A Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone (NCT01142466), a randomized phase 4 study. The primary outcome is Time From Baseline to First Multiple Sclerosis Relapse (in Weeks).

2. Clinical Question

3. Trial Design

This was a Phase IV, multicenter, open-label, randomized, parallel-group study of Rebif 44 mcg three times per week by subcutaneous injection compared with no treatment. The registry record lists an enrollment of 30 participants and a completed status. The study start is listed as 2005-12 and primary completion as 2009-12. Its stated context was treatment after mitoxantrone for people with relapsing multiple sclerosis, where the study sought to examine the use and course of Rebif as basic therapy.

Random allocation supports a planned comparison between treatment groups, but the record does not provide the allocation sequence method, allocation concealment procedures, or details on how randomization was implemented. Masking is listed as none. An open-label design can influence care, reporting, and decisions about when to assess a suspected relapse; the registry record does not describe measures used to limit these possibilities. It also does not report treatment adherence or the amount of follow-up received by each participant.

The primary endpoint was assessed from baseline through Week 96. The listed secondary outcomes include relapse-free participants, changes in T1, T1-gadolinium and T2 lesions at specified follow-up weeks, changes in Expanded Disability Status Scale score, and adverse events. The record describes seven outcome measures overall and lists six secondary outcomes. The results available for interpretation are not equally detailed across these outcomes.

The primary analysis values are based on small endpoint-specific groups: the registry reports n=4 for Rebif and n=8 for no treatment for the mean time-to-relapse results. The separate relapse-free participant outcome uses n=14 and n=15. These denominators describe different endpoint data and should not be treated as interchangeable. The record does not report a sample-size justification, a protocol, an interim analysis plan, or a complete statistical analysis plan. It is therefore not possible to establish from the registry record whether the reported analyses followed a prespecified plan.

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: A total of 36 participants were screened and 30 were randomized to the study treatment. 6 participants were not treated (4 participants were screening failures and 2 participants did not meet the inclusion and exclusion criteria).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) population included all participants who received at least 1 treatment dose (only for Rebif group) and had at least 1 post-baseline efficacy endpoint assessment. Time to relapse was documented for participants who had at least 1 relapse during the study period.

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 Time From Baseline to First Multiple Sclerosis Relapse (in Weeks), measured over Baseline through Week 96.

Time from baseline to first multiple sclerosis relapse measures how long participants remain without a qualifying relapse after the study baseline. This is a time-to-event outcome: the event is the first relapse that meets the protocol definition, and the measurement is the time until that event. The record defines a qualifying relapse as a new or worsening neurological symptom in the absence of fever, lasting at least 48 hours, with an objective change in the relevant Kurtzke Functional Systems.

This outcome is useful in general because it retains information about when an event occurs, rather than recording only whether an event happened during follow-up. A time-to-event method can also account for participants whose observation ends before an event is recorded, although the registry record does not explain whether or how censoring was handled in this analysis. The reported log-rank test is a standard general method for comparing event-time distributions between groups.

The registry reports mean time values and standard deviations for participants whose time to relapse was documented, and the outcome population description says that a time was documented for participants with at least one relapse during the study period. That makes the reported mean values a summary among participants with a recorded relapse, not a direct summary of time without relapse for every randomized participant. The record does not report a hazard ratio, confidence interval for the time-to-event comparison, or a fuller account of censoring. Those omissions limit how precisely the comparative timing result can be interpreted.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the log-rank test compare?

In general, the log-rank test compares time-to-event experience between groups over the observed follow-up. It uses the timing of events and the participants still under observation at each event time, rather than comparing only group means. Its interpretation depends on the handling of censoring and on the pattern of differences between the event-time distributions. The registry reports a log-rank method and p-value of 0.138 for the primary comparison, but does not provide a hazard ratio, confidence interval, detailed event counts, or a description of censoring. The test result therefore gives limited information about the magnitude and precision of the contrast.

The posted group summaries are means with standard deviations. A mean describes the average of the recorded time values, while a standard deviation describes how dispersed those values are around the mean. In general, a standard deviation is not a confidence interval: it reflects variability among observations rather than uncertainty in the estimated mean. Here, the values are based on n=4 and n=8, and the endpoint description restricts documented relapse times to participants who experienced at least one relapse. Those summaries should not be read as a complete account of event-free time among all participants in either group.

