This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Safety Study in Relapsing-remitting Multiple Sclerosis (RRMS) Patients Receiving Betaferon or Rebif (NCT00317941), a randomized phase 4 study. The primary outcome is Percentage of the Sites Developing a Injection Site Reaction (ISR) Reported by Participants 24 Hours After Each Injection.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00317941 |
| Phase | Phase 4 |
| Condition | Relapsing-remitting Multiple Sclerosis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 220 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Bayer |
| Results posted | Yes |
2. Clinical Question
Population
Participants with relapsing-remitting multiple sclerosis, or after a first demyelinating event suggestive of multiple sclerosis, newly started on interferon beta treatment. The registry lists relapsing-remitting multiple sclerosis as the condition. The primary-outcome summaries report 142.0 participants in the Betaferon group and 63.0 in the Rebif group.
Intervention
Subcutaneous interferon beta-1b (Betaferon), with the study description identifying Betaject and Betaject Light autoinjectors. The arm descriptions specify 250 mcg administered every other day. The primary outcome is listed for an IFNB-1b 250 Mcg group, but whether the two device groups were combined in that summary is not reported in the registry record.
Comparator
Subcutaneous interferon beta-1a (Rebif), listed as 44 mcg three times per week using Rebiject II. This is an active-treatment comparison rather than a comparison with no treatment. The primary-outcome summary reports 63.0 participants in the Rebif group.
Primary question
What percentage of injection sites developed a reaction, as reported by participants, 24 hours after each injection during follow-up of up to 3 months? The study also considered injection-site pain and other reaction measures. The registry reports the primary percentages as 31.0 for Betaferon and 37.0 for Rebif, without a confidence interval or a reported inferential comparison for that endpoint.
The study was registered as a randomized, multicenter, phase IV, open-label, prospective, parallel-group comparison. Its stated focus was injection-site reaction and pain after subcutaneous administration of Betaferon or Rebif using different autoinjectors. Because treatment and device were part of the comparison, the question concerns the treatment regimens as studied, not the isolated effect of a drug molecule independent of its delivery method.
3. Trial Design
The AVANTAGE study is recorded as a randomized, multicenter, phase IV, open-label, prospective study with a parallel design and no masking. The registry lists an enrollment of 220 and a completed status. The recorded study dates are 2006-03 for the start and 2008-04 for primary completion. The sponsor is Bayer.
The arm descriptions identify three regimens: interferon beta-1b 250 mcg using Betaject, interferon beta-1b 250 mcg using Betaject Light, and interferon beta-1a 44 mcg using Rebiject II. The beta-1b regimens are described as every-other-day subcutaneous injections, while the beta-1a regimen is described as subcutaneous injections three times per week. The primary-outcome summaries, however, list a Betaferon group and a Rebif group rather than separate Betaject and Betaject Light groups. Whether the device-specific beta-1b arms were pooled for those summaries is not reported in the registry record.
Randomization can support a fair comparison by helping balance participant characteristics across groups, but the registry record does not report the allocation procedure, concealment method, or details of the randomization sequence. Since masking is recorded as none, participants and study personnel knew which regimen was being used. This is relevant for outcomes based on participant or physician reports, which can be influenced by awareness of treatment assignment.
The primary outcome was assessed repeatedly after injections for up to 3 months. The registry describes the outcome as the percentage of sites developing an injection-site reaction, reported by participants 24 hours after each injection. The endpoint description says that sites were assessed using a reaction-intensity score and that the number of injection sites per month per participant was analyzed. Further details about how repeated site-level observations were handled are not reported in the registry record.
Although the registry lists enrollment of 220, the primary summaries list 142.0 participants for Betaferon and 63.0 for Rebif. The analysis population, reasons for the difference from enrollment, and handling of missing observations are not reported in the registry record. The reported safety-group denominators also differ from the primary-outcome denominators, so they should be read as outcome-specific figures rather than assumed to represent the same analysis population.
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.
