MSC cells implantation; Drug: CTSTMD PBS without WJ-MSC; Drug: Conventional drug therapy

• Registration Number: NCT03533153
• Lead Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2018-01-24
• Study First Submitted QC: 2018-05-09
• Study First Posted: 2018-05-23
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-18
• Last Update Posted: 2021-02-21
• Study Start: 2021-03-01
• Primary Completion: 2023-12-30
• Study Completion: 2025-12-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

1. Age between 18 and 75;
2. First performance of anterior acute ST-segment elevation myocardial infarction (STEMI), Killip grade 2 or below on admission;
3. Completing emergency percutaneous coronary intervention within 12h, with TIMI flow grade 0 or 1 (before stent implantation) and 3 (after stent implantation);
4. LVEF in echocardiography is 45% or below primary PCI.

Exclusion Criteria

1. Medical history of Q wave myocardial infarction, significant valve disease, pericarditis, pericardial tamponade, myocardiopathy, chronic heart failure or cardio embolism;
2. Non ST-segment elevation myocardial infarction;
3. Chronic occlusion in LCX or RCA besides LAD;
4. Diagnosed with severe coronary artery disease but not yet causing a loss of heart function;
5. Hemodynamic disorders, shock or respiratory failure on admission;
6. Atrial fibrillation with warfarin treatment only or at high risk of bleeding;
7. Constant tachycardia, malignant arrhythmia, complete atrioventricular block, new-onset complete left bundle branch block (LBBB) or pacemaker implantation;
8. 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;
9. Chronic pulmonary heart disease (COPD, bronchial asthma, chronic bronchitis, emphysema or pulmonary heart disease), autoimmune disease or patients on immunosuppressive therapy;
10. Acute infective disease;
11. Hepatitis B/C virus or HIV;
12. Blood system diseases (thrombocytopenia, severe anemia, leukemia, etc.);
13. Severe renal insufficiency, with creatinine clearance (CCr) <33 ml/min or serum creatinine >133 μmol/L;
14. Obvious abnormalities in liver function (ALT and AST 3 times higher than the upper limit of normal value);
15. Medical history of cerebral hemorrhage;
16. Medical history of the malignant tumor;
17. Cognitive impairment, dementia or severe mental illness (SMI);
18. Substantial disability negatively influenced regular follow-up research;
19. Systematic diseases not been effectively controlled or life expectancy < 1 year;
20. Pregnant or lactating women;
21. Not suitable for MRI examination, or could not stick to treatment plans;
22. Could not or not willing to give written informed consent.

Exit Criteria:

1. Intolerable infaust events or changed treatment strategy leading to serious violations of trial conduct;
2. Requiring to exit the clinical trial;
3. Research scheme violations, severely disrupted safety and effectiveness of the trail;
4. Lost to follow-up cases;
5. Conceiving children or want to do that during the treatment period;
6. Candidates not fit to carry on the trial.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
WJ-MSC cells implantation group	WJ-MSC cells implantation	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".
WJ-MSC cells implantation group	Conventional drug therapy	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".
CTSTMD PBS without WJ-MSC group	CTSTMD PBS without WJ-MSC	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".
CTSTMD PBS without WJ-MSC group	Conventional drug therapy	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".

Primary Outcome Measures

Name	Time	Method
IS	at Month 3 after treatment.	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.

Secondary Outcome Measures

Name	Time	Method
MVO and Hemorrhage	at Day 4 to Day 7 after PCI.	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.
CMR Markers of Myocardial and Microvascular Damage	at Month 3 after PCI.	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.
Serum BNP	at Hour 7, Month 1, Month 6 and Year 1 after PCI.	Changes in patients' serum BNP level would be tested at Hour 7, Month 1, Month 6 and Year 1 after treatment.
MACCE	within 1 year after PCI.	Follow up main adverse cardiovascular and cerebrovascular events (MACCE) such as death, myocardial infarction, stroke and heart failure within 1 year after treatment.
CK-MB and Troponin	at baseline and at Hour 6, Hour 12, Hour 24 and Hour 48 after PCI.	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
Echocardiographic Changes	at Hour 6, Week 1, Month 1, Month 6 and Year 1 after PCI.	Changes in echocardiography would be tested at Hour 6, Week 1, Month 1, Month 6 and Year 1 after treatment.
6-min Walk Test	at Hour 6, Week1, Month 1, Month 6 and Year 1 after PCI.	Changes in 6-min walk test would be tested at Hour 6, Week1, Month 1, Month 6 and Year 1 after treatment.
MLHFQ Scale	at Week1, Month 1, Month 6 and Year 1 after PCI.	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.