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 Retrospective Cohort Study of Rebif® Use in Pediatric Multiple Sclerosis (MS) Subjects (REPLAY) (NCT01207648), a registered phase not stated study. The primary outcome is Number of Participants With Pre-specified Medical Events.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01207648 |
| Phase | Phase not stated |
| Condition | Multiple Sclerosis |
| Allocation | Not Stated |
| Design model | Not Stated |
| Masking | Not Stated |
| Enrollment | 307 |
| Arms in the primary outcome | n/a |
| Lead sponsor | EMD Serono |
| Results posted | Yes |
2. Clinical Question
Population
Children aged less than 12 years and adolescents aged 12 to less than 18 years with demyelinating events, who were exposed to Rebif® and evaluated in the retrospective study. The total analysis set is described as all participants meeting those criteria; the registry lists an enrollment of 307.
Intervention
Rebif® (subcutaneous interferon beta-1a), recorded as a drug intervention. This was an exposure reviewed through existing medical records, rather than an intervention assigned in a prospective randomized comparison.
Comparator
No separate comparator group is described. The registry record does not state an allocation method, and its study description is a retrospective cohort of Rebif®-exposed participants.
Primary question
How many participants had the prespecified medical events recorded during the observation period? The event categories included injection-site reactions, flu-like symptoms, hepatic and blood-cell disorders, allergic reactions, epilepsy and convulsive disorders, thyroid dysfunction, autoimmune diseases, bone, epiphyseal and cartilage disorders, serious infections, and malignancies.
The stated aim was to review and describe safety, tolerability, and efficacy using information already recorded in medical records. The secondary outcomes concern the annualized rate of medically confirmed clinical relapses before Rebif® initiation and during treatment, and time to first medically confirmed clinical relapse after initiation. Numerical results for those secondary outcomes are not reported in the registry record. The retrospective design can describe what was recorded among exposed participants, but without a described comparator it does not by itself estimate how outcomes would have differed under another treatment or no treatment.
3. Trial Design
REPLAY is described as a retrospective cohort study of Rebif® use in pediatric multiple sclerosis. The registry lists 307 participants and a completed status. Its brief summary says the study reviewed information already recorded in medical records, for participants evaluated between 1997 and 2009. The cohort description includes children aged less than 12 years and adolescents aged 12 to less than 18 years who were exposed to Rebif® for treatment of demyelinating events.
The registry lists the study start as 2010-07 and primary completion as 2011-07. The brief summary gives the data-collection period as 13 July 2010 to 13 July 2011, from first data collected to last data collected. Those dates describe the study’s data-collection period; they are distinct from the years in which the medical records being reviewed concerned participants. The primary endpoint’s observation window began with the first medical record available on site and ended at the last medical record available on site or 31 December 2009, whichever occurred first.
Because this is a retrospective review, treatment exposure and clinical events were assessed from existing records rather than assigned by a trial allocation described in the registry. No randomized comparison is described, and allocation is not stated. The registry therefore does not establish a like-for-like control group. The record does not report a protocol-level explanation of how records were selected, how event information was abstracted, or how incomplete records were handled. These details are important when interpreting results from a medical-record cohort because the available documentation can shape which events are captured.
The stated study aim includes safety, tolerability, and efficacy. The primary outcome concerns the number of participants with prespecified medical events, while the secondary outcomes concern relapse rate and time to first relapse. Numerical results for the primary endpoint and secondary outcomes are not reported in the registry record. The posted adverse-event counts provide some descriptive safety information, but they are not a substitute for the missing outcome results or for a controlled comparison.
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 | Retrospective Cohort |
|---|---|
| STARTED | 307 |
| COMPLETED | 307 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: Total analysis set included all the participants who were exposed to Rebif® for treatment of demyelinating event and were evaluated in this retrospective study.
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 | Retrospective Cohort |
|---|---|---|
| Participants analysed | 307 | |
| Age, Continuous | years | 14.0 (SD 3.0) |
| Sex: Female, Male: Female | Participants | 190 |
| Sex: Female, Male: Male | Participants | 117 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Pre-specified Medical Events, measured over Start of observation period (first medical record available on site) up to last medical record available on site or the end of the observation period (31 December 2009), whichever occurred first..
