Safety Study to Evaluate Immune Response of Vaccines in Participants With Relapsing Forms of Multiple Sclerosis Who Receive Ozanimod Compared to Non-Pegylated Interferon (IFN)-β or No Disease Modifying Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study to Evaluate Immune Response of Vaccines in Participants With Relapsing Forms of Multiple Sclerosis Who Receive Ozanimod Compared to Non-Pegylated Interferon (IFN)-β or No Disease Modifying Therapy (NCT05028634), a non-randomized phase 3 study. The primary outcome is Percentage of Participants Meeting Immune Serological Response Criteria to Tetanus Toxoid Antigen.

2. Clinical Question

3. Trial Design

This was a Phase 3b, multicenter, open-label, parallel-group study with non-randomized allocation. The registry record lists multiple sclerosis and relapsing-remitting multiple sclerosis as conditions. Enrollment was 63, and the study status is completed. The recorded start date is 2021-11-11, and the primary completion date is 2023-11-15.

The study compared participants receiving oral ozanimod with a non-ozanimod group comprising participants receiving non-pegylated interferon-beta or no disease-modifying therapy. The non-ozanimod group combines two care situations, rather than representing a single treatment. Participants were not randomly allocated to these groups, so the comparison is observational within the study design. Open-label means the study was not masked; the registry lists masking as none.

Vaccination was central to the study. Cohort 1 descriptions include tetanus, diphtheria, and acellular pertussis vaccine, pneumococcal polysaccharide vaccine, and seasonal inactivated influenza vaccine. Cohort 2 descriptions include tetanus, diphtheria, and acellular pertussis vaccine and pneumococcal polysaccharide vaccine. The registry states that enrollment is closed for the ozanimod arm of Cohort 1. Further details about the relationship between cohorts, timing of vaccination, or reasons for cohort assignment are not reported in the registry record.

The total enrollment of 63 should not automatically be treated as the analysis population for every endpoint. For the primary endpoint, the registry describes a modified intent-to-treat population based on receiving at least one vaccination and having data at the specified timepoint. The adverse-event figures separately list 30 participants at risk in the ozanimod group and 33 in the non-ozanimod group. The record does not provide endpoint-specific denominators for the primary response result because that result is not reported.

The study’s stated purpose was to provide information on immune response and safety after vaccination in people with relapsing multiple sclerosis receiving ozanimod, compared with non-ozanimod care. The record also notes that these data were intended to support labeling for ozanimod in multiple sclerosis. That stated purpose does not establish what the results were. Numerical primary endpoint findings and statistical comparisons are not reported in the registry record.

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.

Before assignment: As pre-specified per protocol, Cohort 1 and Cohort 2 are pooled per the following treatment groups. i. Ozanimod treatment group ii. Non-Ozanimod treatment group

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Intent-to-Treat (mITT) Population consists of all participants who received at least one vaccination and summarized according to their initial treatment status (ozanimod vs. non-ozanimod) regardless of systemic use of corticosteroids. Participants with data available at the specified timepoint are included in the analysis.

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.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Meeting Immune Serological Response Criteria to Tetanus Toxoid Antigen, measured over Day 28.

The primary endpoint is the percentage of participants meeting the study’s serological response criteria for tetanus toxoid at Day 28. It classifies each participant according to antibody titers before and after vaccination. For a pre-vaccination titer at or below 0.10 IU/mL, the stated criterion is a post-vaccination level at or above 0.40 IU/mL. For a pre-vaccination titer above 0.10 IU/mL and at or below 2.7 IU/mL, the criterion is at least a 4-fold increase. For a pre-vaccination titer above 2.7 IU/mL, the criterion is at least a 2-fold increase.

This threshold-based endpoint turns a laboratory measurement into a responder classification, then summarizes the proportion of participants who meet the criterion. It allows the study to assess whether participants reached a prespecified antibody response rather than relying only on a change in antibody titer. The different rules account for the starting titer: participants beginning at different levels are assessed using different response thresholds.

