| 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 | 18.1 |
| 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 (LAD). |
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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 on left ventricular remodelling, microvascular obstruction, and the relationship between time from onset of ischemic symptoms to primary percutaneous coronary intervention.
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 acute AMI (pain, etc.) for 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 in 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 in a maximum of 12 hours of onset of symptoms
And:
Occlusion or flow limiting lesion with TIMI Flow Grade 0 or 1 in the left anterior descending (LAD) coronary artery
5. Successful revascularization of the culprit lesion in the LAD within a maximum of 12 hours from the onset of AMI symptoms defined as (1) primary percutaneous coronary intervention (PCI) with stent implantation, resulting in TIMI 3 or 2 flow AND (2) residual stenosis of less than 20% by on-line QCA.
NOTE: Subject is eligible if in addition to requiring a primary PCI plus stenting for the culprit lesion they have a stenosis of the LAD that is both distinct from the culprit lesion and requires PCI at the time of the index cardiac catheterization procedure. For example, if the culprit lesion is in the mid LAD but there is also a high-grade first diagonal (D1) stenosis, then the latter lesion may undergo PCI (plus stenting) during the index catheterization This specifically excludes patients who may require a PCI to a non-LAD coronary artery during the index catheterization.
6. If a female subject is of childbearing potential (i.e. not amenorrheic for 12 or more months and/or not surgically sterile), the subject must be willing to use highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device [IUD] or intrauterine system [IUS], condom occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence)) for at least 16 weeks after investigational agent infusion.
7. 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 or aortic valve regurgitation 3/4 classification as defined by ESC/ACC guidelines).
3. Unsuccessful revascularization of culprit artery defined as TIMI 1 or 0 flow or residual diameter stenosis of ≥ 20% by on line QCA analysis.
4. 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 infusion with the investigational agent. EXCEPT: Patients who present at the index catheterization with a need for a staged PCI of a non-LAD coronary artery will be eligible if:
-The staged PCI vessel does not have important collaterals to the LAD, and
-Agreement from the PI that the staged PCI can be safely scheduled after the day 30 cMRI has been determined by the Core cMR Imaging Laboratory to satisfy quality-control criteria
5. 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
6. Prior coronary artery bypass graft to LAD.
7. History of persistent atrial fibrillation.
8. Prior PCI involving the LAD.
9. Malignancy within last 3 years from screening. The subject has had an active malignancy, within the past 3 years except for cervical carcinoma in situ, or non-melanoma skin cancer that has been definitively treated.
10. Acute or chronic bacterial or viral infectious disease.
11. Pacemaker, ICD or any other contraindication for cMRI. This is inclusive of patients with an MRI compatible device that was implanted prior to the potential qualifying event.
12. Known history of severe chronic obstructive pulmonary Disease (Forced Expiratory Volume (FEV1) <35% in 1 second).
13. Known glomerular filtration rate (GFR) of less than 30 mL/min at study entry.
14. Known history of sensitization to human leukocyte antigens (such as via pregnancy, transfusions or organ transplant).
15. Known hypersensitivity to any radiographic contrast.
16. Known hypersensitivity to DMSO, murine proteins, bovine proteins, acetylsalicylic acid (ASA), clopidogrel, prasugrel, and/or metallic stents.
17. Prior or current participation in any bone marrow derived autologous and allogeneic stem cell or gene therapy study.
18. Prior participation in any other investigational drug trial in the past 30 days.
19. Pregnant or lactating women.
20. Intent to participate in any other investigational drug, cell or gene therapy study during the 2-year follow-up period of this study.
21. 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) |
Feasibility of the infusion of the investigational agent will monitored by measurement of TIMI flow and perfusion measurements prior to, during (after approximately 50% of total investigational agent volume infused) and following the investigational agent infusion after successful PCI and stenting.
The primary safety analysis will be performed on the following safety and feasibility parameters up to 30 days post-treatment:
- TIMI flow prior to, during (approximately 50% of total investigational agent volume infused) and following the investigational agent infusion after successful PCI.
- Serious adverse event (SAE)/adverse event (AE) rates.
- 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, and temperature.
The primary efficacy endpoint is the change in left ventricular end-systolic volume (LVESV) as assessed by cardiac MRI from baseline to 6 months post investigational agent infusion in each MPC treatment group compared with the Placebo group.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary safety analysis will be assessed at 30 days post-treatment.
The primary efficacy endpoint will be assessed at 6 months post treatment. |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
•The change in LVESV as assessed by 2D-echocardiography from baseline to 6 months post investigational agent infusion.
•The change in relative infarct size as assessed by late contrast enhancement MRI (% infarct volume/total LV tissue volume) from baseline to 6 months post investigational agent infusion
•Additional functional efficacy endpoints will be assessed with the following diagnostic studies:
• Cardiac MRI at 2-4 and 30 days, month 6 and 24
- LVEF
- LV-ESV
- LVEDV
- Left ventricular wall thickness and thickening in all segments including infarct area
- Regional wall motion score
- Myocardial MVO measured as reduced signal intensity in the region of interest
- Myocardial salvage index
• 2D echocardiogram at 2-4 and 30 days, months 6, 12 and 24
- LVEF
- Cardiac dimensions (LVESD/ LVEDD)
- Regional wall motion score index
•If neither MPC arm is found to be better than the placebo arm and there is no difference between the MPC groups (using the ANCOVA test with alpha=.1) in the effect on LVESV then the pooled MPC group will be compared to the placebo group for all functional parameters.
•In addition, a subset analysis will be evaluated at the following ischemia duration time points:
≤2 hours
>2 hours to ≤6 hours
>6 to ≤12 hours
• NT-Pro-BNP serum levels (as measurement ofbiomarker for heart failure) at baseline, days 2-4 and 30 and months 3, 6, 12, and 24
• Score changes for TIMI Flow Grade and Perfusion assessments at the following day 0 time points:
- pre-PCI,
- immediately post-PCI,
- after approximately 50% of intracoronary infusion of investigational agent,
- at completion of intracoronary infusion of investigational agent.
Safety endpoints:
Serious adverse events (SAEs) / adverse events (AEs) rates
- Occurrence of MACCE including:
o Cardiovascular death,
o Non-fatal myocardial infarction
o Non-fatal stroke
o Cardiac hospitalization due to heart failure
- Target vessel (or other vessel) revascularization, post index cardiac catheterization and new or worsening heart failure during the index hospitalizationwill be tracked as “Adverse Events of Special Interest”.
- Total number of subjects with documented ventricular arrhythmia (sustained and non-sustained VT/VF) throughout the study period.
- 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.
- TIMI flow and perfusion measurements following intracoronary infusion of the MPC cell solution compared with placebo.
- Physical examinations, monitoring of vital signs (heart rate, respiratory rate, BP, and oral temperature
- Results of clinical laboratory tests (hematology, serum chemistry, inflammatory markers), and immunogenicity assays; (flow cytometry Class I and Class II HLA percent reactivity % 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 and 30 days, month 6 and 24
• 2D echocardiogram at 2-4 and 30 days, months 6, 12 and 24
•Subset analysis will be evaluated at the following ischemia duration time points:
≤2 hours
>2 hours to ≤6 hours
>6 to ≤12 hours
• NT-Pro-BNP serum levels (as measurement ofbiomarker for heart failure) at baseline, days 2-4 and 30 and months 3, 6, 12, and 24
• Score changes for TIMI Flow Grade and Perfusion assessments.
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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| Portugal |
| Spain |
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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