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the number of participants with prespecified medical events during the observation period. The event categories include injection-site reactions, flu-like symptoms, hepatic disorders, blood-cell disorders, allergic reactions, epilepsy and convulsive disorders, thyroid dysfunction, autoimmune diseases, bone, epiphyseal and cartilage disorders, serious infections, and malignancies. The registry says categories were defined using medical-dictionary queries or customized queries, depending on the category.
A participant count is a descriptive way to report how many people had at least one event meeting a category definition. The registry cautions that a participant may appear more than once within a category if several events fit it, and may also appear in more than one category. Consequently, category counts should not be added together as if they represented distinct participants. A count also does not describe how many events each participant experienced or how long each person was observed.
General statistical context: event counts are useful for describing the recorded burden of events in a cohort, while rates or time-to-event measures address different questions involving follow-up time or event timing. The registry’s secondary outcomes include relapse rate and time to first relapse, but their numerical results are not reported in the registry record. The primary endpoint’s numerical result is also not reported in the registry record. Without that count and information about completeness of follow-up, the primary endpoint cannot be interpreted quantitatively from the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a cohort of 307 Rebif®-exposed pediatric participants and describes a retrospective review of medical records. It does not report the numerical result for the primary endpoint, the number of participants with each prespecified medical-event category, or numerical results for the secondary relapse outcomes. The posted results therefore do not permit a quantitative reading of the primary endpoint or the stated efficacy outcomes.
The adverse-event information reports 12 participants in the serious-event count and 184 in the other-event count, each among 307 participants at risk. These are descriptive counts recorded for the retrospective cohort. They do not establish whether an event was caused by Rebif®, and they do not provide a comparison with an untreated group or another treatment group. The listed serious-event terms—Injection site injury, Injection site necrosis, Irritability, Autoimmune hepatitis, Cholelithiasis, and Anaphylactic reaction—are each reported as 0.3%. These term-level percentages should be read as reported, not as estimates of comparative risk.
General statistical context: a count describes the number of people meeting a recorded event definition, but interpretation also depends on how events were sought, the observation time, the completeness of records, and the denominator. Here the registry gives a cohort denominator and an observation-window description for the primary endpoint, but does not report participant-level follow-up durations or the completeness of the records. It also notes that participants could be counted in multiple event categories, so category totals need not correspond to unique individuals.
No inferential analysis count is reported in the registry record. No confidence intervals, adjusted estimates, or tests comparing groups are reported in the registry record. A confidence interval, in general, expresses the statistical uncertainty around an estimate under a specified model and sampling framework; it cannot remedy missing outcome values or create a comparator that the study did not describe. Since the record provides no primary endpoint estimate, its precision cannot be assessed from the posted information.
The design is observational and retrospective. General statistical context: in an observational cohort, differences in baseline characteristics, treatment history, record availability, and clinical monitoring can affect what is observed. Without a control group and an analysis addressing such differences, descriptive event counts should not be interpreted as estimates of treatment effects. The registry’s stated aim includes safety, tolerability, and efficacy, but the posted information supports only a limited descriptive reading of the adverse-event counts. It does not establish a causal effect or quantify relapse outcomes.
9. Statistical Methods Explained
The registry describes a retrospective cohort assembled from existing medical records. The primary outcome is a count of participants with events in prespecified medical-event categories. The outcome population is described as all participants exposed to Rebif® for treatment of a demyelinating event and evaluated in the study. The record lists 307 participants. It does not report a separate statistical analysis result for the primary endpoint, and the number of analyses is recorded as zero.
What does a participant count represent?
A participant count records how many people had an event that met a defined category during the observation period. It is not necessarily the number of individual event episodes. The registry explicitly allows a participant to have several events within a category and to appear in more than one category. Thus, categories describe different clinical concepts and may overlap at the participant level. General statistical context: counts are often easiest to interpret when the event definition, denominator, and observation period are clear. Here, the category definitions are described in broad terms, but the primary endpoint’s actual category counts are not reported in the registry record.
