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

Primary Purpose

Myocardial Infarction

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
WJ-MSC cells implantation
CTSTMD PBS without WJ-MSC
Conventional drug therapy
Sponsored by
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myocardial Infarction focused on measuring MSC

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    WJ-MSC cells implantation group

    CTSTMD PBS without WJ-MSC group

    Arm Description

    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".

    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".

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    MACCE
    Follow up main adverse cardiovascular and cerebrovascular events (MACCE) such as death, myocardial infarction, stroke and heart failure within 1 year after treatment.
    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.
    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.
    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
    Echocardiographic Changes
    Changes in echocardiography would be tested at Hour 6, Week 1, Month 1, Month 6 and Year 1 after treatment.
    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.
    Serum BNP
    Changes in patients' serum BNP level would be tested at Hour 7, Month 1, Month 6 and Year 1 after treatment.
    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.

    Full Information

    First Posted
    January 24, 2018
    Last Updated
    February 18, 2021
    Sponsor
    The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03533153
    Brief Title
    Intravenous MSC Therapy on Ischemia-Reperfusion Injury in Patients With Myocardial Infarction
    Official Title
    Clinical Study on Ischemia-Reperfusion Injury Using Intravenous Administration of MSC in Patients With Myocardial Infarction Intended to Improve MVO and Prognosis After Surgery
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    February 2021
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    March 1, 2021 (Anticipated)
    Primary Completion Date
    December 30, 2023 (Anticipated)
    Study Completion Date
    December 30, 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Myocardial Infarction
    Keywords
    MSC

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    Participant
    Allocation
    Randomized
    Enrollment
    90 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    WJ-MSC cells implantation group
    Arm Type
    Experimental
    Arm Description
    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".
    Arm Title
    CTSTMD PBS without WJ-MSC group
    Arm Type
    Placebo Comparator
    Arm Description
    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".
    Intervention Type
    Biological
    Intervention Name(s)
    WJ-MSC cells implantation
    Other Intervention Name(s)
    WJ-MSC
    Intervention Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    CTSTMD PBS without WJ-MSC
    Other Intervention Name(s)
    CTSTMD PBS
    Intervention Description
    For Case-control study only.
    Intervention Type
    Drug
    Intervention Name(s)
    Conventional drug therapy
    Other Intervention Name(s)
    Conventional
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    IS
    Description
    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.
    Time Frame
    at Month 3 after treatment.
    Secondary Outcome Measure Information:
    Title
    MACCE
    Description
    Follow up main adverse cardiovascular and cerebrovascular events (MACCE) such as death, myocardial infarction, stroke and heart failure within 1 year after treatment.
    Time Frame
    within 1 year after PCI.
    Title
    MVO and Hemorrhage
    Description
    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.
    Time Frame
    at Day 4 to Day 7 after PCI.
    Title
    CMR Markers of Myocardial and Microvascular Damage
    Description
    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.
    Time Frame
    at Month 3 after PCI.
    Title
    CK-MB and Troponin
    Description
    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
    Time Frame
    at baseline and at Hour 6, Hour 12, Hour 24 and Hour 48 after PCI.
    Title
    Echocardiographic Changes
    Description
    Changes in echocardiography would be tested at Hour 6, Week 1, Month 1, Month 6 and Year 1 after treatment.
    Time Frame
    at Hour 6, Week 1, Month 1, Month 6 and Year 1 after PCI.
    Title
    6-min Walk Test
    Description
    Changes in 6-min walk test would be tested at Hour 6, Week1, Month 1, Month 6 and Year 1 after treatment.
    Time Frame
    at Hour 6, Week1, Month 1, Month 6 and Year 1 after PCI.
    Title
    Serum BNP
    Description
    Changes in patients' serum BNP level would be tested at Hour 7, Month 1, Month 6 and Year 1 after treatment.
    Time Frame
    at Hour 7, Month 1, Month 6 and Year 1 after PCI.
    Title
    MLHFQ Scale
    Description
    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.
    Time Frame
    at Week1, Month 1, Month 6 and Year 1 after PCI.

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    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.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    ZILUN WEI, PGT
    Phone
    86-18066045583
    Email
    ljdwdth@outlook.com
    First Name & Middle Initial & Last Name or Official Title & Degree
    JUN XIE, Ph.D.
    Phone
    86-13913859989
    Email
    darcy_pann@hotmail.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    BIAO XU, Ph.D.
    Organizational Affiliation
    Drum Tower Hospital, Nanjing University Medical School
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    We have not decided to make it open.
    Citations:
    PubMed Identifier
    28728654
    Citation
    Ahn JM, Park DW, Lee CW, Chang M, Cavalcante R, Sotomi Y, Onuma Y, Tenekecioglu E, Han M, Lee PH, Kang SJ, Lee SW, Kim YH, Park SW, Serruys PW, Park SJ. Comparison of Stenting Versus Bypass Surgery According to the Completeness of Revascularization in Severe Coronary Artery Disease: Patient-Level Pooled Analysis of the SYNTAX, PRECOMBAT, and BEST Trials. JACC Cardiovasc Interv. 2017 Jul 24;10(14):1415-1424. doi: 10.1016/j.jcin.2017.04.037.
    Results Reference
    background
    PubMed Identifier
    28823746
    Citation
    Symons R, Pontone G, Schwitter J, Francone M, Iglesias JF, Barison A, Zalewski J, de Luca L, Degrauwe S, Claus P, Guglielmo M, Nessler J, Carbone I, Ferro G, Durak M, Magistrelli P, Lo Presti A, Aquaro GD, Eeckhout E, Roguelov C, Andreini D, Vogt P, Guaricci AI, Mushtaq S, Lorenzoni V, Muller O, Desmet W, Agati L, Janssens S, Bogaert J, Masci PG. Long-Term Incremental Prognostic Value of Cardiovascular Magnetic Resonance After ST-Segment Elevation Myocardial Infarction: A Study of the Collaborative Registry on CMR in STEMI. JACC Cardiovasc Imaging. 2018 Jun;11(6):813-825. doi: 10.1016/j.jcmg.2017.05.023. Epub 2017 Aug 16.
    Results Reference
    background
    PubMed Identifier
    24135835
    Citation
    Cuculi F, Dall'Armellina E, Manlhiot C, De Caterina AR, Colyer S, Ferreira V, Morovat A, Prendergast BD, Forfar JC, Alp NJ, Choudhury RP, Neubauer S, Channon KM, Banning AP, Kharbanda RK. Early change in invasive measures of microvascular function can predict myocardial recovery following PCI for ST-elevation myocardial infarction. Eur Heart J. 2014 Aug 1;35(29):1971-80. doi: 10.1093/eurheartj/eht434. Epub 2013 Oct 17.
    Results Reference
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    PubMed Identifier
    23594591
    Citation
    Robbers LF, Eerenberg ES, Teunissen PF, Jansen MF, Hollander MR, Horrevoets AJ, Knaapen P, Nijveldt R, Heymans MW, Levi MM, van Rossum AC, Niessen HW, Marcu CB, Beek AM, van Royen N. Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur Heart J. 2013 Aug;34(30):2346-53. doi: 10.1093/eurheartj/eht100. Epub 2013 Apr 17.
    Results Reference
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    Intravenous MSC Therapy on Ischemia-Reperfusion Injury in Patients With Myocardial Infarction

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