An Efficacy and Safety Study of Ravulizumab in Adult Participants With NMOSD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Efficacy and Safety Study of Ravulizumab in Adult Participants With NMOSD (NCT04201262), a non-randomized phase 3 study. The primary outcome is Number of Participants With an Adjudicated On-trial Relapse in the Primary Treatment Period.

2. Clinical Question

3. Trial Design

This is a Phase 3, multicenter, open-label study with non-randomized allocation and a single-group model. Its official description identifies an external placebo-controlled design. Those labels matter: open-label means the study was not masked, while non-randomized means treatment assignment was not determined by random allocation. The external placebo control is not the same design feature as a randomized placebo arm, and the record does not establish that the groups were exchangeable.

The registry reports enrollment of 58 participants and describes ravulizumab as the intervention. During the Primary Treatment Period, participants were to receive open-label ravulizumab by intravenous infusion starting on Day 1. The registry lists a placebo group for that period as well. It also lists a Long-Term Extension ravulizumab group. These are distinct reported treatment-period groups; they should not be combined into one simple comparison without information about participant overlap and the analysis used.

The primary outcome timeframe is baseline up to 2.25 years, ending with the Primary Treatment Period. The intervention description indicates that the period end was triggered when the last enrolled participant completed between 26 and 50 weeks in the study, with the exact point depending on a condition whose description is incomplete in the registry record. The registry records the study as completed, with a start date of 2019-12-09 and a primary completion date of 2022-03-15.

The registry lists 10 outcome measures and 2 analyses, but the numerical primary-outcome findings and the details of those analyses are not reported in the registry record. The record also does not report a detailed allocation process or enough information to judge whether the external placebo group and ravulizumab group were comparable on prognostic characteristics.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Primary Treatment Period

Reasons for not completing this period:

Long-term Extension Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The full analysis set (FAS) included all participants who had received at least 1 dose of study drug (ravulizumab or placebo).

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The safety set included all participants who received at least 1 dose of study drug (ravulizumab or placebo).

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With an Adjudicated On-trial Relapse in the Primary Treatment Period, measured over Baseline up to 2.25 years (end of the Primary Treatment Period).

The primary endpoint is the number of participants with an adjudicated on-trial relapse during the Primary Treatment Period. It is a participant count: it records whether participants met the specified relapse definition, rather than directly measuring the intensity of symptoms or a change in a continuous score.

The definition combines a clinical event with an objective examination finding. A relapse required new neurologic symptoms or worsening of existing symptoms, accompanied by an objective change on neurologic examination that persisted for more than 24 hours. The treating physician confirmed the event, and an independent relapse adjudication committee had to positively adjudicate it. Adjudication is intended to apply a common event definition and review process, which can reduce reliance on an individual clinician’s unaided classification.

A relapse count is clinically interpretable as the number of participants experiencing the event during the stated period. It is not the same as an annualized relapse rate, which is listed as a secondary outcome, and it does not by itself describe when events occurred or how long participants were observed. Follow-up duration and completeness therefore matter when interpreting counts. The registry specifies the primary timeframe as baseline up to 2.25 years, but does not report the primary event count or a comparative estimate. The endpoint’s purpose and definition can be described; the treatment contrast cannot be quantified from the reported primary results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with identifying what is counted, who is included, and over what period. The primary outcome counts participants with at least one adjudicated on-trial relapse during the Primary Treatment Period. The registry defines the full analysis set as all participants who received at least 1 dose of ravulizumab or placebo. The stated primary timeframe runs from baseline up to 2.25 years, ending with that treatment period. A count of participants with an event is not a rate: it does not adjust for differences in time under observation.

What does adjudication add?

The endpoint definition requires new or worsening neurologic symptoms, an objective change on neurologic examination, and persistence for more than 24 hours. The treating physician confirms the event, and an independent relapse adjudication committee must positively adjudicate it. In general, prespecified criteria and independent review can make event classification more consistent. They do not by themselves prove that every event was captured or eliminate possible differences in ascertainment, especially in an open-label study.

What does the design imply for a comparison?

The trial is described as open-label, non-randomized, and external placebo-controlled. General statistical principle: randomization helps make treatment groups comparable, on average, with respect to both measured and unmeasured baseline factors. Non-randomized groups can differ for reasons associated with prognosis, care, enrollment, or follow-up. An external control also raises questions about whether participants were recruited under comparable conditions and assessed over comparable periods. The registry does not report sufficient detail to resolve these questions. Thus, even if a numerical group contrast were available, it would need interpretation in light of these design features rather than as if it came from a randomized comparison.

How should a confidence interval be read?

General explanation: a confidence interval describes uncertainty around an estimated effect under the statistical model and its assumptions. A narrow interval indicates greater statistical precision than a wide interval, but neither width nor statistical significance resolves design bias, measurement limitations, or whether the endpoint captures outcomes that matter to participants. No primary estimate or confidence interval is reported in the registry record, so precision cannot be evaluated for this endpoint.