Overall Study
| Stage | Group A: IFNB-1b 250 Mcg (Betaseron) Via Betaject | Group B: IFNB-1b 250 Mcg (Betaseron) Via Betaject Light | Group C: IFNB-1a 44 Mcg (Rebif) Via Rebiject II |
|---|---|---|---|
| STARTED | 73 | 79 | 68 |
| Participants Received Treatment | 73 | 79 | 68 |
| Fulfilled Requirement Safety Population | 73 | 77 | 65 |
| Fulfilled Requirements PP Population | 66 | 76 | 63 |
| COMPLETED | 66 | 74 | 60 |
| NOT COMPLETED | 7 | 5 | 8 |
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.
| Characteristic | Unit | IFNB-1b 250 Mcg (Betaseron) | IFNB-1a 44 Mcg (Rebif) Via Rebiject II | Total |
|---|---|---|---|---|
| Participants analysed | 142 | 63 | 205 | |
| Age Continuous | Years | 39.2 (SD 10.3) | 38.4 (SD 10.5) | 38.7 (SD 10.4) |
| Sex: Female, Male: Female | Participants | 106 | 47 | 153 |
| Sex: Female, Male: Male | Participants | 36 | 16 | 52 |
| Number of relapses | Relapses | 2.2 (SD 1.2) | 2.1 (SD 1.0) | 2.1 (SD 1.1) |
| Expanded disability status scale at screening (EDSS) | Scores on a scale | 1.7 (SD 1.2) | 1.9 (SD 1.4) | 1.8 (SD 1.3) |
| Time since diagnosis | Years | 3.3 (SD 5.7) | 3.3 (SD 6.7) | 3.3 (SD 6.4) |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of the Sites Developing a Injection Site Reaction (ISR) Reported by Participants 24 Hours After Each Injection, measured over Up to 3 months assessed every 24 hours after each injection.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Percentage of sites |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the percentage of injection sites developing an injection-site reaction, as reported by participants 24 hours after each injection. The registry defines a site as having a reaction when the participant's reaction-intensity score for that site is at least 1. Assessment continued for up to 3 months, with the registry describing site counts per month per participant as the analyzed quantity.
This endpoint focuses on a local reaction at the injection site rather than on a broader disease outcome. Repeated assessment after injections can describe how often participants reported a reaction at treated sites during the observation period. Participant reporting also captures the experience from the person receiving the injection, although open-label awareness may influence reporting. The registry does not report how the intensity scale was constructed beyond its threshold for classifying a site as having a reaction.
The posted primary values are 31.0 for Betaferon and 37.0 for Rebif. They are percentages of sites, not percentages of participants. Those quantities have different denominators and should not be read interchangeably. The primary summary does not include an uncertainty interval or a reported statistical test. The registry record therefore gives descriptive percentages for this endpoint, but not enough information to judge the precision of the between-group contrast or whether a formal inferential analysis was conducted.
Injection-site pain and several other reaction measures were listed as secondary outcomes. They address related but distinct aspects of tolerability, with some based on participant reports and others on physician reports or reaction severity at later assessments.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The primary endpoint is reported as 31.0 for Betaferon and 37.0 for Rebif: the percentages of injection sites classified as developing a reaction, based on participant reports 24 hours after injection. These are descriptive arm summaries. The registry does not report a confidence interval, standard error, or statistical test for this primary comparison, and no analysis estimate for it is posted. The values alone therefore do not establish how precisely the groups differ or whether the observed contrast is compatible with no underlying difference.
The endpoint concerns injection sites, with repeated injections and site assessments over follow-up of up to 3 months. It is not a percentage of participants who experienced at least one reaction. A participant may contribute multiple site observations, and the registry says that the number of sites per month per participant was analyzed. How within-participant dependence and variation in the number of observed sites were handled is not reported in the registry record. This makes it especially important not to treat the two percentages as if they were simple participant-level event rates.