How were event categories defined?
The registry says that some categories used a standard medical dictionary for regulatory activities query, while others used a customized query. For example, malignancies were defined using the narrow-scope Malignancies query, and serious infections were defined using events assessed as serious in the infections and infestation system organ class. The description indicates that the categories were assembled from groups of event terms rather than each being a single symptom or diagnosis. General statistical context: standardized definitions can support consistent event classification, but broad queries may include many types of terms. Interpretation therefore depends on the exact definitions, how they were applied to the records, and whether the classifications were checked. Further operational details about event review are not reported in the registry record.
What does the observation window mean?
The primary endpoint timeframe starts at the first medical record available on site and ends at the last medical record available on site or the end of the observation period, 31 December 2009, whichever occurred first. This means the endpoint is based on each participant’s available record window within the study’s stated observation period. The registry does not report how long each participant contributed records or whether observation time was similar across participants. General statistical context: a raw count does not adjust for unequal time under observation. Rates and time-to-event methods can incorporate time information, but the primary endpoint is described as a participant count, and the necessary numerical results are not reported.
What can the relapse outcomes add?
The secondary outcomes are the annualized medically confirmed clinical relapse rate before Rebif® initiation and during Rebif® treatment, and time to the first medically confirmed clinical relapse after initiation. These outcomes address event frequency and timing, rather than only whether a participant had an event. General statistical context: an annualized rate uses event frequency in relation to observation time, while a time-to-event analysis considers when an event occurs and may account for participants who have not had an event by the end of observation. The registry record names these outcomes but does not report their numerical results, estimates, or analysis methods.
How should uncertainty and comparisons be understood?
General statistical context: an estimate is more informative when accompanied by a measure of precision, such as a confidence interval. A confidence interval describes a range of values compatible with the observed data under the chosen statistical model; it is not a guarantee that the true value lies within that range. No confidence intervals or inferential comparisons are reported in the registry record for these outcomes. The retrospective cohort also has no described control group, so a treatment-versus-control effect estimate is not available from the posted information.
The record includes planning illustrations based on fractions of an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated illustrations use participants per arm except for time-to-event calculations, which use a total number of events. These are planning assumptions, not a description of the study’s own design: REPLAY is described as a retrospective cohort without a stated allocation or like-for-like control comparison. Such planning illustrations are not observed power and do not establish that the study was designed or conducted with those assumptions. The registry record does not report a sample-size justification for the retrospective cohort.
10. Multiplicity, Missing Data and Analysis Populations
The primary endpoint covers multiple medical-event categories, and the registry also names secondary outcomes for relapse rate and time to first relapse. When several outcomes or categories are examined, general statistical context is that the chance of at least one apparently unusual finding can increase if each is tested separately without accounting for multiplicity. The registry record does not report a multiplicity adjustment, a hierarchy among outcomes, or which analyses, if any, were intended as confirmatory. It also reports zero analyses, so no inferential results are available to evaluate.
The registry’s primary outcome description defines a total analysis set as participants exposed to Rebif® for treatment of a demyelinating event and evaluated in the retrospective study. Enrollment is listed as 307, and the adverse-event counts use 307 as the number at risk. The record does not report a participant flow showing how records were screened, whether any enrolled participants were excluded from particular outcomes, or the number with complete data for each measure.
Missing-data methods are not reported in the registry record. The primary outcome’s observation window depends on medical records available on site, so differences in record availability could affect event capture. General statistical context: missing records do not necessarily mean that no event occurred, and analyses based only on available observations can be biased if availability is related to participant health, follow-up, or treatment. The posted information does not describe how such possibilities were assessed or handled.
The record does not report a protocol for interim analyses, a statistical analysis plan, or the handling of incomplete relapse information. Those details are not reported in the registry record and cannot be inferred from the retrospective design or from the stated outcomes.
