JET-GBS - Japanese Eculizumab Trial for GBS

NCT02493725 | Completed Phase 2

• 1 other identifier: 100069
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 13

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.

Conditions

Gullain Barre Syndrome

Outcome Measures

Primary Outcomes (2)

• [Safety] Expressed frequency and severity of incidence of AE/SAEs after treatment with investigational product.

  6 months

• [Efficacy] Proportion of subjects who reach a score of FG2 or lower on the Hughes functional grading scale at week 4（Response Rate）

  4 weeks

Secondary Outcomes (16)

• Proportion of subjects with improvement of one or more scores on the functional grading scale at each visit

  6 months

• Proportion of subjects who are able to walk unaided (FG2 or lower) at each visit

  6 months

• Duration required for improvement by at least one grade on the Hughes functional grading scale

  6 months

• Proportion of subjects who reach FG1 or 0 at week 24

  6 months

• Change in the FG score between peak disability score and the scores at each visit

  6 months

Other Outcomes (3)

• Antiganglioside antibodies (Antibodies to GM1・GD1a・GalNAc-GD1a・GQ1b, and their complexes)

  6 months

• Concentration of eculizumab in serum

  6 months

• Hemolytic complement activity in serum

  6 months

Study Arms (2)

Eculizumab

ACTIVE COMPARATOR

Eculizumab, 900 mg intravenously once a week

Drug: Eculizumab

Placebo

PLACEBO COMPARATOR

Matched placebo, intravenously once a week

Drug: Placebo

Interventions

Eculizumab DRUG

Eculizumab

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Subjects ≥ 18 years of age at the time of obtaining informed consent.
• Patients with onset of muscular weakness due to GBS less than 2 weeks before the time of consent.
• Patients unable to walk unaided for ≥5 meters (progressively deteriorating FG(Functional Grade)3 or FG 4-5).
• Patients who are already on IVIg or deemed eligible for and who will start IVIg (Generally, administration of 400mg/kg over 5 days).
• 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.
• 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.
• Patients who can be hospitalized during IP administration period.
• Patients who have signed the informed consent form.
• Patients who are being considered for or are already on plasmapheresis.
• Patients who are pregnant or lactating.
• 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.
• Patients who have received immunosuppressive treatment (e.g. azathioprine, cyclosporine, tacrolimus, or \>20 mg prednisolone daily) during the 4 weeks prior to providing consent.
• 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).
• Patients who are unable to comply with study procedures and the treatment regimen.
• Patients who have received rituximab within 24 weeks prior to providing consent.

Sponsors & Collaborators

• Chiba University: lead
• Japan Agency for Medical Research and Development: collaborator

Study Sites (13)

Nagoya University Hospital

Nagoya, Aichi-ken, Japan

Location

Hokkaido University Hospital

Sapporo, Hokkaido, Japan

Location

Kobe City Medical Center General Hospital

Kobe, Hyōgo, Japan

Location

Kitasato University Hospital

Sagamihara, Kanagawa, Japan

Location

Kindai University Hospital

Ōsaka-sayama, Osaka, Japan

Location

National Defence Medical College Hospital

Tokorozawa, Saitama, Japan

Location

Dokkyo Medical University Hospital

Mibu, Tochigi, Japan

Location

Tokyo Medical and Dental University Hospital

Bunkyo-ku, Tokyo, Japan

Location

Tokyo University Hospital

Bunkyo-ku, Tokyo, Japan

Location

Keio University Hospital

Shinjuku-ku, Tokyo, Japan

Location

Chiba University Hospital

Chiba, Japan

Location

Kyushu University Hospital

Fukuoka, Japan

Location

Tokushima University Hospital

Tokushima, Japan

Location

Related Publications (2)

• 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.

  PMID: 29685815 DERIVED

• 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.

  PMID: 27821382 DERIVED

MeSH Terms

Interventions

eculizumab

Study Officials

• Satoshi Kuwabara, MD

  Chiba University Graduate School of Medicine Department of neurology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 7, 2015
• First Posted: July 9, 2015
• Study Start: July 1, 2015
• Primary Completion: May 1, 2016
• Study Completion: October 1, 2016
• Last Updated: October 11, 2017

Record last verified: 2017-10

Locations

JP (13)