The registry also posts unadjusted comparisons for two secondary outcomes. For participants without an injection-site reaction, the reported percentages are 21.3 for Betaferon and 9.5 for Rebif. The reported risk difference for Rebif relative to Betaferon is -0.116, with a 95% confidence interval from -0.215 to -0.017 and an unadjusted p-value of 0.044. The interval excludes zero, but this is an unadjusted secondary result, and the registry does not report an adjustment for examining multiple outcomes.
For participants without pain, the reported percentages are 5.6 for Betaferon and 17.7 for Rebif. The risk difference for Rebif relative to Betaferon is 0.118, with a 95% confidence interval from 0.017 to 0.219 and an unadjusted p-value of 0.007. This result also concerns a secondary outcome, and its interpretation should take account of the number of outcomes considered and the absence of a reported multiplicity procedure.
The two secondary outcomes point in different directions because they measure different experiences: absence of a reaction and absence of pain. Neither replaces the primary endpoint, and neither establishes an overall ranking of the regimens. In addition, the registry does not post a detailed statistical analysis plan, analysis populations, or methods for handling repeated observations and missing data. Those omissions limit the conclusions that can be drawn from the reported contrasts.
Sample-size figures associated with the secondary comparisons are planning illustrations based on observed effects. They are not evidence of the trial's original design assumptions or of observed power. The registry record does not report the trial's sample-size justification. The posted estimates and p-values should therefore be read as results from the recorded summaries, with their stated uncertainty and reporting limitations, rather than as a complete account of the study's statistical analysis.
9. Statistical Methods Explained
The primary outcome is a count-based percentage: the percentage of injection sites classified as having a reaction. The registry reports arm-level percentages but does not post a comparison estimate, uncertainty interval, or inferential test for this endpoint. Consequently, the primary numerical summaries support a descriptive account, not a quantified estimate of the uncertainty around the between-group difference.
What does a confidence interval convey?
A confidence interval describes the range of estimates compatible with the observed data under the statistical method used. A narrower interval indicates greater precision under that method; a wider interval indicates more uncertainty. For a risk difference, an interval containing zero is compatible with no difference under the model, while an interval that excludes zero indicates that zero is outside the interval. This does not by itself establish clinical importance, remove bias, or account for analyses that were not included in the interval calculation.
The posted secondary risk differences have confidence intervals. For participants without an injection-site reaction, the risk difference is -0.116, with an interval from -0.215 to -0.017. For participants without pain, it is 0.118, with an interval from 0.017 to 0.219. These are unadjusted comparisons. The registry does not identify a multiplicity adjustment, so the intervals and p-values do not reflect an adjustment for considering several outcomes.
Why are these outcomes not interchangeable?
A risk difference compares the observed proportions between groups on an absolute scale. Here, the two comparisons concern the proportions of participants without a reaction and without pain. The primary endpoint instead concerns the percentage of injection sites with a reaction. Its measurement unit and analysis structure differ from those of the secondary participant-level outcomes. The primary percentages cannot be treated as participant-level risks, and the secondary risk differences cannot be substituted for a primary-endpoint contrast.
The registry also reports relative risk and odds-ratio estimates for the secondary comparisons. These are alternative scales for describing a binary outcome comparison. A relative risk compares proportions as a ratio, while an odds ratio compares odds. Each scale answers a different descriptive question; its interpretation depends on the underlying outcome and population. The estimates are not adjusted analyses, and they do not resolve potential issues from missing observations, outcome multiplicity, or the open-label design.
What does an unadjusted p-value mean?
A p-value is a measure, under a specified statistical model, of how incompatible the observed data are with a null hypothesis of no difference. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of a difference. The posted p-values, 0.044 for participants without an injection-site reaction and 0.007 for participants without pain, are explicitly unadjusted. The registry does not report whether these comparisons were prespecified as part of a formal testing hierarchy, or whether any other multiplicity strategy was used.