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 |
|---|---|---|---|
| Retrospective Cohort | 12 | 307 | 3.9% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 1% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Retrospective Cohort | 184 of 307 |
Most frequent serious adverse event terms
| Event term | Organ system | Retrospective Cohort |
|---|---|---|
| Injection site injury | General disorders | 1 of 307 |
| Injection site necrosis | General disorders | 1 of 307 |
| Irritability | General disorders | 1 of 307 |
| Autoimmune hepatitis | Hepatobiliary disorders | 1 of 307 |
| Cholelithiasis | Hepatobiliary disorders | 1 of 307 |
| Anaphylactic reaction | Immune system disorders | 1 of 307 |
| Hypersensitivity | Immune system disorders | 1 of 307 |
| Cellulitis | Infections and infestations | 1 of 307 |
| Injection site cellulitis | Infections and infestations | 1 of 307 |
| Convulsion | Nervous system disorders | 1 of 307 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Retrospective Cohort |
|---|---|---|
| Influenza like illness | General disorders | 75 of 307 |
| Injection site erythema | General disorders | 48 of 307 |
| Injection site pain | General disorders | 34 of 307 |
| Headache | Nervous system disorders | 19 of 307 |
| Alanine aminotransferase increased | Investigations | 13 of 307 |
| Pyrexia | General disorders | 9 of 307 |
| Hepatic enzyme increased | Investigations | 9 of 307 |
| Liver function test abnormal | Investigations | 8 of 307 |
| Aspartate aminotransferase increased | Investigations | 7 of 307 |
| Leukopenia | Blood and lymphatic system disorders | 7 of 307 |
Serious events with the highest arm-level rate: injection site injury (0.3%), injection site necrosis (0.3%), irritability (0.3%), autoimmune hepatitis (0.3%), cholelithiasis (0.3%).
The posted adverse-event data list a serious-event count of 12 among 307 participants at risk, and an other-event count of 184 among 307 participants at risk. These are counts for the retrospective cohort, not a comparison between treatment groups. The record also lists Injection site injury, Injection site necrosis, Irritability, Autoimmune hepatitis, Cholelithiasis, and Anaphylactic reaction among the serious-event terms, each at 0.3%.
These figures describe events recorded in the medical-record review. They do not show whether the events began before or after Rebif® exposure, whether they were judged to be caused by the drug, or how long each participant was observed. The event-category definitions can include multiple terms, and participants may appear in multiple categories. The registry does not report the primary endpoint’s category-specific counts, so the listed adverse-event figures should not be treated as a complete numerical account of every prespecified medical-event category.
General statistical context: safety counts need to be interpreted with their definitions, observation windows, and denominators in view. In a retrospective record review, unrecorded or incompletely documented events may not be captured. Without a comparable control group, these counts cannot establish whether the frequency differs from what would have occurred under another treatment or without Rebif®.
12. What the Result Does, and Does Not, Mean
REPLAY describes a retrospective review of medical records for 307 pediatric participants exposed to Rebif® for demyelinating events. The registry’s stated aim was to describe safety, tolerability, and efficacy. The posted adverse-event results include a serious-event count of 12 and an other-event count of 184, each among 307 participants at risk. Six serious-event terms are listed with a reported value of 0.3% each.
Those data show what the registry reports for this cohort; they do not establish that Rebif® caused or prevented any event. The study description does not include a control group or a stated allocation method. Without a like-for-like comparison, the counts cannot show how event frequency would compare with another treatment or with no treatment. They also do not account for differences in observation time or event documentation across participants.
The primary endpoint is the number of participants with prespecified medical events, but its numerical result is not reported in the registry record. Numerical results for the secondary relapse outcomes are also not reported. Therefore, the stated outcomes do not support a quantitative assessment of relapse frequency, time to first relapse, or the overall count across the prespecified medical-event categories. The listed adverse-event information is not a replacement for those missing results.
General statistical context: precision and causal interpretation are separate issues. A confidence interval can express uncertainty around an estimate, but even a precise descriptive estimate from an uncontrolled retrospective cohort would not by itself demonstrate a treatment effect. The registry record reports no confidence intervals or comparative effect estimates for these outcomes. Its information is most appropriately read as a description of recorded safety data in the studied cohort, with substantial limits on what can be concluded beyond that description.
