Fingolimod Versus Interferon Beta 1b in Cognitive Symptoms: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fingolimod Versus Interferon Beta 1b in Cognitive Symptoms (NCT01333501), a randomized phase 4 study. The primary outcome is Change From Screening in Selective Reminding Test - Long-Term Storage (SRT-LTS) Raw Score.

2. Clinical Question

The trial was described as a pilot study intended to assess the effect of fingolimod relative to interferon beta 1b on cognitive symptoms associated with relapsing-remitting multiple sclerosis. It also set out to assess which test in the cognitive battery was most sensitive to differences between groups and to examine a possible relationship between treatment effects and regional brain atrophy. The primary posted outcome is one component of that broader study question. The results summarized for the primary comparison address the SRT-LTS score, not every cognitive test or the proposed brain-atrophy relationship.

3. Trial Design

The registry identifies this as a randomized, parallel-group, active-controlled phase 4 pilot study. Its official title describes an 18-month, open-label, rater-blinded, randomized, multicenter study. The registry’s masking field says none, so the record does not establish masking of participants or study personnel; the distinction between the title’s description and the masking field should be kept in view. The registry lists the study as completed.

Enrollment is listed as 151. The posted primary-outcome arm summaries use the full analysis set defined in the registry, with 80 participants in the fingolimod group and 28 in the interferon beta 1b group. Those outcome analysis counts should not be treated as the enrollment count or as a description of every analysis population. The registry does not explain the difference between the enrollment figure and the primary analysis counts, or report the reasons participants were not represented in those summaries.

The study start is recorded as 2011-05 and primary completion as 2015-09. The primary endpoint was change from screening to the 18-month assessment in SRT-LTS raw score. The registry also lists outcomes concerning MRI lesion measures, depression, quality of life, fatigue, and brain-volume change. The brief summary describes cognitive testing with the Brief Repeatable Battery and the Delis-Kaplan Executive Function System. The registry record does not report the original sample-size justification, the planned treatment effect used for design, or a detailed protocol-level statistical analysis plan.

Because this was an active-controlled pilot study and the posted primary analysis contains fewer participants than the enrollment listing, precision and the analysis population are important when reading the comparison. The randomized design supports a between-group comparison, but the available registry summary does not by itself answer questions about adherence, treatment discontinuation, missing observations, or the full conduct of the analysis.

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: Total patients randomized in the study (157). Patients who took at least one dose of study drug are 151. The study there were 6 patients who were enrolled but who never took any dose of study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations.

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 Change From Screening in Selective Reminding Test - Long-Term Storage (SRT-LTS) Raw Score, measured over Screening (-1month), 18 month.

The primary endpoint is change from screening in the Selective Reminding Test Long-Term Storage raw score, assessed at the 18-month time point. The SRT is part of the Brief Repeatable Battery, described in the registry as a clinical and research tool consisting of serial administration of five tests. It assesses episodic memory, including verbal learning and delayed recall.

During the SRT, a word recalled on two consecutive trials is treated as having entered long-term storage on the first of those trials and is scored as long-term storage on subsequent trials. The total number of words in long-term storage across all six trials forms the score. The score ranges from 0 to 72, and higher values represent a better outcome. These features give the endpoint a direct connection to the memory function the study sought to evaluate.

A change score compares a participant’s later assessment with the screening reference, while a between-group comparison asks whether the average change differs between randomized treatment groups. The registry reports least-squares means and standard errors for the primary endpoint. The endpoint is therefore a measure of cognitive test performance, not a direct measure of overall disease status or every aspect of cognition. The registry describes the battery as having 68% sensitivity and 85% specificity, but those general characteristics do not determine how precisely this particular trial estimated a treatment difference.

7. Results Posted in the Registry

• Interferon Beta 1b: mean 4.46 versus 6.32 on control; difference -1.86 (95% CI -7.03 to 3.31), standardized effect d = -0.16; z-test p = 0.481.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Screening in the Volume of Total T2 Lesions

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Interferon Beta 1b: mean 711.81 versus 176.25 on control; difference 535.56 (95% CI -143.36 to 1,214), standardized effect d = 0.38; z-test p = 0.122.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Interferon Beta 1b and the control. The interval gives the range of effects that remain compatible with the data.

Change From Screening in Montgomery-Asberg Depression Rating Scale (MADRS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Interferon Beta 1b: mean 0.13 versus -0.77 on control; difference 0.90 (95% CI -2.10 to 3.90), standardized effect d = 0.13; z-test p = 0.556.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Interferon Beta 1b and the control. The interval gives the range of effects that remain compatible with the data.