How should the relapse-free comparison be read?

Relapse-free status is a binary outcome: each participant is classified as relapse-free or not relapse-free over the stated follow-up. The posted results report 10 relapse-free participants among n=14 in the Rebif group and 7 among n=15 in the no-treatment group. A risk difference expresses the difference between the two groups' event proportions on an absolute scale. The recalculated risk difference is -0.248, with a 95% confidence interval from -0.594 to 0.098. The sign depends on the comparison direction used in the reported calculation; it should be read alongside the named groups and the stated event definition.

A confidence interval gives a range of values compatible with the observed data under the method's assumptions. It conveys uncertainty in the estimate; it does not guarantee that the true effect lies within that particular interval. In this result, the interval spans zero, which corresponds to no risk difference. The unadjusted recalculated p-value is 0.176. The registry also reports a Fisher Exact p-value of 0.264. Fisher's exact test is a general method for comparing categorical outcomes that calculates a test result from the observed group counts, and it can be used when counts are small. The recalculation and sponsor-reported result come from distinct analyses and need not have identical p-values.

Why do dispersion and small groups matter?

In general, high variability relative to the amount of information in a study makes estimates less precise. The primary standard deviations are large relative to the reported means, and the endpoint-specific groups are small. Those features caution against treating the group means as stable estimates of what would occur in a broader population. Small groups also mean that changing the status of a participant can have substantial influence on a binary summary. Over-dispersion, in general, occurs when observed variability exceeds what a model assumes; it can make model-based standard errors too small if the model does not allow for that extra variation. The registry does not report an over-dispersion assessment or a model-based adjustment, so it is not possible to say whether over-dispersion was considered.

What do the planning illustrations mean?

The planning illustrations are not observed power and are not the trial's original sample-size justification. The record states that they use a two-sided significance level of 0.05, equal allocation, a normal approximation, and a stated fraction of the observed effect. For the binary secondary comparison, the illustrations list participants per arm for 80% power and participants per arm for 90% power across planning for 100%, 75%, and 50% of the observed effect. They are conditional estimates: a smaller effect to detect requires more participants under the stated assumptions. The registry record does not report that those assumptions were used to design or conduct this study.

In general, a sample-size calculation depends on the target effect, variability or event rate, significance level, power target, allocation, and statistical method. A post hoc planning illustration based on the observed effect can be unstable, especially when the observed groups are small. It should be viewed as a planning aid under explicit assumptions, not as evidence that the completed study had adequate power or that a result is reliable. The record does not report the assumptions behind the original enrollment of 30 or a prespecified target effect.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Rebif 44 Mcg", "No Treatment")
n   <- c(4, 8)
m   <- c(35.5, 40.9)
sp  <- c(40.8, 28.7)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Rebif 44 Mcg  4  35.500  40.800  -29.422  100.422
CARM  No Treatment  8  40.900  28.700  16.906  64.894

11. Analyses Reported by the Sponsor

The registry reports the sponsor's log-rank p-value for the primary time-to-relapse comparison as 0.138. It does not report a sponsor-estimated hazard ratio, a confidence interval for that comparison, or a sponsor-reported comparative effect estimate. The posted mean and standard deviation values describe the groups, but they do not supply the missing comparative precision information.

For relapse-free participants, the sponsor-reported analysis is Fisher Exact, with p=0.264. The unadjusted recalculation reports a risk difference of -0.248, a 95% confidence interval from -0.594 to 0.098, and p=0.176. The recalculation is a simple unadjusted analysis of the posted summary counts; its method and target quantity differ from the sponsor's reported Fisher Exact test. A difference between those p-values is not, by itself, evidence of an error or a contradiction.