With many outcomes, repeated testing can increase the chance that at least one result appears more striking than it would in a single planned test. This is a general statistical concern, not a claim about which results are true in this trial. Because 18 outcome measures are recorded and 14 secondary outcomes are posted, the absence of a reported multiplicity plan matters when interpreting the secondary p-values. The count of outcomes does not reveal how many were formally tested or how the investigators intended to interpret them.
Why can repeated site observations require special handling?
Sites assessed within the same participant are not necessarily statistically independent. A participant's experiences, reporting tendencies, and treatment conditions can affect more than one site observation. Treating correlated observations as independent can make uncertainty appear smaller than it is. General methods for clustered or repeated data can account for this dependence, but the specific method used for the primary endpoint is not reported in the registry record. The number of injection sites per participant may also vary, and the record does not explain whether or how that variation was accounted for.
Over-dispersion is a general issue for count data: the observed variability can be greater than a statistical model assumes. If it is ignored, standard errors and confidence intervals can be poorly calibrated. The registry describes a count-based primary endpoint but does not provide enough analysis detail to determine whether over-dispersion was assessed or how it was handled. No assumption about the analysis model should be inferred from the endpoint label alone.
How should the planning illustrations be read?
The registry's planning illustrations use observed secondary effects and describe participant counts per arm for target power levels under stated assumptions: two-sided significance level 0.05, equal allocation, and a normal approximation. Rows use 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. These figures are hypothetical planning scenarios, not the trial's original sample-size justification and not observed power. The registry does not report the trial's own sample-size assumptions or justification. A calculation based on an observed effect cannot establish the probability that the completed study detected a true effect.
The registry lists 220 enrolled participants, while the posted primary summaries use group sizes of 142.0 and 63.0. It also reports different denominators for the safety summaries. The analysis populations and reasons for these differences are not reported. The posted results do not state how missing outcomes, protocol deviations, or exclusions were handled. These details affect how estimates can be interpreted and limit independent evaluation of the analysis.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 18 outcome measures and records 14 secondary outcomes as posted. Two secondary outcomes have reported unadjusted comparisons. The registry record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a distinction between confirmatory and exploratory secondary analyses. In a study with several outcomes, interpreting individual p-values without such context can overstate how definitive a finding is. This concern applies to the posted secondary comparisons, not as a claim that any particular result is false.
The primary endpoint has descriptive percentages but no reported comparison test or confidence interval. The registry record does not make clear whether the primary comparison was analyzed but not posted, whether it was not conducted, or what inferential method may have been planned. A statistical analysis plan is not reported in the registry record. Details of the prespecified analysis, decision rules, and any interim analyses are also not reported in the registry record.
Missing-data handling is not reported in the registry record. The enrollment figure is 220, while the primary-outcome summaries list 142.0 and 63.0 participants. The safety groups have denominators of 150 and 65. These figures refer to different posted outcome summaries; the registry does not explain the relationship between the denominators, the analysis populations, or any exclusions. It also does not state how missing assessments or participants who did not complete follow-up were handled.