Changes From Baseline in Fatigue Impact Scale (mFIS, Total Score and Scores of the 3 Individual Domains).

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Interferon Beta 1b: mean 6.67 versus 2.36 on control; difference 4.31 (95% CI -1.96 to 10.58), standardized effect d = 0.29; z-test p = 0.178.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Interferon Beta 1b and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes spanning MRI lesion measures, depression, quality of life, fatigue, and brain-volume change. It reports nine posted secondary outcomes, while numerical arm summaries and recalculated comparisons are available for only a subset in the registry summary. Among the secondary comparisons with numerical summaries, the reported intervals cross zero. This pattern does not establish a clear between-group difference on those comparisons, but it also does not demonstrate that the groups are equivalent.

The secondary outcomes provide context around the primary cognitive endpoint, but they do not resolve the uncertainty in the SRT-LTS comparison. They address different domains and measures, and a result on one cannot be treated as confirmation or refutation of the primary result without an appropriate analysis plan. In particular, the registry’s stated objective of assessing sensitivity among cognitive tests is broader than the primary endpoint alone; the available posted summaries do not establish which test was most sensitive.

Unadjusted secondary results carry less inferential weight when many outcomes are examined. In general, repeated testing increases the chance that at least one result will appear unusual by chance, even when there is no underlying effect. Adjustment methods or a prespecified hierarchy can address this issue, but the registry record does not report a multiplicity strategy for these secondary outcomes. Consequently, isolated secondary p-values should be treated as exploratory rather than as independent proof of a treatment effect. The overall pattern is best read as additional descriptive evidence, with uncertainty and multiplicity kept in view, rather than as a substitute for the primary analysis.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Screening in the Volume of Total T2 Lesions
• Change From Screening in Montgomery-Asberg Depression Rating Scale (MADRS)
• Changes in Quality of Life, by Means of the Multiple Sclerosis Quality of Life (MSQoL-54)
• Changes From Baseline in Fatigue Impact Scale (mFIS, Total Score and Scores of the 3 Individual Domains).
• Change From Screening in the Number of New T2 Lesions
• Change From Screening in the Volume of Total T1 Hypointense Lesions
• Change From Screening in the Number of T1 Gd+ Enhancing Lesions
• Change From Screening in the Percentage of Brain Volume Change

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary score represent?

The SRT-LTS raw score is a continuous measure: it can take values across a numerical scale, and its group summary is expressed as a mean. The endpoint is change from screening, so the clinical question concerns the difference in average change between groups rather than a comparison of isolated end-of-study scores. The registry reports least-squares means, which are model-based group means, together with standard errors. It does not report the covariates used to obtain those least-squares means.

What is the role of ANCOVA?

The registry lists ANCOVA for its reported primary comparison. In general, analysis of covariance compares group outcomes while accounting for one or more covariates. Its purpose and behavior depend on which covariates were included, how they were measured, and how the model was specified. Those details are not reported in the registry record, so the ANCOVA result can be described but its adjustment cannot be independently reconstructed from the listed summaries. The registry reports a net mean difference, a 95% confidence interval, and a p-value.

What does the recalculation do?

The recalculated comparison is an unadjusted contrast formed from the posted group summaries. It places interferon beta 1b first and subtracts the fingolimod mean, which gives a negative estimated contrast because the posted means are 4.46 and 6.32, respectively. Reversing the group order reverses the sign but does not change the substantive direction. This calculation is useful as a transparent summary-statistic check, but it is not a replacement for the sponsor’s model-based analysis. It does not reproduce covariate adjustment or any other model features not included in the summary data.

The recalculation uses a pooled standard deviation estimated from the posted standard errors for the primary endpoint; the record marks that estimate as approximate. A standard deviation describes variability among individual observations, whereas a standard error describes uncertainty in an estimated mean. Converting between them requires information about the number of observations and assumptions about the summaries. When a standard deviation is reconstructed approximately, the recalculated standardized contrast and associated planning illustrations inherit that approximation. The sponsor’s ANCOVA result remains the registry-reported analysis; the unadjusted recalculation should be understood as a separate analytical view.

Why do uncertainty intervals matter?

A confidence interval describes the range of values compatible with the observed data under the statistical model and its assumptions. It reflects both the estimated contrast and its uncertainty. An interval that includes zero does not establish that the true contrast is zero; rather, the data do not sharply distinguish a zero contrast from other values within the interval. A wide interval indicates limited precision, which can arise when variability is substantial, the analysis groups are small, or both. These are general statistical explanations, not claims about the protocol’s design choices.

