A prospective, double blind, randomized, placebo-controlled clinical trial of intracoronary
infusion of immunoselected, bone marrow-derived Stro3 mesenchymal precursor cells (MPC) in
the treatment of patients with ST-elevation myocardial infarction

Healing of an MI is complicated by the need for viable myocytes at the
peri-infarct margin to undergo compensatory hypertrophy in order to increase
pump function in response to the loss of infarcted tissue. This initiates a
process termed *cardiac remodeling,* which is characterized by apoptotic loss
of hypertrophied myocytes, expansion of the initial infarct area, progressive
collagen replacement, that collectively result in the development of heart
failure. The Sponsor has recently advanced the hypothesis that hypertrophied
cardiac myocytes undergo apoptosis because the endogenous capillary network
cannot provide the compensatory increase in perfusion required for cell
survival. Vascular network formation is the end result of a complex process
that begins in the prenatal period with induction of vasculogenesis. Cells that
can differentiate into endothelial and smooth muscle elements also exist in
adult bone marrow12-14 and can induce vasculogenesis in ischemic tissues. The
Sponsor has identified a specific population of MPCs derived from human adult
bone marrow which has phenotypic and functional characteristics of vascular
pericyte precursor cells that provide the building blocks necessary for
arteriogenesis. Since recent observations
have suggested that a second compensatory response of viable cardiomyocytes is
to proliferate and regenerate following injury. It is theoretically possible
that further increase in the infarct bed capillary network through regulated
neovascularization could result in increased regenerative capacity of the heart
leading to improvement in myocardial function. Administration of MPCs resulted
in significant improvement in several key parameters of myocardial function in
rodents following AMI. In particular, epicardial injection of MPCs resulted in
a dose-dependent arteriogenesis at the infarct border zone. This arteriogenesis
was coupled with echocardiographic improvement in EF as well as restoration of
near normal contractility and LV end-diastolic pressure. Additionally, MPCs
have been shown to secrete cytokines in a paracrine manner that could augment
their direct trans differentiation potential. The use of the *off-the-shelf*
allogeneic MPCs derived from healthy donors with the Sponsor*s proprietary
process requires no cell culture and can be infused directly following
recanulation of the involved artery and reperfusion of the infarcted tissue
during a time period of myocardial infarction. The use of allogeneic donor
cells obviates the need for second catheterization, hospitalization or
anesthetic for treatment. Therapy can be provided without the delay,
necessitated by days or weeks of cell culture, commonly observed with the use
of mesenchymal stem cells obtained from bone marrow.
Furthermore, the Sponsor has demonstrated, in clinical trials using allogeneic
MPCs, that the therapy is safe and potentially effective in restoring cardiac
function. This study will, for the first time, investigate the use of
intra-coronary delivery of an allogeneic mesenchymal stem cell product in a
subject demographic undergoing standard of care percutaneous coronary
intervention following AMI.
By combining an allogeneic, off-the-shelf, cell-based therapy, with
intracoronary delivery, the Sponsor seeks to investigate a treatment that aims
to limit the progression of heart failure and increase overall survival and
quality of life.

Primary Objective:
• To determine the safety and feasibility of intracoronary allogeneic,
immuno-selected, bone marrow-derived Stro3 MPC delivery in the treatment of
subjects with STEMI undergoing PCI of the LAD coronary artery.
Secondary Objectives:
• To explore a dose-response effect of intracoronary delivered MPC in the
treatment of subjects with an anterior wall STEMI on LV remodelling,
microvascular obstruction, and the relationship between time from onset of
ischemic symptoms to primary PCI.
• To determine the effect of intracoronary delivery of allogeneic
immunoselected, bone marrow-derived MPC, on infarct size reduction in the
treatment of subjects with STEMI undergoing primary PCI of the LAD coronary
artery.
• To explore additional functional and clinical effects of MPC in STEMI.