The primary endpoint involved repeated site assessments following injections over up to 3 months. The registry does not report the specific method used to account for repeated observations within participants, varying numbers of sites, or any correlation among measurements. Nor does it report whether the analysis followed an intention-to-treat, per-protocol, or other population definition. These are important uncertainties when interpreting the estimates and their precision. No assumptions about these methods can be recovered from the posted summaries alone.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| IFNB-1b 250 Mcg (Betaseron) | 2 | 150 | 1.3% |
| IFNB-1a 44 Mcg (Rebif) Via Rebiject II | 1 | 65 | 1.5% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| IFNB-1b 250 Mcg (Betaseron) | 83 of 150 |
| IFNB-1a 44 Mcg (Rebif) Via Rebiject II | 42 of 65 |
Most frequent serious adverse event terms
| Event term | Organ system | IFNB-1b 250 Mcg (Betaseron) | IFNB-1a 44 Mcg (Rebif) Via Rebiject II |
|---|---|---|---|
| Lumbago | Musculoskeletal and connective tissue disorders | 1 of 150 | 0 of 65 |
| Cytolitic hepatitis | Hepatobiliary disorders | 1 of 150 | 0 of 65 |
| Acute coronary syndrome | Cardiac disorders | 0 of 150 | 1 of 65 |
Most frequent non-serious adverse event terms
| Event term | Organ system | IFNB-1b 250 Mcg (Betaseron) | IFNB-1a 44 Mcg (Rebif) Via Rebiject II |
|---|---|---|---|
| Influenza like illness | General disorders | 32 of 150 | 15 of 65 |
| Multiple sclerosis relapse | Nervous system disorders | 12 of 150 | 8 of 65 |
| Injection site pain | General disorders | 7 of 150 | 6 of 65 |
| Asthenia | General disorders | 6 of 150 | 5 of 65 |
| Headache | Nervous system disorders | 6 of 150 | 3 of 65 |
| Fatigue | General disorders | 6 of 150 | 2 of 65 |
| Pyrexia | General disorders | 4 of 150 | 3 of 65 |
| Transaminase increase | Investigations | 5 of 150 | 1 of 65 |
| Myalgia | Musculoskeletal and connective tissue disorders | 5 of 150 | 1 of 65 |
| Alopecia | Skin and subcutaneous tissue disorders | 3 of 150 | 2 of 65 |
Serious events with the highest arm-level rate: acute coronary syndrome (1.5%), lumbago (0.7%), cytolitic hepatitis (0.7%).
The safety summary reports serious adverse events for 2 of 150 participants in the Betaferon group and 1 of 65 participants in the Rebif group. It also reports other adverse events for 83 of 150 and 42 of 65, respectively. These are descriptive counts and denominators; the registry does not provide a comparative safety estimate or uncertainty interval for them. The safety denominators differ from those in the primary outcome summaries, and the relationship between the analysis populations is not reported in the registry record.
The serious-event terms listed include acute coronary syndrome at 1.5%, lumbago at 0.7%, and cytolitic hepatitis at 0.7%. The record does not identify these terms by treatment group in the listed summary, so they cannot be assigned to either regimen from that information. Deaths are not reported in the registry record. The posted figures do not establish whether an event was caused by treatment, and the registry summary does not provide enough detail to compare the groups formally.
Serious adverse-event counts are usually sparse, so small counts can yield considerable uncertainty. This is a general statistical point, not a trial-specific estimate of uncertainty. The figures should be read as the events recorded in the registry summary, not as a complete assessment of comparative safety.
12. What the Result Does, and Does Not, Mean
The posted primary summaries describe the percentage of injection sites reported by participants as having a reaction 24 hours after injection: 31.0 for Betaferon and 37.0 for Rebif. They do not include a confidence interval or a reported statistical test. The figures therefore show the recorded arm-level percentages but do not quantify the uncertainty in their contrast. They also do not describe the percentage of participants with any reaction, because the primary outcome is based on injection sites.
The secondary results provide additional, but distinct, measures. The registry reports unadjusted differences for participants without an injection-site reaction and participants without pain. Those findings concern different outcomes from the primary site-level measure, and the two secondary contrasts point in different directions. They should not be compressed into a single conclusion about which regimen is preferable. The absence of a reported multiplicity plan and analysis details limits the weight that can be placed on individual secondary p-values.
This is a randomized, open-label comparison of treatment regimens that include different drugs and autoinjectors. The registry record does not allow the contribution of drug choice to be separated from delivery-device differences. The arm descriptions identify two beta-1b device regimens, while the primary summaries list a single beta-1b group; whether those device groups were pooled is not reported. Participant and physician awareness of treatment is also relevant because several outcomes rely on reported symptoms or reactions.
