Evaluation of the Safety and Efficacy of Using Insulin-like Growth Factor-1 in Patients With a Heart Attack (RESUS-AMI)

There are currently over 3 million ST-elevation myocardial infarcts (STEMIs)
worldwidei, approximately 20% of which progress to chronic heart failure (HF)
contributing enormous human cost in terms of morbidity and mortality and
substantial economic cost in terms of long term care. Reduction in infarct size
after STEMI remains an untouched treatment frontier. Improvement in left
ventricular ejection fraction (LVEF) from less than 30% to greater than 35%
would obviate the need for automatic cardiac defibrillator implantation in
these patients, reducing health care costs significantly. Moreover the savings
in returning such patients to active lives and reducing subsequent hospital
admissions and chronic heart failure treatment may be estimated at 10 to 50
million euro/year in Ireland alone.ii
Insulin-like growth factor-1 (IGF-1) is a peptide similar in structure to
insulin and has been known for more than two decades as a key regulator of
cardiac structure. More recently key functions in cardiomyocyte homeostasis for
this growth factor have been described including promotion of growth,
inhibition of apoptosis and potentiation of calcium signaling. The most
intriguing cardiac function of IGF-1 from a therapeutic perspective remains its
prosurvival effect which is mediated in large part through the PI3kinase/Akt
signaling pathway. IGF-1 when produced locally in the heart is a potent cardiac
survival factor.iii In the circulation free IGF-1 accounts for approximately 1%
of the total IGF-1 which is predominantly bound in serum to insulin-like growth
factor binding proteins.iv The half life of injected IGF-1 is approximately 14
minutes in humans. Based on known signaling events associated with activation
of the IGF-1 receptor, the actions of IGF-1 on cells includes, inter alia,
effects on cell size, proliferation, apoptosis, glucose metabolism,
intracellular calcium regulation as well as contractility. IGF-1 pro-survival
signaling is complex but following receptor binding and phosphorylation insulin
receptor substrate is recruited, phosphorylated and subsequently PI3Kinase /Akt
activated which inhibits propapoptotic initiators such as Bad.v
There is evidence from human studies that relatively low circulating IGF-1
levels in patients post-myocardial infarct (MI) has an adverse effect on left
ventricular (LV) remodelling.vi The first uncontrolled clinical trial to
suggest positive IGF-1-like effects in HF patients involved administration of
human growth hormone (hGH) the tissue effects of which are mediated through
IGF-1.vii Subsequent randomised controlled trials however showed no sustained
benefit of hGF and indeed chronic administration was associated with a variety
of side effects including bone tenderness, arthralgias, edema, orthostatic
hypotension and tachycardia.viii Consequently interest in use of IGF-1 in
cardiac disease diminished.
Recently, Caplice et al have shown in a porcine model, a single low dose of
recombinant IGF-1 (600pg/animal) administered via the coronary artery 2hrs
after reperfusion of an acute MI had potent cardiac repair effects. At 30
minutes post IGF-1 therapy, IGF-1 receptor but not insulin receptor
phosphorylation was significantly augmented in the infarct border zone but not
the remote zone. This was associated with significant increase in
phosphorylation of Akt and Erk signaling pathways. Consistent with activation
of survival pathways in the infarct zone, apoptosis was also significantly
reduced in vivo by low dose IGF-1 compared to vehicle at 24 hours post infarct.
Acute low dose IGF-1 effects on cell survival were associated at 8 weeks with a
very significant decrease in infarct size and a marked improvement in end
systolic and end-diastolic volumes and systolic ejection fraction. These
salutary improvements in LV remodeling were confirmed by marked improvement in
wall motion and wall thickening abnormalities seen on CT in the IGF-1 treated
compared to the control treated animals (data unpublished). These data
underscore a hitherto unrecognized acute effect of low dose IGF-1 which may
have profound implications for cardiac repair post-MI

The primary objective of the study will be to evaluate two low doses of a
single intracoronary injection of rhIGF-1 compared with saline placebo on
global LVEF by cardiac MRI and for safety (hypoglycaemia) in select subjects
with STEMI and severe left ventricular dysfunction undergoing PCI.

This is a randomised, placebo-controlled, double-blind study to assess the
safety and efficacy of intracoronary recombinant human insulin-like growth
factor-1 (rhIGF-1) administered during percutaneous coronary intervention (PCI)
for ST-elevation myocardial infarction (STEMI). Subjects will be consented
prior to PCI and following successful reperfusion and stenting, 45 subjects
with TIMI 3 flow in the infarct related artery (IRA) and a left ventricular
ejection fraction (LVEF) <40% will be randomised 1:1:1 to a single
intracoronary injection of 1.5 ng or 15 ng rhIGF or saline placebo.
Randomisation will be stratified by presence of diabetes mellitus. Subjects
will undergo cardiac magnetic resonance imaging (MRI) and echocardiogram within
24 hours (baseline) of study drug administration to assess global LVEF. Phone
follow-up to assess for clinical and adverse events will occur at day 30.
Repeat cardiac MRI, echocardiogram and clinical and adverse event assessments
will occur at a Week 8 visit and repeat echocardiogram and clinical and adverse
event assessments will occur at Month 6 and Month 12 visits.

WHAT IS INVOLVED IN THE STUDY AND WHAT WILL I BE ASKED TO DO?
If you take part in this study, you will be asked to read and sign a consent
form. After you sign the consent form, the study procedures below will take
place:

* A member of the study team will ask you questions about your medical
history. Your medical record will be examined and your cardiologist may be
asked questions to collect data regarding your procedure and hospital stay.

* A brief physical examination of your heart, lungs, pulse and blood pressure
will be done.

* Women able to have children will have a urine or blood pregnancy test to see
if they are pregnant. Pregnant females are not allowed in the study.

* During your angioplasty procedure, if your consultant cardiologist has opened
the blocked artery that has caused your heart attack, he/she will check your
heart muscle function by injecting contrast into your heart chamber. This is a
standard procedure. If he/she determines that your heart muscle function is
weak and you meet all the other criteria for the study, you will be assigned to
receive either mecasermin (the study drug) at one of two doses or a placebo
infusion in the blocked artery over 30 seconds. You will have an equal chance
of receiving one of the three treatments. Neither your consultant nor study
team members will know which treatment you received however your consultant can
get this information if needed. If your heart muscle is not weak enough to
meet the criteria for the study, your participation is finished and no further
study tests will be done.

* A half hour and one hour after the procedure your blood will be drawn to
check your blood sugar. Other regular blood work may be drawn at the same time
to monitor your treatment for your heart attack. Your blood pressure and pulse
will be checked frequently for the first hour after your procedure.

* Within 24 hours of your procedure you will undergo a cardiac MRI and
echocardiogram (a heart ultrasound) to look at your heart function. The study
team will continue to review your medical records and ask you how you are
feeling during your hospital stay.

* Approximately 30 days after your procedure, a study team member will call you
at home to ask you about your health since your hospital stay.

* Eight weeks after your procedure you will have another cardiac MRI and
echocardiogram and a study member will ask you about your health.

* Six months and one year after your procedure you will have another
echocardiogram and a study member will ask you about your health.