As a general statistical point, a percentage is easier to interpret alongside its denominator and a measure of uncertainty. A percentage based on a small analysis group can be imprecise, even when it appears large or small. The registry record does not report the primary endpoint percentage, its endpoint-specific denominator, or an uncertainty interval. The response criteria are reported, but the resulting participant classifications and group comparison are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a percentage of participants meeting a serological response criterion for tetanus toxoid at Day 28. The endpoint is binary at the participant level: each participant either meets the specified rule or does not, and the group summary is a percentage. The registry specifies the antibody thresholds and fold-change rules, but does not report the primary endpoint result, its endpoint-specific denominator, or a statistical analysis for the comparison.

What does a percentage measure?

As a general statistical explanation, a percentage describes the frequency of an outcome among a defined set of participants. Its interpretation depends on who is included in the numerator and denominator. For this endpoint, the numerator would consist of participants classified as meeting the serological response criteria, and the denominator would be the eligible participants with the required endpoint information in the analysis population. The registry’s primary endpoint description refers to a modified intent-to-treat population and participants with data at the specified timepoint. The actual endpoint denominator and responder count are not reported in the registry record, so no endpoint percentage can be interpreted from the record.

A percentage is an estimate, not a perfectly precise description of a wider population. General statistical reasoning therefore considers uncertainty as well as the point estimate. A confidence interval is one common way to express uncertainty around an estimate: it gives a range of values compatible with the data under the method’s assumptions. The registry record does not report a confidence interval for the primary outcome. Without an estimate and its uncertainty, the precision of the primary response comparison cannot be assessed.

Why does the response rule depend on baseline titer?

The response criterion uses different rules according to the pre-vaccination antibody titer. Participants starting at or below 0.10 IU/mL must reach at least 0.40 IU/mL after vaccination. Those starting above 0.10 IU/mL and at or below 2.7 IU/mL must have at least a 4-fold increase, while those starting above 2.7 IU/mL must have at least a 2-fold increase. This is a classification rule based on both starting level and subsequent response. As a general statistical point, baseline-dependent rules can make the exact definition of a responder important: a participant’s classification depends not only on the post-vaccination value but also on the pre-vaccination value.

What does non-randomized allocation imply?

General statistical explanation: random allocation is designed to make treatment groups comparable on average with respect to both measured and unmeasured characteristics. In a non-randomized study, treatment status may be associated with participant characteristics, clinical decisions, or other factors. A difference in response between groups could therefore reflect treatment status, differences between the participants, or both. Adjustment for measured characteristics can sometimes address part of this problem, but it cannot guarantee removal of all confounding. The registry record does not report a primary analysis or an adjustment strategy, so it is not possible to determine whether any such approach was used.

The comparison group also combines participants receiving non-pegylated interferon-beta with participants receiving no disease-modifying therapy. These are distinct care categories in the record, but the reported group label treats them together. A combined comparison can describe the group as defined, but does not by itself distinguish outcomes for its constituent categories. Separate subgroup results are not reported in the registry record.

How should the planning illustrations be read?

The registry describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence that the study was designed using those assumptions. The registry record does not report the trial’s own sample-size justification. It also does not report the numerical planning illustration results or the observed primary endpoint effect needed to interpret them.

As a general statistical explanation, a sample-size calculation asks how many participants would be needed under specified assumptions to attain a chosen probability of detecting a defined effect at a chosen significance level. It is conditional on the assumed effect, variability or event frequency, allocation, and analysis method. A calculation based on an observed effect is especially dependent on that effect estimate; if the estimate is uncertain, the resulting planning figure is uncertain too. Such planning figures are not “observed power,” and they do not show that the completed study had a particular probability of finding a result.

The registry lists no analyses. It does not report a statistical model for the primary comparison, an inferential test, an adjustment for covariates, or an interval estimate. The normal approximation stated for planning illustrations should not be mistaken for a documented primary-outcome analysis method. Without the analysis details and primary result, no independent assessment of the study’s inferential method or precision is possible.

