E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ST-elevation myocardial infarction |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064345 |
E.1.2 | Term | ST segment elevation myocardial infarction |
E.1.2 | System Organ Class | 100000004849 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the safety and feasibility of intracoronary allogeneic, immuno-selected, bone marrow-derived Stro3 mesenchymal precursor cell (MPC) delivery in the treatment of subjects with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention of the left anterior descending coronary artery. |
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E.2.2 | Secondary objectives of the trial |
To determine the effect of intracoronary delivery of allogeneic immunoselected, bone marrow-derived Stro3 mesenchymal precursor cells (MPC) on infarct size reduction in the treatment of subjects with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention of the left anterior descending coronary artery.
To explore a dose-response effect of intracoronary delivered MPC in the treatment of subjects with an anterior wall STEMI.
To explore additional functional and clinical effects of MPC in STEMI.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects will be entered into this study only if they meet ALL of the following criteria:
1. Willing and able to understand and sign the Informed Consent Form (ICF).
2. Males or females ≥ 18 years.
3. Clinical symptoms consistent with AMI (pain, etc.) for a minimum of 2 and a maximum of 12 hours from onset of symptoms to percutaneous coronary intervention (PCI).
4. De novo anterior Acute Myocardial Infarct (AMI) defined as:
≥ 0.2 mV ST elevation in 2 or more V1 – V6 leads with presentation for a minimum of 2 hours and a maximum of 12 hours of onset of symptoms
Or:
Presumed new left bundle branch block with a minimum of 0.1 mV concordant ST elevation with presentation for a minimum of 2 hours and a maximum of 12 hours of onset of symptoms
And:
Occlusion or flow limiting lesion in the left anterior descending coronary artery
5. Successful revascularization of the culprit lesion in the LAD within 2-12 hours of the onset of AMI symptoms defined as (1) primary percutaneous coronary intervention (PCI) with stent implantation, resulting in TIMI 3 flow AND (2) residual stenosis of less than 20% by on-line QCA.
6. If a female subject is of childbearing potential (not amenorrheic for the previous 24 months or not surgically sterile), the subject must be willing to use adequate contraception (hormonal pill, implant or intrauterine device, barrier methods only if used consistently) from the time of screening and for a period of at least 16 weeks after procedure.
7. Female subjects of childbearing potential (not amenorrheic for the previous 24 months or not surgically sterile) must have a negative urine pregnancy test at screening, prior to study intervention.
8. Must be willing and able to return for required follow-up visits.
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E.4 | Principal exclusion criteria |
Subjects will not be enrolled into this study if they meet ANY of the following criteria:
1. Prior MI, known cardiomyopathy, or hospital admission for heart failure (HF)
2. Significant valvular disease (mitral of aortic valve regurgitation 3/4 classification as defined by ESC/ACC guidelines)
3. More than 12 hours between the onset of first symptoms of AMI and revascularization
4. Unsuccessful revascularization of culprit artery defined as less than TIMI 3 flow or residual diameter stenosis of 20% by on line QCA analysis
5. Need for staged treatment of coronary artery disease, or other interventional or surgical procedures to treat heart disease (e.g., valve replacement, PCI or CABG) planned or scheduled within 6 months after the study procedure
6. Cardiogenic shock or hemodynamic instability within 24 hours prior to randomization,
defined as the presence of any of the following:
• Systolic blood pressure <80 mmHg lasting for more than 30 minutes
• Heart rate >120 bpm for more than 1 hour
7. Prior coronary artery bypass graft to LAD
8. History of persistent atrial fibrillation
9. Prior PCI to LAD
10. Malignancy within last 3 years from screening. The subject has had an active malignancy, within the past 3 years except for localized prostate cancer treated with hormone therapy or radiation therapy, cervical carcinoma in situ, breast cancer in situ, or non-melanoma skin cancer that has been definitively treated
