JET-GBS - Japanese Eculizumab Trial for GBS
- Registration Number
- NCT02493725
- Lead Sponsor
- Chiba University
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 34
Not provided
- 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.
- Patients with a history of or unresolved Neisseria meningitides.
- 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.
- Patients who that cannot be treated with antibiotic prophylaxis due to allergies.
- Patients who are allergic to eculizumab.
- Patients who are known to have or are suspected of having hereditary complement deficiencies.
- Patients who have been administered another investigational product within 12 weeks prior to providing consent or are currently participating in another trial.
- 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.
- Patients who have a history of Eculizumab treatment for GBS.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Matched placebo, intravenously once a week Eculizumab Eculizumab Eculizumab, 900 mg intravenously once a week
- Primary Outcome Measures
Name Time Method [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 Outcome Measures
Name Time Method Duration of ventilatory support 8 weeks Proportion and frequency of subjects who require ventilatory support (F 5) 4 weeks 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 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 6 months 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 6months Occurrence of relapse from the start of the IP(Investigational Product) administration period until the end of the post IP period 2 years Overall survival from the start of the IP administration period until the end of the post IP period (OS) 6 months Change in grip strength at each visit from baseline 6 months Change in results of the manual muscle test (MMT score) at each visit from baseline 6 months 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 6 months Change in vital capacity and % vital capacity at each visit from baseline 6 months Proportion of patients who undergo re-administration of IVIg 6 months
Trial Locations
- Locations (13)
Nagoya University Hospital
🇯🇵Nagoya, Aichi, Japan
Hokkaido University Hospital
🇯🇵Sapporo, Hokkaido, Japan
Dokkyo Medical University Hospital
🇯🇵Mibu, Tochigi, Japan
Tokyo Medical and Dental University Hospital
🇯🇵Bunkyo-ku, Tokyo, Japan
Kobe City Medical Center General Hospital
🇯🇵Kobe, Hyogo, Japan
Kyushu University Hospital
🇯🇵Fukuoka, Japan
Kitasato University Hospital
🇯🇵Sagamihara, Kanagawa, Japan
Keio University Hospital
🇯🇵Shinjuku-ku, Tokyo, Japan
Kindai University Hospital
🇯🇵Osaka-sayama, Osaka, Japan
Chiba University Hospital
🇯🇵Chiba, Japan
Tokyo University Hospital
🇯🇵Bunkyo-ku, Tokyo, Japan
Tokushima University Hospital
🇯🇵Tokushima, Japan
National Defence Medical College Hospital
🇯🇵Tokorozawa, Saitama, Japan