A p-value describes how unusual a result at least as far from the null as the observed result would be under a specified null model and assumptions. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of a difference. The primary recalculated p-value is unadjusted, and the sponsor’s reported p-value comes from its ANCOVA. The registry record does not report a multiplicity adjustment for the reported secondary outcomes, so secondary p-values should not be treated as if they had been protected against the effects of examining multiple outcomes.

What is over-dispersion, and is it relevant?

Over-dispersion is a general issue in count or event data when variability exceeds what a simpler probability model expects. It can make standard errors and confidence intervals too small if the extra variability is ignored. The primary SRT-LTS endpoint is a continuous score, not an event count, and the registry record does not report an over-dispersion analysis for it. This concept should not be used to infer a problem in the primary analysis. It may matter in other settings, depending on the outcome model, but the record does not provide enough model detail to assess such a question.

What should be kept separate?

The randomized comparison, the sponsor’s ANCOVA, and the recalculation answer related but not identical analytical questions. Randomization is a design feature; ANCOVA is a model-based method; and the recalculation is an unadjusted reconstruction from summary statistics. A close correspondence in the direction and central contrast does not make the methods interchangeable. The analysis population also matters: the primary full analysis set requires receipt of study drug, post-baseline information on both primary efficacy variables, and no major protocol violations. The registry record does not report the detailed missing-data method, sensitivity analyses, or covariate list. General statistical interpretation must therefore remain conditional on the methods actually used, with unreported details left unresolved.

11. Confidence Intervals and Precision

The primary recalculated interval runs from -7.033 to 3.313 for interferon beta 1b minus fingolimod. It spans zero and includes estimates favoring either direction. In the sponsor’s opposite group order, the reported 95% confidence interval runs from -3.51 to 7.23. That interval also includes zero and allows a range of possible treatment contrasts rather than concentrating narrowly around one value. The signs differ because the contrasts are expressed in reverse order.

These intervals signal that the estimated difference is not precise enough to rule out no difference or a range of nonzero differences. The confidence interval is not a probability statement about a specific effect after observing the data. In general, a 95% confidence procedure is designed to cover the true value in 95% of repeated applications under its model assumptions. The realized interval gives a range of values consistent with the data and analysis; it does not guarantee that any particular value within it is true.

The reported primary analysis counts are 80 for fingolimod and 28 for interferon beta 1b. The unequal analysis-group sizes and the observed standard errors are relevant context for precision, but the registry record does not identify why the analysis counts differ or provide a full account of missingness. The recalculation’s interval also depends on approximate reconstruction from summary statistics. The sponsor’s ANCOVA interval is the registry-reported model-based result. Neither interval should be read as establishing equivalence, absence of effect, or clinical importance. The record does not report a threshold for a clinically important SRT-LTS difference, so statistical uncertainty cannot be translated into a judgment about clinical relevance.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations describe participants per arm for the continuous-outcome comparisons in this study. They are not total event counts. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the planned number of participants per arm under those assumptions for a design with an 80% chance of detecting the specified effect if that effect were the true one and the assumptions held. The 90% power column gives the corresponding per-arm planning number for a 90% chance. These are planning targets, not a description of the number analyzed in the trial. They depend on the assumed effect size and variability, as well as the stated statistical design assumptions.

The rows for 100%, 75%, and 50% of the observed effect illustrate how the planning requirement changes when the target effect is reduced. Smaller effects need more participants to detect, because they are harder to distinguish from random variation. The observed effect is a noisy estimate from this pilot comparison, so these figures should not be taken as a definitive design recommendation for a future study. The sample-size illustrations are not observed power; observed power is not a useful substitute for interpreting the estimate and its confidence interval.

Read each figure as a conditional planning illustration: it answers what per-arm enrollment would be indicated by the listed assumptions and selected fraction of the observed contrast. It does not show that the trial achieved the listed power, and it does not explain why the original enrollment was chosen. The registry record does not report the original protocol’s target effect, expected variability, allocation rationale, or planned allowance for missing observations.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -1.860; pooled standard deviation σ = 11.939.
2. n = 2 × (1.96 + 0.842)² × 11.939² / -1.860² = 646.8, rounded up to 647 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -1.86                      # observed difference in means
sigma <- 11.9390900699389                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1333501)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 647 (80% power), 866 (90% power)
 75% of observed effect: n per arm = 1,150 (80% power), 1,540 (90% power)
 50% of observed effect: n per arm = 2,588 (80% power), 3,464 (90% power)
power.t.test: 647.7 
Simulated power at n = 647 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary analysis as ANCOVA, with a net mean difference of 1.86 for fingolimod relative to interferon beta 1b, a 95% confidence interval from -3.51 to 7.23, and p = 0.494. This is the trial’s reported model-based result. Its interval includes zero, so the posted analysis does not establish a clear between-group difference on the primary outcome.

