Clinical trial NCT02493725: JET-GBS - Japanese Eculizumab Trial for GBS
Official title: A PROSPECTIVE, MULTI-CENTER, PHASE II STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ECULIZUMAB IN SUBJECTS WITH GUILLAIN-BARRÉ SYNDROME
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gullain Barre Syndrome
Lead sponsor: Chiba University
Sponsor class: OTHER
Collaborators: name: Japan Agency for Medical Research and Development
First posted: 2015-07-09
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: * Patients who have been diagnosed with GBS with reference to GBS NINDS(National Institute of Neurological Disorders and Stroke) diagnostic criteria and those who meet all the following inclusion criteria and do not fall under any of the exclusion criteria will be included in this trial.

Inclusion Criteria：

1. Subjects ≥ 18 years of age at the time of obtaining informed consent.
2. Patients with onset of muscular weakness due to GBS less than 2 weeks before the time of consent.
3. Patients unable to walk unaided for ≥5 meters (progressively deteriorating FG(Functional Grade)3 or FG 4-5).
4. Patients who are already on IVIg or deemed eligible for and who will start IVIg (Generally, administration of 400mg/kg over 5 days).
5. Patients who can start their first dose of eculizumab within 2 weeks from onset of weakness and before the end of the IVIg treatment period.
6. Female subjects of child bearing potential with a negative result in their pregnancy test. All subjects must be able to practice an effective, reliable, medically approved method of contraception during the IP(Intraperitoneal) administration period and up to 5 months after IP administration is ended.
7. Patients who can be hospitalized during IP administration period.
8. Patients who have signed the informed consent form.

Exclusion Criteria:

1. Patients who are being considered for or are already on plasmapheresis.
2. Patients who are pregnant or lactating.
3. Patients showing clear clinical evidence of peripheral polyneuropathy other than GBS, e.g. diabetic (except for mild sensory disturbance) or severe vitamin B1 deficiency related.
4. Patients who have received immunosuppressive treatment (e.g. azathioprine, cyclosporine, tacrolimus, or \>20 mg prednisolone daily) during the 4 weeks prior to providing consent.
5. Patients who are known to have severe concurrent disease (such as malignancy with uncontrolled primary tumors or metastatic lesions, severe cardiovascular disease, severe COPD(chronic obstructive pulmonary disease ), or TB).
6. Patients who are unable to comply with study procedures and the treatment regimen.
7. Patients who have received rituximab within 24 weeks prior to providing consent.
8. Patients with a history of or unresolved Neisseria meningitides.
9. Patients with active infectious diseases determined to be clinically severe by the principal investigator or sub-investigator that are not being appropriately treated with antibiotics.
10. Patients who that cannot be treated with antibiotic prophylaxis due to allergies.
11. Patients who are allergic to eculizumab.
12. Patients who are known to have or are suspected of having hereditary complement deficiencies.
13. Patients who have been administered another investigational product within 12 weeks prior to providing consent or are currently participating in another trial.
14. Patients with any condition that, in the opinion of the principal investigator or sub-investigator, could increase the patient's risk by participating in the study or confound the outcome of the study.
15. Patients who have a history of Eculizumab treatment for GBS.

Primary outcomes:
measure: [Safety] Expressed frequency and severity of incidence of AE/SAEs after treatment with investigational product.
timeFrame: 6 months
measure: [Efficacy] Proportion of subjects who reach a score of FG2 or lower on the Hughes functional grading scale at week 4（Response Rate）
timeFrame: 4 weeks
Secondary outcomes:
measure: Proportion of subjects with improvement of one or more scores on the functional grading scale at each visit
timeFrame: 6 months
measure: Proportion of subjects who are able to walk unaided (FG2 or lower) at each visit
timeFrame: 6 months
measure: Duration required for improvement by at least one grade on the Hughes functional grading scale
timeFrame: 6 months
measure: Proportion of subjects who reach FG1 or 0 at week 24
timeFrame: 6 months
measure: Change in the FG score between peak disability score and the scores at each visit
timeFrame: 6 months
measure: Proportion of subjects with a clinically relevant improvement in the R-ODS score. An increase in the R-ODS score (0-48) converted to the centile metric score (0-100) by at least six points at each visit
timeFrame: 6 months
measure: Proportion of subjects with a clinically relevant improvement in ONLS. (a decrease in the ONLS score from baseline by at least 1 point) at each visit
timeFrame: 6months
measure: Proportion and frequency of subjects who require ventilatory support (F 5)
timeFrame: 4 weeks
measure: Duration of ventilatory support
timeFrame: 8 weeks
measure: Occurrence of relapse from the start of the IP(Investigational Product) administration period until the end of the post IP period
timeFrame: 2 years
measure: Overall survival from the start of the IP administration period until the end of the post IP period (OS)
timeFrame: 6 months
measure: Change in grip strength at each visit from baseline
timeFrame: 6 months
measure: Change in results of the manual muscle test (MMT score) at each visit from baseline
timeFrame: 6 months
measure: Change in the rate and results of below measures on the nerve conduction test parameter from baseline:Median and ulnar nerve 's CMAP amplitude, distal latency, F wave latency , SNAP amplitude, motor sensory nerve conduction velocity
timeFrame: 6 months
measure: Change in vital capacity and % vital capacity at each visit from baseline
timeFrame: 6 months
measure: Proportion of patients who undergo re-administration of IVIg
timeFrame: 6 months
Other outcomes:
measure: Antiganglioside antibodies (Antibodies to GM1・GD1a・GalNAc-GD1a・GQ1b, and their complexes)
timeFrame: 6 months
measure: Concentration of eculizumab in serum
timeFrame: 6 months
measure: Hemolytic complement activity in serum
timeFrame: 6 months
Locations:
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
state: Hyogo
city: Sagamihara
country: Japan
facility: Kitasato University Hospital
state: Kanagawa
city: Osaka-sayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Tokorozawa
country: Japan
facility: National Defence Medical College Hospital
state: Saitama
city: Mibu
country: Japan
facility: Dokkyo Medical University Hospital
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Tokyo Medical and Dental University Hospital
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Tokyo University Hospital
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Tokushima
country: Japan
facility: Tokushima University Hospital
Study officials:
affiliation: Chiba University Graduate School of Medicine Department of neurology
name: Satoshi Kuwabara, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Misawa S, Kuwabara S, Sato Y, Yamaguchi N, Nagashima K, Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi T, Yokota T, Nishida Y, Kanouchi T, Kohara N, Kawamoto M, Ishii J, Kuwahara M, Suzuki H, Hirata K, Kokubun N, Masuda R, Kaneko J, Yabe I, Sasaki H, Kaida KI, Takazaki H, Suzuki N, Suzuki S, Nodera H, Matsui N, Tsuji S, Koike H, Yamasaki R, Kusunoki S; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barre syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018 Jun;17(6):519-529. doi: 10.1016/S1474-4422(18)30114-5. Epub 2018 Apr 21.
citation: Yamaguchi N, Misawa S, Sato Y, Nagashima K, Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi T, Yokota T, Nishida Y, Kohara N, Hirata K, Nishiyama K, Yabe I, Kaida KI, Suzuki N, Nodera H, Tsuji S, Koike H, Kira JI, Hanaoka H, Kusunoki S, Kuwabara S; JET-GBS Group. A Prospective, Multicenter, Randomized Phase II Study to Evaluate the Efficacy and Safety of Eculizumab in Patients with Guillain-Barre Syndrome (GBS): Protocol of Japanese Eculizumab Trial for GBS (JET-GBS). JMIR Res Protoc. 2016 Nov 7;5(4):e210. doi: 10.2196/resprot.6610.