The results do not establish a causal explanation for a reported reaction, and the registry summaries do not establish a formal difference in the primary outcome. They do not answer broader questions about disease control or other outcomes beyond those recorded. The record also does not report how missing data, repeated site observations, or analysis populations were handled. Interpretations should remain tied to the posted outcomes, denominators, and uncertainty information rather than extending beyond them.
13. Why This Trial Matters Statistically
This study raises a statistical issue that is common in injection-based trials: the outcome is measured at the level of injection sites, while the same participant can contribute repeated observations. Site-level percentages may look straightforward, but their precision depends on the number of observations and on how strongly observations within a participant are related. The registry notes that sites per month per participant were analyzed, yet it does not report the method used to handle this structure.
The design also pairs a drug comparison with a device comparison. The arm descriptions distinguish Betaject from Betaject Light for beta-1b, while the posted primary summaries list a single Betaferon group. Since the record does not explain whether the device-specific groups were combined, readers cannot determine from the summary how the device allocation is reflected in the primary estimates.
A further statistical lesson is the importance of distinguishing descriptive values from inferential results. The primary percentages are posted without a confidence interval or test, while the two secondary comparisons include unadjusted p-values and confidence intervals. Those are different levels of statistical reporting. A numerical difference between descriptive percentages does not by itself establish a precise or statistically supported contrast.
Finally, multiple outcomes, incomplete reporting of analysis populations, and absent details about missing data constrain interpretation. Planning illustrations based on observed secondary effects may be useful as hypothetical design scenarios, but they are not the trial's sample-size justification and do not indicate observed power. Taken together, these features make the registry record useful for identifying the questions and observed summaries, while underscoring why analysis methods and transparent reporting are essential for evaluating precision and robustness.
14. 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 registry record contains gaps that limit a detailed assessment of this trial's results. Most notably, the primary outcome is posted as two percentages without an uncertainty interval or an inferential comparison. The record therefore does not show how precisely the primary group summaries differ. The endpoint is site-based and repeated, but the method for handling correlation among sites from the same participant is not reported.
The arm descriptions specify two beta-1b delivery devices and one beta-1a regimen. The primary-outcome summary gives a single beta-1b group, but whether the two device groups were pooled is not reported in the registry record. As a result, the summary does not clarify how the device-specific allocations contribute to the reported primary percentage. The reported primary group sizes also differ from the enrollment figure, and the record does not explain analysis-population membership or the handling of missing assessments.
Several outcomes are listed, but only two secondary comparisons have posted estimates and unadjusted p-values. A multiplicity strategy and the status of secondary outcomes as confirmatory or exploratory are not reported. The open-label design is also relevant to participant- and physician-reported outcomes; the registry reports no masking. It does not provide enough detail about measurement procedures, adherence, protocol deviations, or outcome ascertainment to assess their possible influence.
The safety summary gives event counts and denominators but no formal comparative estimates or uncertainty intervals. The listed serious-event terms are not assigned to treatment groups in the summary, and deaths are not reported in the registry record. These limitations do not show that bias or missingness occurred; they indicate that the posted record does not provide the information needed to assess those issues fully.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Safety Study in Relapsing-remitting Multiple Sclerosis (RRMS) Patients Receiving Betaferon or Rebif — NCT00317941.
- Registry record last updated 2013-10-21; status last verified 2013-08.
- Results first posted 2013-10-21.
- 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.
Continue through the Clinical Biostats statistical pathway
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18. Record Summary
NCT00317941 is the AVANTAGE randomized, multicenter, phase IV, open-label, prospective study comparing injection-site outcomes among participants receiving Betaferon or Rebif. The registry records enrollment of 220, a completed status, and a study period from 2006-03 to 2008-04.
The primary endpoint was the percentage of injection sites with a participant-reported reaction 24 hours after injection over follow-up of up to 3 months. The posted primary percentages are 31.0 for Betaferon and 37.0 for Rebif, without a reported confidence interval or inferential comparison. Two secondary participant-level outcomes have unadjusted comparisons. Analysis methods for repeated observations, missing data, and analysis populations are not reported in the registry record.