Assumptions for sample size and event-driven power calculations were updated following further consideration of the Investigator-sponsored study with eculizumab and incorporating new and unpublished information from 2 academic databases. Updated the anticipated sample size based on power calculations requiring 24 relapses in 24 distinct participants. Updated the IST status randomization strata from: a. Treatment naïve participants versus prior IST and are receiving IST at randomization participants versus prior IST and are not receiving IST at randomization participants to b. Treatment naïve participants versus participants continuing on the same IST(s) since last relapse versus participants with changes in IST(s) since last relapse. Expanded on the clinical information to be collected for historical relapses to aid in describing the participants, their disease severity, prior treatments, and more accurate subgroup assignment based on their treatment history. Safety follow-up was extended from 4 weeks to 8 weeks. Updated the inclusion criterion around historical relapses to be less restrictive. Updated the inclusion criterion around concomitant IST use during the study to be less restrictive and better aligned with current clinical practice. Added exclusion criteria for participants receiving high doses of corticosteroid since this may decrease the relapse rate in some participants, confounding the interpretation of study results.

Changed the inclusion criterion “NMO-IgG seropositive at Screening Visit” to “NMO-IgG seropositive” to allow historically seropositive participants. Allowed qualified non-physician healthcare professionals (for example, nurses) to conduct the EDSS rating with the Sponsor’s approval. Removed an interim analysis, in alignment with recommendations from regulatory agencies. Removed text emphasizing reporting the IST use “within 24 months prior to the Screening Visit” to encourage obtaining all available history on IST use for relapse prevention. Clarified that supportive ISTs are for relapse prevention, so as not to be confused with ISTs administered for relapse treatment or other medical reasons. Extended the Screening Period from 1-3 weeks to 1-6 weeks to allow more time for all screening procedures to be completed and for participants to be vaccinated at least 2 weeks prior to study drug administration, as required by the protocol. Provided some flexibility for the supplemental study drug dose administration time from “within 60 minutes” to “preferably within 1-2 hours” after each PE cycle to address operational challenges. Changed the definition of the Per Protocol Set from participants who have “no major protocol deviations or inclusion/exclusion criteria deviations” to “no major protocol deviations or key inclusion/exclusion criteria deviations that might potentially affect efficacy" to prevent the exclusion of participants from the Per Protocol Set with deviations not relevant for assessing the efficacy and safety of eculizumab.

Established the Relapse Adjudication Committee for adjudication of all On-trial Relapses. Updated the primary end point of the study from “time to first Relapse” to “time to first adjudicated On-trial Relapse”. Added a sensitivity analysis of time to first On-trial Relapse using a log-rank test including strata for the randomization stratification variables. The secondary efficacy end point was changed from ARR to adjudicated ARR. Added a sensitivity analysis for ARR using all On-trial Relapses in a Poisson regression analysis with treatment group, stratification variables, and baseline ARR as covariates in the model, and the log of time in the study was used as the offset variable.