This is a prospective, multicenter, placebo-controlled, double-blind, randomized phase II trial in patients with GBS. A schematic depiction of the trial design is presented in Figure 1. The trial is composed of 3 periods: the screening period, investigation product (IP) administration period, and post-IP period. Screening is conducted within 5 days of randomization to assess eligibility and collect baseline data. Eligible patients were defined as those unable to walk independently (Hughes functional grade [FG] 3-5) within 2 weeks from the onset of weakness, because such patients have a higher risk of progression. They are randomized to receive either eculizumab or placebo at a 2:1 ratio. Eculizumab (900 mg/day) or matching placebo is administered intravenously once a week for a total of 4 doses (day 1, day 8, day 15, day 22) in conjunction with IVIg, the standard treatment for GBS (400 mg/kg daily for 5 consecutive days). IVIg can be readministered if patients show deterioration after initial improvement or stabilization (treatment-related fluctuation) following day 15. Patients are monitored periodically up to week 24. The primary endpoint for efficacy is the proportion of patients who reach FG 2 or lower (able to walk without aid) at day 29 (week 4). The primary endpoints for safety are the proportion and severity of adverse events (AEs) and serious adverse events (SAEs).

GBS patients who meet all of the following inclusion criteria and none of the listed exclusion criteria are enrolled (see Textbox 1). Diagnosis of GBS is made with reference to the National Institute of Neurological Disorders and Stroke criteria [16].

The efficacy and safety of eculizumab will be assessed by the following endpoints. The primary efficacy endpoint is the proportion of patients who reach FG 2 or lower (able to walk without aid) at week 4, and the safety endpoints are the proportion and severity of AEs/SAEs during the trial.

The secondary endpoints include the proportion of patients with improvement of 1 or more Hughes functional grades from baseline at each visit, proportion of patients who are able to walk unaided at each visit, duration required for improvement by at least 1 Hughes functional grade, proportion of FG 1 or 0 at week 24, change from peak FG at each visit, clinically relevant improvement in the Rasch-built Overall Disability Scale (R-ODS) score and the Overall Neuropathy Limitations Scale (ONLS) score at each visit, proportion of ventilatory support, duration of ventilatory support, occurrence of relapse, overall survival, changes in grip strength, manual muscle testing score, median and ulnar nerve conduction parameters, vital capacity respectively from baseline at each visit, and proportion of IVIg readministration.

This study is also investigating antiganglioside antibodies, concentration of serum eculizumab, and serum hemolytic activity as exploratory endpoints. The data of antiganglioside antibodies assay will be used to determine the subtype of GBS, and the results of eculizumab concentration and hemolytic activity will be used to obtain exploratory data on the efficacy of eculizumab.

The schedule for the study visits and assessments are summarized in Tables 1 and 2. Patients are assessed weekly for efficacy and safety during the 4-week IP administration period and on week 6, 8, 12, 16, and 24 during the 20-week post-IP period. Patients are requested to record their FG score independently using a diary until they show an improvement by one grade. If all 4 administrations of the IP cannot be completed due to AEs or other contingencies, patients remain in the trial and tests/assessments will be performed on the patients according to the trial schedule unless they meet the withdrawal criteria.

Study data is recorded in the electronic case report form (eCRF) of Medidata Rave, which was configured for this study by the data management division at Chiba University Hospital Clinical Research Centre. The eCRF data maintain anonymity and identify participating patients by their assigned identification codes. Independent monitors ensure that the study is properly conducted at each site in accordance with the protocol and good clinical practice and verify that the contents of case reports and other reports are current and accurate. The monitors and data managers assure the quality of the data at each stage of handling. Auditors who are independent from all divisions conducting the trial perform audits of the clinical trial sites and verify appropriate quality assurance.

All AEs are recorded on the AE page of the eCRF. The investigator at each site endeavors to obtain the outcome and severity of all AEs. AEs are reported from the time of informed consent to the last trial visit (week 24); however, SAEs with a causal relationship to the IP are monitored until resolution if possible. All SAEs are reported to all investigators and assessed through a Web-based AE reporting system that has been developed by the Japan Medical Association, Centre for Clinical Trials. SAEs that have not been reported previously are reported to the Pharmaceuticals and Medical Devices Agency.

The sample size was based on the results from our previous study [17] and our historical database of GBS patients. For the primary endpoint of efficacy, we estimated that the threshold value for Hughes FG 2 or lower at week 4 would be 50% and the expected value 80%. A sample size of 20 patients in the eculizumab group is required to achieve statistical significance level of 5% (1-sided) at 80% power. To allow for a 10% dropout rate, total sample size in the eculizumab group is 22. Additionally, 11 patients will be randomly assigned to the placebo control to collect efficacy and safety data. The total sample size was set at 33.

Eligible patients who provided informed consent are registered for study enrollment and are randomized to the eculizumab or placebo arm at a 2:1 ratio via a Web-based system developed by ADJUST Co Ltd. Allocation is performed using the minimization method with biased coin assignment [18,19] balancing for FG score (FG=3 or FG≥4) and age (younger than 60 years or 60 years and older).

Each vial of IP contains 300 mg of eculizumab or placebo. The placebo has an identical external appearance to that of eculizumab. All participating patients, investigators, study coordinators, data managers, and outcome assessors remain blinded to group assignment during the trial. In order to maintain blinding, measurements of serum 50% hemolytic complement activity are prohibited during the trial. The levels of antiganglioside antibodies, eculizumab concentrations, and hemolytic activities in serum are measured at a central laboratory and the results are masked to all patients and study personnel during the trial.

Statistical analyses and reporting of this trial will be conducted in accordance with the Consolidated Standards of Reporting Trials statement guidelines with the primary analyses based on the intent-to-treat principle without imputing any missing observations. All efficacy analyses will be primarily based on the full analysis set, which includes all patients who have received at least one dose of the study treatment.

The primary endpoint for efficacy is the proportion of patients with FG≤2 at week 4. We hypothesized that response threshold at week 4 would 50% as H₀ (null hypothesis), whereas the expected response rate would be 80% as H₁ (alternative hypothesis). The exact 90% confidence interval will be calculated by the binominal distribution for the response rate of each treatment group. The confidence limits of the confidence interval will be assessed against the response threshold; however, in primary analysis, we will not perform a statistical testing for comparison of treatment groups.

For the patient characteristics, summary statistics were constructed using frequencies and proportions for categorical data and means and SDs for continuous variables. Patient characteristics were compared using a Fisher exact test for categorical outcomes and a Student t test or the Wilcoxon rank sum test for continuous variables, as appropriate. All comparisons were planned, and all P values are 2-sided. A value of P<.05 is considered statistically significant. Subgroup analysis will be performed for safety and efficacy depending on GBS subtype, baseline FG, and electrodiagnosis.

All statistical analyses are performed using SAS software version 9.4 (SAS Institute) and the R statistical program version 2.13 (The R Foundation). All statistical analyses are described in the statistical analysis plan, which will be fixed prior to database lock.