A Prospective, Multicenter, Randomized Phase II Study to Evaluate the Efficacy and Safety of Eculizumab in Patients with Guillain-Barré Syndrome (GBS): Protocol of Japanese Eculizumab Trial for GBS (JET-GBS)

Abstract

BackgroundGuillain-Barré syndrome (GBS) is an immune-mediated neuropathy that causes acute flaccid paralysis. Immunoglobulin and plasma exchange are established treatments for GBS; however, a substantial number of patients, particularly those with severe disease, have poor recovery and residual deficits. Recent studies suggest that complement activation plays a pivotal role in GBS-associated axonal degeneration, and eculizumab is a humanized monoclonal antibody that specifically binds to complement component 5 and potently inhibits complement activation.ObjectiveThis clinical trial aims to evaluate the efficacy and safety of eculizumab, a humanized monoclonal antibody directed against complement component 5, for treatment of GBS.MethodsThe Japanese Eculizumab Trial for GBS (JET-GBS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase II study conducted at 13 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 33 GBS patients unable to walk independently within 2 weeks from symptom onset (Hughes functional grade 3-5) were randomized at a 2:1 ratio to receive either intravenous eculizumab (900 mg/day) or placebo once weekly for 4 weeks, followed by 20 weeks of follow-up. The primary endpoint for efficacy is the proportion of patients who regain their ability to walk without aid at 4 weeks after the first dose of the study treatment, while primary safety outcomes are the incidence of adverse events and serious adverse events during the trial.ResultsEnrollment for the trial began in August 2015. This trial is still ongoing. All participants have been enrolled, and follow-up will be completed in October 2016.ConclusionsThis study is the first to investigate the efficacy and safety of eculizumab for GBS. In case of a positive result, we will plan a phase III trial to investigate this issue in a larger number of patients.ClinicalTrialUMIN Clinical Trials Registry UMIN 000018171; https:/upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function= brows&action=brows&type=summary&language=J&recptno=R000020978 (Archived by WebCite at http://www.webcitation.org/ 6lTiG8ltG). Clinical Trials.gov NCT02493725; https://clinicaltrials.gov/ct2/show/NCT02493725 (Archived by WebCite at http://www.webcitation.org/6lVJZXKSL)

Markers for Guillain‐Barré syndrome with poor prognosis: a multi‐center study

“…In addition, development of new therapeutic options, such as complement inhibition, may be needed for patients with poor prognosis. This issue is now under investigation (Yamaguchi et al, ; Davidson et al, ) .…”

Guillain‐Barré syndrome: Novel treatment by complement inhibition

“…Based on these, a phase II clinical trial was conducted to investigate the safety and efficacy of eculizumab, humanized monoclonal antibody to complement C5, for the acute phase of GBS in Japan (Table 1). It enrolled 34 patients with GBS who cannot walk independently within 14 days from the onset 26,27 . Patients were randomly assigned (2:1) to IVIG plus eculizumab (900 mg) or placebo, which were administrated for 4 weeks 26 .…”

“…It enrolled 34 patients with GBS who cannot walk independently within 14 days from the onset 26,27 . Patients were randomly assigned (2:1) to IVIG plus eculizumab (900 mg) or placebo, which were administrated for 4 weeks 26 . The primary endpoint was efficacy, the proportion of patients who restored the ability of walking independently (functional grade ≤ 2) at week 4, and safety 26 …”

Immunotherapy of Guillain-Barré syndrome

“…Eculizumab, a humanized monoclonal antibody that specifically binds to complement component 5 (C5) and potently inhibits generation of pro-inflammatory C5a and C5b-9 (implicated in axonal injury in GBS) is currently undergoing clinical trials in the United Kingdom and Japan to determine efficacy in GBS guided by prior animal model studies that demonstrated beneficial effects. 129,130 Other biologic agents are being proposed as potential future therapies based on animal model data or small case reports. 131 Due to the proposed pathogenic differences between demyelinating and axonal variants of GBS, future immunotherapy RCTs may require randomization based on electrophysiologic characterization or perform subgroup analyses dependent on relative numbers of these variants in addition to other demographic factors and measures of disease severity.…”