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("Ozanimod", "Non-Ozanimod")
n      <- c(30, 32)
events <- c(3, 17)
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  Ozanimod  30  3  10.0  2.1  26.5  3.5  25.6  3.6  25.8
ARM  Non-Ozanimod  32  17  53.1  34.7  70.9  36.4  69.1  36.4  69.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures and no analyses. The outcomes span immune response and protection after pneumococcal polysaccharide vaccination, adverse events, and blood chemistry and hematology measures. Listing several outcomes raises a general statistical issue: when many outcomes or comparisons are examined, the chance of observing at least one apparently notable result can increase. Researchers may address this through a prespecified outcome hierarchy, adjustment procedures, or careful interpretation of exploratory findings. The registry record does not report a multiplicity plan, an adjustment method, or which secondary outcomes, if any, were treated as confirmatory.

The primary outcome definition identifies a modified intent-to-treat population consisting of participants who received at least one vaccination, summarized according to initial treatment status—ozanimod or non-ozanimod—regardless of systemic corticosteroid use. The description also refers to participants with data available at the specified timepoint, but the remainder of the population description is not reported in the registry record. The record does not provide a primary outcome denominator or explain how missing Day 28 measurements were handled.

As a general statistical point, missing outcome data can affect both the number of participants contributing to an estimate and the interpretation of that estimate. The consequences depend on why data are missing and on the analysis approach. Excluding participants without an observed endpoint, imputing values, or using another method can lead to different estimates under different assumptions. The registry record does not report a missing-data method, reasons for missing endpoint data, or sensitivity analyses.

The record also does not report whether an analysis population differed from the stated modified intent-to-treat population, how participants were handled if they received more than one vaccine, or whether any prespecified subgroup analyses were performed. These details are needed to evaluate the population represented by the primary result, but that result and the associated analysis are not reported in the registry record.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry’s serious adverse-event figures list 0 affected participants among 30 at risk in the ozanimod group and 0 among 33 at risk in the non-ozanimod group. The registry lists 0 deaths in each group. These are counts for the groups reported in the safety record; they should not be read as proof that serious adverse events cannot occur or that the groups have identical safety.

Zero observed events provide limited information about how frequently an event might occur beyond the participants and observation period represented in the record. A comparative safety conclusion would ordinarily require context about event definitions, follow-up duration, completeness of reporting, and uncertainty around the estimates. Those details are not reported in the registry record. Because the study was non-randomized, safety differences between groups would also require caution about group comparability.

The registry separately lists 5 participants with other adverse events in the ozanimod group and 7 in the non-ozanimod group. These are not the serious adverse-event counts and should not be conflated with them. The record does not provide event terms for serious adverse events; the serious-event term list is empty. The counts alone do not establish a causal relationship between treatment and events.

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

The registry record documents a study of vaccine immune response and safety in participants with relapsing forms of multiple sclerosis receiving ozanimod or non-ozanimod care. It specifies the primary endpoint, including the baseline-dependent tetanus toxoid response criteria, and identifies Day 28 as the assessment timepoint. It also records group-level safety counts, including zero serious adverse events and zero deaths in each listed group.

What the record does not establish is the primary endpoint result. No percentage meeting the tetanus response criteria, endpoint-specific participant count, between-group estimate, confidence interval, or p-value is reported. The study’s stated purpose and endpoint definition cannot substitute for the outcome findings. The registry record therefore does not show the magnitude or precision of a difference in immune response.

The design also limits causal interpretation. The comparison was not randomized, and the non-ozanimod group combines people receiving non-pegylated interferon-beta with people receiving no disease-modifying therapy. Any observed group difference could be related to treatment status or to other differences between the groups. The registry record does not report an analysis that could clarify or adjust for those possibilities.

As a general statistical principle, an estimate should be considered together with its uncertainty, the population included, the outcome definition, and the design that generated the comparison. The record contains no primary estimate or uncertainty measure to assess. Safety counts are descriptive, and the absence of recorded serious events in these groups does not establish absence of risk. The listed secondary outcome titles likewise do not reveal their results; their findings are not reported in the registry record.

The appropriate interpretation is therefore limited: the record describes what the study set out to measure and provides selected safety counts, but it does not provide the primary immune-response result or the statistical analysis needed to quantify a group comparison. It cannot, on its own, establish that one treatment strategy changes vaccine response or safety relative to the other.