No discrepancy is flagged for these results. Where a discrepancy is flagged, the sponsor's own analysis takes precedence; that situation is not indicated for this record. The recalculated comparison can help express the binary outcome as an absolute difference with an interval, while the sponsor-reported test remains the registry's own inferential result. Neither should be interpreted without the small group sizes and the limits of the outcome and population reporting.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes, including repeated assessments of lesion counts and disability scores at specified weeks. Testing multiple outcomes or time points creates a multiplicity issue: in general, the more comparisons examined, the greater the chance that at least one result appears notable by chance alone. The registry record does not report whether a multiplicity adjustment was used, which outcomes were designated confirmatory, or whether a hierarchy of testing was prespecified. The unadjusted secondary p-value should therefore be interpreted cautiously and not as a standalone confirmatory result.

The primary outcome population is described as intent-to-treat, but the definition is qualified: participants had to receive at least one treatment dose in the Rebif group and have at least one post-baseline efficacy assessment. The record further says that time to relapse was documented for participants with at least one relapse during the study period. The primary group sizes for the mean time summaries are n=4 and n=8. For relapse-free status, the reported group sizes are n=14 and n=15. The adverse-event at-risk counts are 15 in each group. These outcome-specific denominators indicate that different sets of participants contribute to different results; the registry record does not provide a complete participant flow or explain the reasons for all differences.

Missing data handling is not reported in the registry record. In general, missing outcome measurements can affect estimates if the participants with observed data differ systematically from those without observed data. For time-to-event analyses, censoring and the timing of loss to follow-up also matter. The registry does not describe how missing assessments, withdrawals, treatment discontinuation, or censoring were handled, or whether sensitivity analyses were performed. The primary analysis population's qualification means the label intent-to-treat should not be assumed to mean every randomized participant contributed to every endpoint analysis.

The record also does not report a protocol, detailed statistical analysis plan, interim analyses, or the sample-size justification. Without those materials, it is not possible to determine which analyses were prespecified or how outcome exclusions and missing observations were managed.

13. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: convulsion (6.7%), status epilepticus (6.7%), angle closure glaucoma (6.7%), cholecystitis chronic (6.7%), cholelithiasis (6.7%).

The registry reports serious adverse events in 5 of 15 participants at risk in the Rebif group and 1 of 15 participants at risk in the no-treatment group. Other adverse events are reported for 15 of 15 participants in the Rebif group and 14 of 15 in the no-treatment group. These are descriptive counts. The record does not provide a comparative safety analysis, exposure-adjusted rates, or enough information to determine whether the groups differed in duration of exposure or observation.

The listed serious adverse-event terms are Convulsion, Status Epilepticus, Angle Closure Glaucoma, Cholecystitis chronic, Cholelithiasis, and Haemorrhoid Operation; each is accompanied by 6.7%. The registry record does not provide further detail on event timing, recurrence, severity beyond the serious classification, or attribution to treatment. Death counts are not reported in the registry record.

These figures should not be interpreted as proof that an event was caused by a treatment or that a treatment is safer. A randomized comparison can inform safety assessment, but the small at-risk groups and limited event detail restrict the precision and scope of conclusions. The counts describe what was recorded during the study and do not by themselves establish a causal relationship.

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

The results describe a randomized comparison of Rebif and no treatment after mitoxantrone, with time to first relapse as the primary endpoint. The registry reports group means and standard deviations among a small set of participants with documented relapse times, as well as a log-rank p-value. The secondary relapse-free outcome has its own group sizes and analysis. Taken together, these records provide some observed information about outcomes, but they do not provide a precise estimated primary treatment contrast with a confidence interval.

A p-value is not a measure of effect size, and it does not tell how likely a treatment is to benefit an individual. A non-small p-value does not establish equivalence or absence of an effect. A confidence interval, when reported, helps show the range of uncertainty around an estimate, but the interval for the secondary risk difference is broad and includes no difference. The primary result lacks a reported comparative interval, making its precision especially difficult to judge.

The results do not establish that Rebif improves, worsens, or has no effect on relapse outcomes. They also do not establish the comparative effect on the lesion, disability, or safety outcomes for which numerical results are not reported. Small endpoint-specific groups, open-label assignment, differing analysis denominators, and unreported missing-data and multiplicity procedures all constrain interpretation. The record does not report enough information to determine how far the results generalize beyond the participants enrolled.