The recalculation uses the posted arm summaries without adjustment. It expresses the contrast in the reverse order, interferon beta 1b minus fingolimod, giving -1.86, with an interval from -7.033 to 3.313 and an unadjusted p-value of 0.481. The opposite signs reflect the reversed group order. The recalculated estimate is a simple summary-statistic comparison and does not reproduce the sponsor’s ANCOVA model or any adjustment that model may have made.

The registry record does not flag a discrepancy between these analyses. Their central contrasts are consistent in direction once group order is aligned, while their intervals and p-values differ. For interpreting the trial’s own inferential result, the sponsor’s reported ANCOVA analysis is the relevant posted analysis; the recalculation is supplementary and should not replace it. The registry record does not report enough model detail to explain the difference in uncertainty estimates or to independently verify the ANCOVA specification.

15. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is identified as change from screening in SRT-LTS raw score, and the registry reports an ANCOVA comparison. The registry record does not report whether the primary endpoint was selected within a formal testing hierarchy, whether interim analyses were planned or conducted, or whether any adjustment for multiple testing was used. These items should not be inferred from the presence of a single posted primary outcome.

The record lists multiple secondary outcomes across cognitive, imaging, mood, quality-of-life, and fatigue domains. It does not report a multiplicity-control procedure for those outcomes. Without a reported strategy, secondary comparisons and their unadjusted p-values should be interpreted cautiously: looking across many outcomes can produce apparently notable results by chance. This general concern does not determine whether any particular secondary result is true or false; it limits how strongly isolated results can support confirmatory conclusions.

The primary full analysis set is defined as randomized patients who received at least one dose, had at least one post-baseline assessment of both primary efficacy variables, and had no major protocol violations. The registry does not report the number excluded for each reason, the handling of missing outcome values, or whether sensitivity analyses examined alternative missing-data assumptions. The full analysis set definition therefore does not provide a complete account of how missingness or protocol violations affected the estimates.

Other details needed to evaluate the statistical plan, including the original sample-size justification and the specific ANCOVA covariates, are not reported in the registry record. Nor is a detailed plan for subgroup analyses or interim monitoring reported. These omissions do not show that the procedures were absent from the protocol; they mean that the registry record does not document them. Interpretation should stay with the analyses and populations that are explicitly posted, without assuming additional safeguards or methods.

16. 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: blood glucose abnormal (2.1%), renal colic (1.9%), atrioventricular block second degree (1.0%), bronchopneumonia (1.0%), urinary tract infection (1.0%).

The registry lists serious adverse events for 104 participants at risk in the fingolimod 0.5 mg group, with 9 affected, and for 47 at risk in the interferon beta 1b group, with 1 affected. For other adverse events, the corresponding listed figures are 104 at risk and 44 affected for fingolimod, and 47 at risk and 22 affected for interferon beta 1b. These are the registry’s counts; they should not be converted into comparative rates without a suitable analysis and a clear understanding of the event definitions and observation periods.

The registry also lists serious-event terms and percentages, including blood glucose abnormal at 2.1%, renal colic at 1.9%, atrioventricular block second degree at 1.0%, bronchopneumonia at 1.0%, urinary tract infection at 1.0%, and facial bones fracture at 1.0%. The record excerpt does not assign these terms to a specific treatment group, so no group attribution is warranted. Death counts are not reported in the registry record.

These safety summaries are descriptive. They do not establish that an event was caused by treatment, and differences in listed counts alone do not establish comparative safety. The adverse-event denominators differ from the primary analysis counts, and the registry record does not explain the populations or follow-up behind each safety summary in detail. The figures should therefore be read in their recorded context rather than combined with the primary efficacy analysis.

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

The primary result is an estimate of the difference between treatment groups in change on a verbal-memory test. The posted mean changes are 6.32 for fingolimod and 4.46 for interferon beta 1b, with higher SRT-LTS values representing better performance. The recalculated contrast and the sponsor’s ANCOVA result both have uncertainty intervals that include zero. The registry record therefore does not establish a clear difference between the groups on this endpoint.

This finding does not mean that the treatments are identical, that neither group changed, or that no difference could exist. A comparison that does not clearly separate from zero can arise when the true difference is small, when data are variable, when the estimate is imprecise, or through a combination of these factors. The posted intervals include a range of possible contrasts. The registry record does not report a clinically important difference threshold for this score, so the statistical results alone cannot establish whether a particular difference would matter to patients.