This is a Phase 2, prospective, double-blind, randomized, placebo-controlled,
dose finding study that will enroll approximately 105 subjects with de novo
anterior STEMI due to a lesion involving the left anterior descending (LAD)
coronary artery who undergo primary PCI at approximately 25 clinical study
sites.
The study will enroll three parallel treatment arms of 35 subjects each, as
follows:
- Intracoronary infusion of 12.5 x10^6 MPCs suspended in 100 mL 0.9% saline
- Intracoronary infusion of 25 x 10^6 MPCs suspended in 100 mL 0.9% saline
- Intracoronary infusion of 100 mL 0.9% saline (placebo control treatment).
Potential subjects will be approached by the site investigator and provided
first with an informed consent form for signature. Following successful and
uneventful PCI, the subjects will be randomized.
Once the subject has been randomized, the stented left anterior descending
artery supplying the area of the heart with the infarction will be infused with
either the saline placebo solution or the allogeneic MPC( RevascorTM) product
via an approved percutaneous infusion microcatheter (e.g. Twin Pass).
The subjects randomized to MPCs will be infused at an infusion rate of 2 ml/min
over a 50 min period (2.5x10^5 MPCs/min (12.5 M), 5.0x10^5 MPCs/min (25 M)).
The subjects randomized to placebo will be infused placebo solution at 2 mL/min
over a 50 min period (0 MPCs/min). The MPC product (12.5M and 25M MPCs) and the
placebo solution will be diluted in 100mL 0.9% saline prior to infusion.
The Sponsor will provide all sites with blinded treatment bags, which contain
the different doses of MPCs or placebo solution.
An intracoronary (IC) bolus of glyceryl trinitrate (GTN)/ nitroglycerin (NTG)
(100-200 mcg) should be administered (blood pressure permitting) prior to the
initial infusion of the investigational agent. Additionally, a similar dose of
intracoronary GTN (NTG) should be given prior to TIMI flow assessment during
the investigational agent infusion period as well as after completion of the
investigational agent infusion and immediately prior to the final coronary
angiographic imaging.
After approximately 50% of the intracoronary infusion of investigational agent
has been completed, an angiographic determination of coronary flow will be
performed. The remaining investigational agent should be infused if either TIMI
2 or TIMI 3 flow is present and ALL of the following are absent:
o Sustained hypotension not responsive to fluid administration;
o Clinical signs/symptoms indicating an acute cerebrovascular event;
o Re-elevation of ST-segments if previously resolved with PCI;
o Onset of the subject*s symptoms of myocardial ischemia unresponsive to
appropriate interventions;
o Two episodes of sustained ventricular tachycardia (VT)/ventricular
fibrillation (VF) requiring cardioversion (infusion can continue if a single
episode of sustained VT/VF requiring cardioversion occurred).
If for any reason, the site investigator withdraws a randomized subject prior
to infusion of the investigational agent, the reason for early termination and
date from the screening visit will be entered into the eCRF by the study site.
The subject will not remain in the study. If for any reason, a subject*s study
infusion is halted due to safety considerations, the subject will remain in the
study. A subject who prematurely withdraws from the study, post-study infusion
will remain in the study. All subjects will undergo cardiac imaging and
functional studies, clinical evaluations, and laboratory testing.
An independent Data Safety and Monitoring Board (DSMB) will review all relevant
acute periprocedural data, serious adverse events, other adverse events, and
efficacy data (if requested) periodically dependent on subject enrollment, and
advise the Executive Steering Committee (ESC) regarding the progression of the
study. An ESC will oversee all aspects of the study. The ESC will consist of
the Principal Investigator, site investigators and representatives from the
Sponsor.
A Clinical Events Committee (CEC) will review appropriate source documents and
adjudicate (blinded per a priori procedure) all MACCE (Major adverse cardiac
and cerebrovascular events) defined as cardiovascular death, non-fatal
myocardial infarction, non-fatal stroke, or 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
hospitalization will be tracked as "Adverse Events of Special Interest" rather
than MACCE.
The investigators, subjects, and sponsor will remain blinded for study
allocation of the individual subjects for the duration of the study (24
months). The DSMB may choose to be unblinded. The DSMB safety reviews to assess
the frequency of total major adverse cardiac and cerebrovascular events
(MACCE), which will be performed after the initial 15, 30, 60, and 90 subjects
have been observed at Day 30 post the index cardiac catheterization.

Intracoronary infusion of Stro-3 mesenchymal precursor cells after
revascularisation of the culprit coronary artery

There are certain known and expected risks associated with products that are
used in the production of RevascorTM as well as expected risks with cardiac
catheterization, cMRI, echocardiography, and blood draws. These risks are
detailed in the sections that follow.

Reaction to Fetal Calf Serum or Murine Mouse Antibody: For immunoselection of
the allogeneic MPCs, the technology incorporates an antibody based sorting
process using murine derived antihuman antibody. In the cell expansion process,
fetal calf serum is used. It is based on these 2 processes that subjects with
known hypersensitivity to murine and/or bovine products are excluded from study
participation. Acceptable study
candidates will be required to undergo serum collection and monitoring for the
potential development of antimurine antibodies and antibovine antibodies,
respectively, and they will be monitored for the clinical significance of these
antibodies, if any. The risk of sensitization from
this formulation is unknown, but expected to be extremely rare. If
sensitization occurs, subsequent therapies containing bovine or murine products
may not be made available to study subjects.

