Gullain Barre Syndrome Clinical Trial
Official title:
A PROSPECTIVE, MULTI-CENTER, PHASE II STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ECULIZUMAB IN SUBJECTS WITH GUILLAIN-BARRÉ SYNDROME
Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy that usually follows an
antecedent infection and causes acute neuromuscular paralysis. GBS is currently classified
into the two major subtypes: a classical demyelinating type and axonal variant type. Whereas
in Europe and North America demyelinating GBS is the major subtype, in East Asia and Central
and South America, axonal GBS is found in 30~65% of patients. Although the pathophysiology of
GBS has not been fully understood, major advances have been made in understanding the
pathophysiology particularly for the axonal form of GBS. It is now established that axonal
GBS is caused by molecular mimicry of human gangliosides by the Campylobacter jejuni
lipo-oligosaccharides. Autoantibodies bind to GM1 or GD1a at the nodes of Ranvier, activate
complements, and disrupt sodium channel clusters and axo-glial junctions, resulting in the
nerve conduction failure and muscle weakness. C. jejuni infection induces production of
antibodies, which cross-react with gangliosides on the human nerve axolemma, and activate the
complements, resulting in formation of membrane attack complex (MAC). The pathology leads to
axonal degeneration.
The standard treatments for GBS are plasma exchange and intravenous immunoglobulin and the
disease progression reaches its nadir within 4 weeks. However, during the acute phase, 18-28
% of the patients require artificial ventilation and 4.1-6.3 % of the patients die of
complications. Recovery takes several months or years, and 16.7-19.7 % of the patients still
require aid to walk one year after onset. Because of such serious disability of GBS patients,
an alternative novel therapy that can prevent death during acute phase or severe sequelae is
needed.
Eculizumab is a humanized monoclonal antibody of murine anti-human C5 antibody and
specifically binds to the final activation complement component C5 and inhibits MAC formation
by suppressing the cleavage reaction of C5 into C5a and C5b. The efficacy of eculizumab
against GBS has been shown in a model of axonal GBS. At present, there are no animal models
of demyelinating GBS. However, autopsy studies have shown that C3d and C5b-9 (MAC) are
deposited on the Schwan cells, and therefore eculizumab can be effective also for
demyelinating GBS.
This clinical trial will be conducted to investigate the efficacy and safety of eculizumab
for GBS to warrant future global clinical trials. Moreover, we also study the relationship
between the efficacy and clinical subtypes of GBS, such as axonal or demyelinating form. Our
trial will provide insights on whether the future global developmental plan should target the
whole spectrum of GBS world-wide or focusing on Asia and South America.
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