The endpoint is one test of memory within a broader cognitive battery. It does not capture every cognitive symptom, the full course of multiple sclerosis, or the study’s proposed relationship between cognitive effects and regional brain atrophy. Nor do the secondary summaries establish a treatment effect across other clinical or imaging domains. The results should be confined to the measures, populations, and analyses reported.

The trial was randomized and active-controlled, but it was described as a pilot study and the primary analysis group counts were 80 and 28. The uncertainty in the primary comparison is therefore central to interpretation. The posted data can inform how much uncertainty remains; they do not support medical advice or a treatment choice. The registry record also does not provide enough detail about missing data, covariate adjustment, or the original design assumptions to resolve every methodological question.

18. Why This Trial Matters Statistically

This trial is statistically informative because it places a randomized, active-controlled comparison around a defined cognitive measure rather than relying on an uncontrolled change within a treatment group. The contrast asks whether average change in SRT-LTS differs between fingolimod and interferon beta 1b. That distinction matters: improvement or change within one arm alone would not establish that its treatment performed differently from the active comparator.

The primary analysis also illustrates why an effect estimate should be read together with its uncertainty. The observed group summaries favor different numerical values, but the confidence intervals span zero and allow a range of contrasts. The result is not a simple yes-or-no verdict about treatment effect. It demonstrates how a pilot study can generate an estimate while leaving substantial uncertainty about the magnitude and direction of a between-group difference.

The registry’s ANCOVA result and an unadjusted recalculation offer complementary views. The sponsor analysis is the reported model-based comparison, while recalculation from summary statistics makes clear how a basic contrast relates to the group means. Their group-order conventions and methods must be distinguished rather than treating them as duplicate tests. This is a useful lesson in reading results across analysis methods.

Finally, the study’s broader cognitive battery and secondary measures raise familiar concerns about interpretation across multiple outcomes. Without a reported multiplicity strategy, isolated secondary findings should not be elevated to confirmatory conclusions. The available record also shows why analysis population definitions and missing-data reporting matter: the enrollment listing and primary analysis counts describe different aspects of the study, and the reasons for the difference are not reported. These issues are central to judging how far a statistical result can be generalized.

19. 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 characterizes the study as a pilot but does not report the original sample-size justification or the treatment effect used to plan enrollment. The posted planning illustrations are based on the observed effect and do not reveal the study’s original design assumptions. The primary analysis group counts are 80 for fingolimod and 28 for interferon beta 1b, while enrollment is listed as 151; the registry does not explain the difference or give a participant-flow account in the information summarized.

The primary outcome analysis population excludes randomized patients who did not meet the stated full analysis set criteria. The registry does not report the number excluded for receiving no study drug, lacking post-baseline assessments, or having major protocol violations. The method for handling missing values, the extent of missingness by group, and sensitivity analyses are not reported in the registry record. These gaps limit assessment of whether the analyzed participants represent the randomized groups.

The official title calls the study open-label and rater-blinded, while the registry masking field is NONE. The record does not explain this difference or specify which assessments, if any, were masked in practice. The posted primary result is ANCOVA, but covariates and model details are not reported, limiting independent reconstruction. The recalculated comparison is unadjusted and the pooled variability estimate is marked approximate.

The registry lists multiple secondary outcomes but does not report a multiplicity-control plan. Numerical summaries are not available for every listed secondary outcome in the record summarized, limiting a complete appraisal of the broader objectives. The record also does not report the clinical importance threshold for SRT-LTS, so the clinical meaning of possible differences cannot be judged from statistical estimates alone. These limitations leave important interpretive questions open; they do not, by themselves, establish that the analyses are invalid.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Fingolimod Versus Interferon Beta 1b in Cognitive Symptoms — NCT01333501.
• Registry record last updated 2017-03-21; status last verified 2017-01.
• Results first posted 2017-03-21.
• 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.

23. Record Summary

NCT01333501 is a completed, randomized, parallel-group, phase 4 pilot study of fingolimod versus interferon beta 1b for cognitive symptoms associated with relapsing-remitting multiple sclerosis. Its official title describes an 18-month open-label, rater-blinded study, while the registry masking field is NONE. The primary endpoint was change from screening in SRT-LTS raw score, with higher scores representing better performance.

The registry reports a sponsor ANCOVA mean difference of 1.86 for fingolimod relative to interferon beta 1b, with a 95% confidence interval from -3.51 to 7.23 and p = 0.494. The unadjusted recalculation expresses the contrast in the opposite order and also has an interval that includes zero. The posted primary result does not establish a clear between-group difference. Secondary outcomes and safety counts provide additional descriptive context, but multiplicity, missing-data methods, and several design details are not reported in the registry record.