11. Acute or chronic bacterial or viral infectious disease
12. Pacemaker, ICD or any other contra-indication for cMRI
13. Known history of severe chronic obstructive pulmonary Disease (Forced Expiratory Volume (FEV1) <35% in 1 second).
14. Known history of sensitization to human leukocyte antigens
15. Known hypersensitivity to DMSO, murine proteins, bovine proteins, aspirin, clopidogrel, prasugrel, and/or metallic stents
16. Prior or current participation in any stem cell study or any other investigational trial in the past 30 days.
17. Pregnant or lactating women
18. Intent to participate in any other investigational drug or cell therapy study during the 2-year follow-up period of this study
19. Any concurrent disease or condition that, in the opinion of the investigator, would make the subject unsuitable for participation in the study
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change in relative infarct size as assessed by late gadolinium enhancement (LGE) MRI (% infarct volume/total left ventricle [LV] tissue volume).
The primary safety analysis will be performed on the following safety and feasibility parameters:
• TIMI flow prior to, during and following the MPC infusion after successful PCI.
• Coronary flow reserve assessment prior to and following the completion of MPC infusion.
• Serious adverse event (SAE)/adverse event (AE) rates. AEs of special interest will
include cardiac arrhythmias and allergic reactions
• Results of clinical laboratory tests (including hematology, serum chemistry,
inflammatory markers, flow cytometry anti-HLA Class I and Class II percent reactivity with specificity, antibovine and antimurine antibody analysis)
• Infusion procedure monitoring of vital signs (heart rate, respiratory rate, BP, temperature, and O2 saturation
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The Primary efficacy endpoint will be assessed at 6 months post treatment.
The primary safety analysis will be assessed at 30 days post-treatment.
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Cardiac MRI:
o LVEF
o LV-ESV
o LV-EDV
o Left ventricular wall thickness and thickening in all segments including infarct area
o Regional wall motion score
o MI size measured in area of MPC distribution (late enhancement)
o Myocardial salvage index
• MIBI-SPECT:
o Perfusion defect (at rest)
o LVEF
o LV-ESV
o LV-EDV
• 2D echocardiogram:
o LVEF
o Cardiac dimensions (LVESD/ LVEDD)
o Regional wall motion score index
o Regional wall thickness
• BNP serum levels (as measurement of heart failure)
• Score changes in the Medical Outcome Study Short Form (SF-36), and the Seattle Angina Questionnaire
Safety endpoints:
• Serious adverse events (SAEs) / adverse events (AEs)
• Occurrence of MACCE including cardiac death, myocardial infarction, target vessel revascularization, stroke, new or worsening congestive heart failure during index hospitalization and cardiac hospitalizations due to congestive heart failure.
• Total number of patients with documented ventricular arrhythmia (sustained and non-sustained VT/VF)
• Angina pectoris as defined by Canadian Cardiovascular Society (CCS) clinical clarification
• New York Heart Association (NYHA) Class
• Telemetry/48 hour Holter monitoring (during hospital admission and at 14 and 30 days, 3 and 6 months follow-up time points) with assessment of occurrence of ventricular arrhythmia
• CFR and TIMI flow following intracoronary infusion of the MPC cell solution compared with placebo
• Physical examinations, monitoring of vital signs (heart rate, respiratory rate, BP, temperature, and O2 saturation)
• Results of clinical laboratory tests (hematology, serum chemistry, inflammatory markers, flow cytometry Class I and Class II PRA % with specificity, antibovine and antimurine antibody analysis)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Endpoints:
• Cardiac MRI at 2-4 days, 6, 12 and 24 months.
• MIBI-SPECT at 2-4 days, 6, 12 and 24 months.
• 2D echocardiogram at 2-4 days, 6, 12 and 24 months.
• BNP serum levels at baseline, day 30 and 3, 6, 12, and 24 months.
• Score changes in SF-36 and the Seattle Angina Questionnaire at 30 days, and 3, 6, 12, and 24 months.
Safety endpoints:
Up to 24 months post-treatment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Czech Republic |
Denmark |
Netherlands |
New Zealand |
Poland |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |