A randomized, double-blind, placebo-controlled, event-driven trial of quarterly subcutaneous canakinumab in the prevention of recurrent cardiovascular events among stable post-myocardial infarction patients with elevated hsCRP (CANTOS study, CACZ885M2301)

Atherosclerosis is a disease characterized by chronically high inflammatory
state. Inflammatory mediators are intimately implicated with the cascade of
events leading to atherosclerotic plaque initiation, progression and rupture.
Adverse conditions such as hyperlipidemia are associated with enrichment of a
pro-inflammatory subset of monocytes. Interleukins are key mediators in the
chronic vascular inflammatory response in cardiovascular disease. Lack of IL-1*
or ablation of IL-1 receptor has been shown to decrease severity of
atherosclerosis in apoE deficient mice. Thus, antagonism of the IL-1* mediated
inflammation is a primary and attractive target for ameliorating the vessel
wall inflammation associated with atherosclerosis.
Canakinumab (ACZ885) is a fully human monoclonal anti-human IL-1* antibody,
being developed for the treatment of IL-1* driven inflammatory diseases. It is
designed to bind to human IL-1* and thus blocks the interaction of this
cytokine with its receptors. The antagonism of the IL-1* mediated inflammation
using canakinumab in lowering high sensitivity C-reactive protein (hs-CRP, an
independent risk factor for future cardiovascular events) and other
inflammatory marker levels has shown an acute phase response in patients with
Cryopyrin-Associated Periodic Syndrome (CAPS) and rheumatoid arthritis. This
evidence has been replicated in patients with type 2 diabetes mellitus (T2DM).
Therefore, canakinumab is expected to reduce the risk of future occurrence of
major cardiovascular events in patients with recent past myocardial infarction
by preventing IL-1* mediated vascular wall inflammation and endothelial
dysfunction.
T2DM is also a disease that is characterized by a high inflammatory state.
Pre-clinical data suggests IL-1* is of key importance in the destruction of *-
cells in type 2 diabetes. IL-1* antagonism inhibits * cell death, promotes *
cell proliferation, potentiates * cell glucoseinduced insulin secretion and
improves insulin sensitivity. For T2DM prevention canakinumab*s primary direct
action is expected to prevent the IL-1* mediated destruction of pancreatic *-
cells and thus prevent or delay progression of disease, which to date is a
completely unmet need
The primary purpose of this trial is to test the hypothesis that canakinumab
treatment of patients with MI at least one month prior to study entry and
elevated hsCRP will prevent recurrent cardiovascular events. A secondary
hypothesis, that canakinumab treatment in patients with MI and pre-diabetes,
will prevent new onset diabetes will also be tested.

Primary: to demonstrate the superiority of at least one dose of canakinumab
compared to placebo in reducing the risk of recurrent major cardiovascular
disease events (cardiovascular death, non-fatal MI and stroke) in a population
of clinically stable post-MI patients with elevated hsCRP receiving standard of
care.
Secondary objectives: Endpoint of CV death, non-fatal MI, stroke, and
hospitalization for unstable angina requiring unplanned revascularizations.
Composite endpoint of all-cause mortality, non-fatal MI and stroke. Endpoint of
all-cause mortality. New onset type 2 diabetes. Long-term safety.

Multicenter randomized double blind phase III parallel group study with placebo
control. Prescreening for elevated hsCRP.
Randomisation (1:1:1:1*) to treatment with:
* Canakinumab 50 mg (s.c. injections week 1 and 3, therafter 1x/3 months)
* Canakinumab 150 mg (s.c. injections week 1 and 3, therafter 1x/3 months)
* Canakinumab 300 mg (s.c. injections week 1 and 3, therafter 1x/3 months)
* Placebo.
Event-driven study, expected duration approx. 6 years.
Independent DSMB.
2 interim analyses for efficacy: after approx. 50 and 75% of CV events are
available.
Approx 17200 patients, 275 in NL
At the end of the study possibility to join an open-label follow-up study.

Treatment with canakinumab or placebo.

Risk: Adverse effects of study medication.
Burden: Max. study duration approx. 6 years. 5 visits in 1st 3 months,
therafter every 3 months. Duration 1-2 h.
Physical examination annually.
Blood tests 1st year 8x, therafter 2x/year, 20-55 ml/occasion. At screening HIV
and hepatitis B-C. Optional pharmacogenetic/-genomics blood tests (3x 10 ml).
Pregnancy test (if relevant) 2x.
ECG annually.
TBC test at screening (blood), if needed chest X ray.
Monitoring for macula degeneration every 6 months.
EQ-5D questionnaire (in NL the other questionnaires will not be used) 6x in 1st
year and year 3 and 4.
Life style councelling.