What is the role of the planning calculations?

The stated planning illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They consider detecting a stated fraction of the observed effect. These are planning assumptions, not a description of the trial’s own design or evidence that the study had a particular probability of detecting an effect. In general, planning calculations depend on assumptions about the target effect, variability or event frequency, allocation, and analysis. If those assumptions differ from the eventual study, the illustrative sample sizes may not describe the actual operating characteristics. The record does not report a protocol sample-size justification, so the illustrations should not be interpreted as the trial’s original design rationale.

For binary outcomes, general methods compare event counts or proportions across groups, with the choice of effect measure depending on the analysis plan and design. Such a comparison should account for the number of participants observed and the observation period, and should state how missing outcome information is handled. The primary endpoint is a count of participants with a relapse, while annualized relapse rate is separately listed as a secondary outcome. Those endpoints answer related but different questions. A rate incorporates time at risk; a participant count over a specified period does not directly do so.

The registry lists 10 outcome measures and 2 analyses. The numerical primary results and the specific analysis procedures are not reported in the registry record. There is no reported estimate, interval, or p-value from which to describe the observed treatment contrast. General statistical explanations can clarify what such quantities would mean, but they cannot fill that reporting gap or supply a result for this study.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Ravulizumab", "Placebo (ECU-NMO-301)")
n      <- c(58, 47)
events <- c(0, 20)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Ravulizumab  58  0  0.0  0.0  6.2  0.0  6.2  0.0  6.1
ARM  Placebo (ECU-NMO-301)  47  20  42.6  28.3  57.8  29.5  56.7  29.5  56.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures, including the primary count of participants with an adjudicated relapse and secondary outcomes such as annualized relapse rate, disability measures, quality-of-life measures, adverse events, serum ravulizumab concentration, and free C5 concentration. When a study evaluates multiple outcomes, the chance of at least one apparently unusual result can increase if each is tested separately without a plan for controlling multiplicity. General approaches include prespecifying a hierarchy, adjusting significance thresholds, or treating some analyses as exploratory. The registry record does not report a multiplicity strategy, outcome-testing hierarchy, or detailed statistical analysis plan.

Missing-data handling is also not reported in the registry record. This matters because participants may have different follow-up times, and an outcome may be unavailable for some participants. General methods can include complete-case analysis, imputation, or sensitivity analyses, but their suitability depends on why data are missing and on the endpoint and estimand. No method should be assumed for this study from the outcome definition alone.

The primary analysis population is defined as the full analysis set, including participants who received at least 1 dose of study drug, either ravulizumab or placebo. The registry does not report details about exclusions after dosing, the handling of participants with incomplete relapse assessments, or whether any additional analysis populations were used. It also lists 2 analyses without reporting their procedures or numerical results. These omissions prevent assessment of how population selection, missing outcomes, or multiple testing may affect interpretation.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neuromyelitis optica spectrum disorder (34.0%), ankle fracture (3.6%), pancytopenia (2.1%), myocardial ischaemia (2.1%), abdominal pain (2.1%).

The registry reports serious adverse-event figures separately for the Primary Treatment Period placebo group, the Primary Treatment Period ravulizumab group, and the Long-Term Extension ravulizumab group. It lists 26 affected participants among 47 at risk for placebo, 8 among 58 at risk for ravulizumab during the Primary Treatment Period, and 9 among 56 at risk during the Long-Term Extension. The groups represent different treatment periods and a non-randomized design; these counts should not be read as a randomized head-to-head safety comparison.

The record lists the serious-event term neuromyelitis optica spectrum disorder at 34.0%, followed by ankle fracture at 3.6%, pancytopenia at 2.1%, myocardial ischaemia at 2.1%, abdominal pain at 2.1%, and pancreatitis at 2.1%. The registry information does not specify the denominator for these term percentages in the registry record for this analysis, so they should not be converted into participant counts or assigned to a particular treatment group.

The recorded death counts are 0 in the placebo group, 0 in the Primary Treatment Period ravulizumab group, and 1 in the Long-Term Extension ravulizumab group. These figures describe the reported groups and periods; they do not establish causation. The registry also lists affected participants for other adverse events, but the interpretation of those fields is not elaborated in the record. Differences in group size, follow-up, and design prevent simple causal conclusions from raw counts alone.

13. What the Result Does, and Does Not, Mean

The registry record establishes that the study was designed to evaluate ravulizumab efficacy and safety in adults with NMOSD, with an adjudicated on-trial relapse count as its primary outcome. It also provides a detailed clinical definition of relapse, identifies a full analysis set, and describes an open-label, non-randomized, external placebo-controlled design. Those details help readers understand the question and the structure of the evidence.