In general, a randomized trial is most informative when its population, outcome definitions, analysis plan, follow-up, and handling of missing data are clearly documented and when estimates are accompanied by measures of precision. Here, the registry record gives an outline of the design and selected outcomes, but important details needed for a full appraisal are not reported. The findings should therefore be read as limited registry evidence rather than a complete account of the study's analysis or a basis for individual treatment decisions.

15. Why This Trial Matters Statistically

This study raises statistical questions that are common in small clinical trials: how to interpret time-to-event outcomes when event counts are limited, how to distinguish an endpoint-specific analysis set from the randomized cohort, and how to assess secondary outcomes across several domains and follow-up times. Its primary endpoint is a time-to-event measure, while the record presents mean times among participants with recorded relapses. Those summaries and the log-rank test answer related but not identical statistical questions, making clear population definitions important.

The trial also illustrates why denominators must accompany outcome summaries. The primary mean time results use n=4 and n=8, whereas the relapse-free outcome uses n=14 and n=15. A reader who overlooks that distinction could mistakenly compare the results as though they described the same participants or estimand. Reporting a numerical estimate with an interval, a clear analysis population, event counts, and information about censoring would help readers assess uncertainty more directly.

The secondary findings raise a further issue: several outcomes are listed, including measurements repeated over follow-up. Without a reported multiplicity plan, individual unadjusted comparisons can be misleading if treated as confirmatory. The planning illustrations also demonstrate a useful distinction between sample-size planning and observed evidence: they are conditional illustrations, not observed power and not evidence that the study was designed for a particular target effect.

These statistical features matter because interpretation depends not only on a p-value but also on the estimand, population, precision, missing-data assumptions, and analysis plan. The record's omissions make those elements especially important to identify, rather than filling them in by assumption.

16. 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.

Several limitations are specific to the information reported for this trial. The primary mean time-to-relapse results are based on n=4 in the Rebif group and n=8 in the no-treatment group. The endpoint description restricts the recorded time to participants who experienced at least one relapse, so the means do not represent event-free time for all participants. The registry does not report a primary comparative effect estimate or confidence interval, which limits assessment of the size and precision of the contrast.

The secondary relapse-free result has a separate analysis population and a wide confidence interval for the recalculated risk difference. Numerical results for the other listed secondary outcomes are not reported in the registry record. The record also lacks a detailed participant flow, complete account of missing assessments, censoring details, adherence information, and explanation of why endpoint-specific denominators differ. These gaps prevent a full assessment of potential selection or attrition effects.

The trial is described as open label, with no masking. In general, knowledge of assignment can influence symptom reporting, clinical assessment, or decisions about event classification, though the record does not report whether such effects occurred or how they were addressed. The relapse definition requires an objective functional-systems change, but the record does not describe adjudication or blinded assessment procedures.

Finally, the statistical analysis plan, sample-size justification, and multiplicity approach are not reported in the registry record. The available information is insufficient to verify which analyses were prespecified or how missing data and repeated outcomes were handled. These limitations apply to the interpretation of the registry results; they do not establish that unreported procedures were absent from the study itself.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: A Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone — NCT01142466.
• Registry record last updated 2014-02-27; status last verified 2014-01.
• Results first posted 2011-06-10.
• 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.

20. Record Summary

The registry record describes a completed Phase IV, multicenter, open-label, randomized, parallel-group study of Rebif 44 mcg three times per week by subcutaneous injection compared with no treatment after mitoxantrone in relapsing multiple sclerosis. Enrollment is listed as 30, with study start 2005-12 and primary completion 2009-12.

The primary endpoint was time from baseline to first relapse through Week 96. Mean times and standard deviations are reported for small endpoint-specific groups, alongside a log-rank p-value of 0.138. A secondary relapse-free outcome is also reported, with separate group sizes and both a sponsor-reported Fisher Exact p-value and an unadjusted recalculation. Serious and other adverse-event counts are reported, but detailed outcome results and key methods information are incomplete.

Important details not reported in the registry record include a full statistical analysis plan, sample-size justification, multiplicity strategy, missing-data procedures, and primary comparative confidence interval. Those omissions limit assessment of precision and confirmatory interpretation.