14. Why This Trial Matters Statistically

This study addresses a statistical question in which both treatment status and the vaccine response are relevant: whether antibody response after vaccination differs between participants receiving ozanimod and participants receiving non-ozanimod care. The registry defines a participant-level response using baseline antibody titers and a Day 28 assessment. That definition matters because a responder percentage is interpretable only when the rule for classifying participants is explicit.

The design also illustrates why a clear endpoint definition is not enough to evaluate a comparison. Participants were not randomly allocated, and the comparison group combines two types of non-ozanimod care. The observed groups may therefore differ in ways that affect response. Statistical interpretation needs to keep design limitations separate from the endpoint’s measurement properties: a well-defined outcome does not remove confounding from non-randomized allocation.

The record provides a useful example of the distinction between study purpose, planned measurement, and reported evidence. It states that the study was intended to provide data on immune response and safety, and it identifies several vaccine and laboratory outcomes. Yet the primary response result and its statistical uncertainty are not reported in the registry record. Without those, readers cannot assess the size or precision of the primary comparison, regardless of the stated rationale for conducting the study.

The safety counts also demonstrate why denominators and outcome categories matter. The serious adverse-event counts are zero in both groups, while other adverse events are listed separately. Keeping these categories distinct avoids treating all reported events as equivalent. At the same time, descriptive counts should not be turned into claims of comparative safety without considering follow-up, uncertainty, and the non-randomized design.

Finally, the registry identifies multiple outcomes but reports no analyses. That makes multiplicity, missing data, and analysis-population choices important questions that cannot be resolved from the record. This trial is statistically informative as an example of how design, outcome definition, reporting completeness, and uncertainty jointly determine what conclusions can be drawn—not as a basis for an unreported primary result.

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 primary limitation for interpreting the study is that the registry record does not report the primary endpoint result. Although the response criteria and Day 28 timeframe are described, the responder count, percentage, denominator, and comparative estimate are absent. The precision of any primary estimate is therefore not assessable. Statistical analyses are not listed, and the record does not report a test, model, confidence interval, or p-value for the primary comparison.

Non-randomized allocation is an additional limitation. Treatment groups may differ in participant characteristics or other factors related to antibody response and safety. The registry record does not report enough information to assess those differences or determine whether an adjustment strategy was used. The non-ozanimod group also combines participants receiving non-pegylated interferon-beta with those receiving no disease-modifying therapy, preventing interpretation of those care categories as separate comparisons from the information recorded.

The primary population description is incomplete in the registry record. It states that the modified intent-to-treat population includes participants who received at least one vaccination and is categorized by initial treatment status regardless of systemic corticosteroid use; it also refers to participants with data available at the specified timepoint. Further details about endpoint availability, missing-data handling, and analysis exclusions are not reported.

The record lists multiple secondary outcomes but no analyses. A multiplicity strategy, the status of secondary outcomes as confirmatory or exploratory, and any prespecified subgroup approach are not reported. For safety, the record gives group counts but does not report follow-up duration or further details needed to interpret event ascertainment. These limitations mean that the design and selected safety counts can be described, but the primary immune-response comparison and its uncertainty cannot be evaluated from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety Study to Evaluate Immune Response of Vaccines in Participants With Relapsing Forms of Multiple Sclerosis Who Receive Ozanimod Compared to Non-Pegylated Interferon (IFN)-β or No Disease Modifying Therapy — NCT05028634.
• Registry record last updated 2025-02-11; status last verified 2025-01.
• Results first posted 2025-01-22.
• 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

NCT05028634 is a completed Phase 3b, multicenter, open-label, parallel-group study with non-randomized allocation and enrollment of 63. It examined vaccine immune response and safety among participants with relapsing forms of multiple sclerosis receiving oral ozanimod or non-ozanimod care. The non-ozanimod group comprised participants receiving non-pegylated interferon-beta or no disease-modifying therapy.

The primary endpoint was the percentage meeting tetanus toxoid serological response criteria at Day 28. The registry describes the criteria but does not report the primary endpoint result or an analysis. It lists zero serious adverse events among 30 participants at risk in the ozanimod group and among 33 in the non-ozanimod group, with zero deaths in each group. The study’s primary immune-response findings, statistical uncertainty, and missing-data methods are not reported in the registry record.