The result does not establish the risk of an event for all children or adolescents with multiple sclerosis, because the record concerns the participants evaluated in this retrospective cohort. It also cannot answer whether Rebif® is preferable to another treatment, or whether treatment should be started or stopped. Those comparative and clinical questions are not resolved by the posted information.
13. Why This Trial Matters Statistically
This study is statistically useful as an example of what a retrospective cohort can and cannot answer. Medical records allow researchers to describe events among participants whose treatment and clinical history were already documented. That design can be relevant when the objective is to review accumulated experience, but its conclusions depend heavily on the completeness and consistency of the records and on how events are defined and extracted.
REPLAY’s primary endpoint is a participant count across prespecified medical-event categories, and the registry explicitly notes that participants can appear in multiple categories. This matters because category counts are not necessarily counts of distinct people when considered together. It also illustrates why an outcome definition needs to be read alongside its denominator and observation window. The registry provides those design details, but does not report the primary endpoint’s category-specific numerical results.
The study also illustrates the distinction between descriptive data and comparative evidence. The posted adverse-event counts describe events in the Rebif®-exposed cohort. No like-for-like control group is described, and allocation is not stated. As a result, the counts do not estimate a treatment contrast. The registry’s secondary relapse outcomes could address event frequency and timing, but their numerical results are not reported in the registry record.
General statistical context: retrospective studies can be informative while remaining vulnerable to incomplete documentation, unequal observation, and differences between people who receive different care. These are not solved simply by reporting a larger participant count or a statistical test. Clear analysis plans, outcome definitions, denominators, and measures of uncertainty help readers understand what the data can support. In this record, key analysis details and outcome results are not reported, making a careful separation of the stated study aims from the posted numerical evidence particularly important.
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 study is retrospective and relies on medical records, so event capture depends on what was documented and available. The registry does not report the completeness of the records, how missing information was handled, or whether event review was standardized. The primary observation window is bounded by each participant’s first and last available on-site record, subject to the end date of 31 December 2009; participant-specific observation durations are not reported.
No comparator group is described, and allocation is not stated. The adverse-event counts therefore provide no controlled estimate of the difference between Rebif® and another treatment or no treatment. The registry also does not report adjusted estimates or a strategy for addressing differences among participants. Because the event categories can overlap, category counts should not be interpreted as mutually exclusive groups of participants.
The numerical result for the primary endpoint is not reported in the registry record. Numerical results for the secondary relapse rate and time-to-first-relapse outcomes are not reported either. The record reports zero analyses and does not provide confidence intervals, analysis details, a multiplicity strategy, or a sample-size justification for the cohort. The planning illustrations described in the record use hypothetical two-arm assumptions and are not the study’s own design or observed power.
The registry lists an enrollment of 307, but does not report a participant flow or outcome-specific data completeness. The adverse-event counts do not establish causality, and the term-level percentages do not provide a comparative risk estimate. These limitations mean the posted information supports a narrow descriptive account rather than a firm conclusion about treatment effects or outcomes beyond the cohort.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Retrospective Cohort Study of Rebif® Use in Pediatric Multiple Sclerosis (MS) Subjects (REPLAY) — NCT01207648.
- Registry record last updated 2015-05-15; status last verified 2015-04.
- Results first posted 2013-05-30.
- 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
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT01207648 is the completed registry record for the Retrospective Cohort Study of Rebif® Use in Pediatric Multiple Sclerosis (MS) Subjects (REPLAY), sponsored by EMD Serono. The record lists 307 participants and describes a retrospective review of medical records for children and adolescents exposed to Rebif® for demyelinating events.
The registry lists a start of 2010-07 and primary completion of 2011-07. Its summary describes data collection from 13 July 2010 to 13 July 2011 and medical records concerning participants evaluated between 1997 and 2009. The primary endpoint is the number of participants with prespecified medical events during the observation period. Secondary outcomes concern clinical relapse rate and time to first relapse.
The posted adverse-event information reports 12 participants in the serious-event count and 184 in the other-event count, each among 307 at risk; six listed serious-event terms are reported at 0.3% each. The primary endpoint result and numerical secondary-outcome results are not reported in the registry record. No randomized comparison is described.