They do not establish the size or direction of the primary treatment contrast. The numerical primary outcome findings are not reported in the registry record. There is no reported primary event count by group, effect estimate, confidence interval, or p-value from which to judge how many relapses occurred, how groups differed, or how precisely a difference was estimated. No conclusion about efficacy can be drawn from the endpoint definition or study design alone.

The design also affects causal interpretation. In general, a non-randomized external-control comparison may be influenced by differences between groups that are not caused by treatment. Open-label status can also matter for clinical assessment and reporting, although the independent adjudication process provides a structured review of relapse events. The registry entries do not quantify how these issues affected the findings.

The safety record reports affected-participant counts for serious adverse events and lists several serious-event terms, alongside death counts for each reported group. These are descriptive data. Because the comparison is non-randomized and the treatment periods differ, the counts cannot by themselves determine whether an event was caused by treatment or establish a comparative safety effect. Interpretation also depends on exposure time, event definitions, and complete ascertainment, details not fully reported in the registry record.

In short, the record supports a description of the study question, endpoint, design, and selected safety counts. It does not support a quantitative conclusion about the primary outcome or a causal conclusion about benefit or harm.

14. Why This Trial Matters Statistically

This trial illustrates why the design label and the endpoint definition must be read together. The primary outcome is not simply a report of neurologic symptoms: it requires an objective examination change, persistence for more than 24 hours, physician confirmation, and positive independent adjudication. That operational definition makes the intended event clearer and helps readers distinguish the primary endpoint from the separately listed annualized relapse rate.

At the same time, the external placebo-controlled, non-randomized, open-label design makes the comparison structurally different from a randomized blinded trial. General statistical principle: an observed contrast is most persuasive when differences between groups can plausibly be attributed to the intervention rather than to how participants entered or were assessed. External controls can contribute useful context, but their interpretation depends on comparability and follow-up. Those conditions cannot be assumed simply because placebo appears as a group label.

The record also demonstrates the difference between a registered outcome and a reported result. The primary endpoint and its analysis population are defined, but its numerical findings are not reported in the registry record. Without those findings, readers cannot assess event frequency, effect magnitude, or precision. This is a central statistical limitation, not a detail that can be resolved by reading the endpoint description more closely.

Finally, the safety figures require attention to periods and denominators. The Primary Treatment Period and Long-Term Extension ravulizumab groups are reported separately, and the placebo group is not a randomized comparator. Raw counts are descriptive and do not account for duration of exposure or potential differences in baseline risk. These distinctions are important for any responsible statistical reading of the record.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most direct limitation is that numerical results for the primary relapse endpoint are not reported in the registry record. The registry gives the endpoint definition, timeframe, and analysis population, but no group-specific primary count or comparative estimate. As a result, neither the magnitude nor precision of a primary-outcome difference can be assessed.

The study is non-randomized, open-label, and uses an external placebo control. The record does not report enough information to evaluate how the control group was selected, whether baseline characteristics were comparable, or whether outcome ascertainment and follow-up were aligned between groups. These are especially relevant when interpreting any contrast between the listed placebo and ravulizumab groups.

The primary timeframe extends from baseline up to 2.25 years, while the treatment-period description says its endpoint was triggered when the last enrolled participant completed between 26 and 50 weeks, depending on a condition not fully described in the registry record. The available information does not report participant-level follow-up, exposure time, or completeness of relapse assessment. These omissions limit interpretation of event counts over time.

The registry does not report the statistical analysis plan, multiplicity approach, missing-data methods, or sample-size justification. It lists 10 outcome measures and 2 analyses, but does not give their detailed procedures or numerical primary findings. Safety counts and listed event-term percentages also lack enough context in the available record to establish comparative risk or causation. Together, these limitations mean the record supports a design and endpoint description, not a complete statistical evaluation of efficacy or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Efficacy and Safety Study of Ravulizumab in Adult Participants With NMOSD — NCT04201262.
• Registry record last updated 2025-10-14; status last verified 2025-09.
• Results first posted 2023-08-09.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes a completed Phase 3, multicenter, open-label study of ravulizumab in adults with NMOSD. Allocation was non-randomized, the model was single-group, and the study was described as externally placebo-controlled. Enrollment was 58. The recorded start date was 2019-12-09, and the primary completion date was 2022-03-15.

The primary outcome was the count of participants with an adjudicated on-trial relapse during the Primary Treatment Period. Relapse required new or worsening neurologic symptoms with an objective examination change persisting for more than 24 hours, confirmed by the treating physician and positively adjudicated by an independent committee. The full analysis set included participants who received at least 1 dose of ravulizumab or placebo.

Serious adverse-event counts are reported for the Primary Treatment Period placebo and ravulizumab groups and the Long-Term Extension ravulizumab group. However, numerical results for the primary endpoint, comparative effect estimates, uncertainty intervals, missing-data procedures, and detailed analysis methods are not reported in the registry record.