Reaction to Dimethyl Sulfoxide
Dimethyl sulfoxide 7.5% is used as part of the RevascorTM cryopreservation
process. The therapeutic and toxic effects of DMSO include its own rapid
penetration and enhanced penetration of other substances across biologic
membranes, free radical scavenging, and effects on coagulation,
anticholinesterase activity, and DMSO-induced histamine release by mast cells.
The systemic toxicity of DMSO is considered to be low. The DMSO exposure in
this therapy is minimal and is locally applied. Subjects with known
hypersensitivity to DMSO will be excluded
from the study.

Potential Cell Contamination
RevascorTM is an allogeneic, immunoselected, ex vivo expanded cell product,
which has the potential to become contaminated and subsequently cause infection
in the study subject at the time of surgical implantation. This risk is greatly
minimized by the use of a Good
Manufacturing Practice (GMP)-compliant production facility. Prior to the
release of RevascorTM from the GMP facility, rigorous screening tests for
multiple infections agents are performed in order to ensure that no
contaminated product is released for use. As with any blood or marrow derived
biological agent, infectious risks from unknown pathogens are possible.

Potential Inflammatory Responses
The administration of allogeneic MPCs may elicit immunogenic and/or
inflammatory responses resulting from allogeneic exposure to the donor cells
and/or manufacturing content. To date, no clinical signs or symptoms have been
associated with the development of antibodies to HLA, bovine, or murine
proteins. The risks of exposure are not fully known but there is a remote
potential risk that subsequent allogeneic transplant donor selection may be
limited in the presence of persistent, cross-match reactive anti-HLA
antibodies. Subjects will be monitored for these responses by performing
antibody screening tests to HLA, bovine, and murine antibodies at designated
follow-up visits.

Possible Effects of Cells on the Fetus
Because of potential or unknown side effects of the study on the fetus, if the
subject is a female of childbearing potential, the subject must have a negative
urine pregnancy test prior to study entry. In addition, females of
childbearing potential will be included in study participation
provided that she is 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 surgery.

Cardiac Catheterization and PCI
The risk of producing a major complication during cardiac catheterization is
reported well below 1%. Some of the potential complications during cardiac
catheterization may include death; MI; stroke and transient ischemic attack;
vascular complications including bleeding, hematoma, acute thrombosis, distal
embolization, pseudo aneurysm, arteriovenous fistula; arrhythmias; perforation
of the heart or great vessels; allergic reactions; atheroembolism; acute renal
failure; infection; radiation exposure. Potential complications related more
specifically to stenting can include failure of stent deployment and stent
thrombosis. The contrast agent injected during these procedures may create a
sensation of warmth and/or pain. Other adverse events experienced by <1% of
subjects include things such as hives, sneezing, coughing, hypotension,
hypertension, arrhythmias, anginal symptoms, shivers, collapse, anxiousness,
confusion, blurred vision, taste sensation, headache, fever and chills.

cMRI
The MRI scan itself is painless, but it may cause some people to feel
claustrophobic. There is a small risk of an allergic reaction to the contrast
agent. MR imaging may be performed with either dipyridamole or adenosine and
both cause coronary vasodilation therefore they can cause some transient side
effects. The most common side effects of dipyridamole administration are chest
discomfort and headache. The most common side effects of adenosine
administration are chest discomfort, headache, dyspnea, and flushing. In
addition nausea, low blood pressure, and rarely, heart block have been
experienced during adenosine administration.

Echocardiogram
Rarely, some subjects complain of discomfort to the skin where the ultrasound
probe is pressed against the chest by the technician.

Electrocardiogram
The actual procedure for the ECG is safe with no known side effects.
Occasionally there are complaints that the adhesive that the leads attach to
cause slight skin irritation.

Laboratory or Blood Work
The risks for blood drawing are rare but possible as described by the
following: pain at the needle insertion site, bleeding, bruising or a hematoma
at the needle entry site, damage to surrounding tissue or nerves, fainting,
nausea, and vomiting.
The total blood draw for this study is approximately 81 ml:
Baseline: 11 ml
Visit 3: 2 ml
Visit 4: 2 ml
Visit 5: 2 ml
Visit 6: 9 ml
Visit 7-12: 11 ml