Evaluation of the subcutaneous administration of 30 mg of S78989 versus placebo and evaluation of the subcutaneous administration of 60mg of S78989 versus placebo, on the reduction of arterial wall inflammation in patients with marked atherosclerotic plaque inflammation.
A 28-weeks, randomized, double-blind, parallel-group, placebo controlled, international multicenter exploratory pilot study.

Despite many therapeutic improvements, atherosclerosis remains a leading cause
of mortality in developed countries and its prevalence is increasing in
developing ones.
Within the cytokines, IL-1* has been shown to be present in human
atherosclerotic lesions where it may contribute to vascular pathogenesis by
induction of adhesion molecules, chemokines and procoagulant activity.
Gevokizumab (S 78989) is a recombinant Human Engineered* monoclonal antibody
(mAb) that binds human IL-1* and regulates the activation of IL-1 receptors.
Administration of gevokizumab to patients suffering from IL-1*-mediated
systemic inflammatory diseases is expected to produce rapid and sustained
reductions in symptoms.
To date, the clinical experience with gevokizumab includes over 500 subjects
who have been exposed to gevokizumab in a variety of clinical settings,
primarily type 2 diabetes, but also type 1 diabetes, Behçet disease uveitis,
rheumatoid arthritis, and acne vulgaris.

Following the availability of new preclinical and clinical data, as well as
tolerance data, it was decided to evaluate an additional group of 45 patients
using a higher dose of 60mg gevokuzimab (part B of same study).

The objective of this study is to evaluate the effect of the 4 successive
monthly subcutaneous administrations of 30 mg of gevokizumab (in part A) , as
well as 60mg (in part B) of the protocol, versus placebo on the reduction of
arterial wall inflammation in adult patients with marked arterial wall
inflammation following a recent acute coronary syndrome.

This study is a phase II, randomised (2:1), double-blind, parallel-group,
placebo controlled, international, multicentre, pilot, exploratory study,
The study will be performed in 45 patients (30 patients are receiving
gevokuzimab, and 15 placebo), in each part of the study (A and B), with a total
of 90 patients for the whole study. Gevokuzimab 30mg or 60mg will be given onze
monthly, SC (4 injections in total for the study). The total duration of the
study is 28 weeks, and the estimated duration of recruitment has been prolonged
till 12 months. See plan in protocol Fig(8.2.1)1.
There are 7 study visits per patients: Selection (ASSE), inclusion (W000),
W004, W008, W012, W016 (eind ) + follow-up W028; + 2 visits for the PET-CT
scan.

placebo or gevokizumab

Risks: All drugs can cause side effects. Until now gevokizumab has been well
tolerated.
As any therapy targeting IL-1*, gevokizumab may increase the risk of
infections.Though it has not been observed with gevokizumab so far, there is a
possibility of developing allergic reactions because of the nature of this new
drug. Fever, chills and rigors, typically occurring within the first two hours
following infusion, characterize these reactions. Other symptoms sometimes
associated with infusion reactions include nausea, vomiting, rash, pruritus,
bronchospasm (difficulty of breathing), angioedema, hypotension, hypertension,
and cardiac arrhythmias. In general, most injection reactions are manageable
and mild to moderate in severity, but the possibility of life-threatening
reactions cannot be excluded, even if never observed with gevokizumab.

Burden:
There are 9 visits, with a probable total time investment of 17 -19 hours. The
total duration of the study is 28 weeks.
There are 4 subcutaneous injections with studymedication (1ml/ time) (1
injection per month).
Physical examination: 7 times
ECG: 7 times
Bloodsampling: 5 times(ca 40 ml/ sampling time)
FDG PET-CT scan: 2 times
Optional pharmacogenomic analysis: 3 times (no extra bloodsampling) (ca
10ml/sampling time)