Inhibition of Mast cell Activation in AtheroScleroTic lesions using an Anti-IgE antibody approach (MAST-trial)

Atherosclerosis, the main underlying pathology of cardiovascular disease is the
principal cause of death in the Western society. The mast cell is a prominent
immune effector cell, that has been shown to accumulate within atherosclerotic
plaques. Mast cells are activated by a various stimuli, of which crosslinking
of the Fc*RI via IgE-antigen complexes is most prominent. Previously, we have
demonstrated that acute mast cell activation contributes to destabilization of
advanced plaques in mice. Moreover, mast cell numbers positively correlate with
plaque progression and the mast cell is the only cell type within
atherosclerotic plaque that is associated with future acute cardiovascular
events (ACE), which is suggestive for a causal relation between mast cells
within plaques and disease outcome. This indicates that inhibition of mast cell
activation may serve as a novel therapeutic strategy to limit ACE*s. Recently,
we have established that anti-IgE treatment in mice results in a reduction in
mast cell activation, and subsequently a significant reduction in
atherosclerotic plaque size. We hypothesize that in humans anti-IgE treatment
with omalizumab can be markedly effective in inhibiting mast cell activation
within plaques.

This study has been transitioned to CTIS with ID 2024-513581-19-00 check the CTIS register for the current data.

The primary objective is, to determine whether short term anti-IgE treatment
with an anti-IgE monoclonal antibody (omalizumab) can limit intraplaque mast
cell activation in atherosclerotic plaques.

Single centre double blind randomized placebo-controlled trial

Intervention: a single treatment moment three days before carotid
endarterectomy, patients will receive a total of four subcutaneous injections
with omalizumab of 150mg (1.2mL) each.

Control intervention: placebo (physiological saline solution) in four
subcutaneous injections (1.2mL each).

Patients which are scheduled for a CEA based on (a)symptomatic atherosclerotic
carotid stenosis, with a suitable timeframe between possible study inclusion
and the scheduled surgery to participate in this study, will be approached.
Study participants will be required to make an additional visit to the
outpatient clinic for the withdrawal of extra blood samples (total blood volume
9mL: EDTA whole blood 2ml, EDTA 2ml and serum 5ml) through venepuncture, the
administration of the study drug and the subsequent observation period of at
least two hours after administration of the study drug.

Omalizumab is a FDA and EMA approved anti-IgE antibody which is on the market
to treat severe allergic asthma and idiopathic chronic urticaria. The most
common adverse events (e.g. injection site reactions, viral infections and
upper tract infections) are relatively mild and similar rates of these adverse
events were observed in the placebo control groups in studies where patients
received omalizumab for asthma, urticaria or other diagnosis. There is a small
chance (<0.09%) that patients treated with omalizumab develop an anaphylactic
reaction after the administration of omalizumab. To minimize the potential harm
of such a reaction, all study participants will be kept under observation for
at least two hours after the administration of the study drugs. In the case of
an anaphylactic reaction patients will be treated immediately according the
local guideline for treating anaphylaxis. As patients will receive the study
drug once, we expect that the risk of harmful effects are minimal.

On the day of surgery additional blood (total blood volume 9mL: EDTA whole
blood 2ml, EDTA 2ml and serum 5ml) for the study will be drawn through a single
venepuncture. During the standard CEA the atherosclerotic plaque will be
collected for further processing. We do not know if omalizumab will reduce
cardiovascular events in the enrolled patients. However, if omalizumab can
indeed limit mast cell activation in atherosclerotic plaque than this finding
is potentially of great value for future research and for the non-invasive
treatment of patients with atherosclerosis.