Natalizumab (BG00002, Tysabri) Study in Japanese Participants With Relapsing-Remitting Multiple Sclerosis (RRMS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Natalizumab (BG00002, Tysabri) Study in Japanese Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) (NCT01440101), a randomized phase 2, phase 3 study. The primary outcome is Part B: Rate of Development of New Active Lesions Over 24 Weeks.

2. Clinical Question

3. Trial Design

The study had two parts with different purposes. Part A was an open-label evaluation of natalizumab focused on safety, tolerability, pharmacokinetics and pharmacodynamics in Japanese participants with RRMS. Part B was randomized, double-blind and placebo-controlled, and evaluated safety and efficacy. The registry lists the trial phases as phase 2 and phase 3, a parallel-group model, and quadruple masking. The record does not specify which roles were masked.

The listed natalizumab regimen was 300 mg by intravenous infusion over 60 minutes every 4 weeks for 20 weeks. The placebo group received intravenous infusions over the same schedule. The primary efficacy outcome was assessed from baseline (Week 0) to Week 24. This means the treatment schedule and the stated outcome assessment period are not identical lengths; the record describes both but does not give further explanation of their relationship.

The registry lists 106 participants enrolled overall. For the primary Part B comparison, the posted groups each contain 47 participants. The open-label natalizumab safety group has 12 participants at risk in the adverse-event record. These group counts should not be used to infer unreported allocation or analysis-population details.

The study is marked completed. Its recorded start is 2010-11 and primary completion is 2012-08. Biogen is listed as sponsor. The registry record does not report the original sample-size justification, the detailed randomization procedure, or further operational details of masking.

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: This was a 2-part, multicenter study, each part (open-label, double-blind) comprising discrete cohorts of BG00002-naïve participants.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received study drug.

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.

Population: This was a 2-part, multicenter study, each part (open-label, double-blind) comprising discrete cohorts of BG00002-naïve participants.

6. Primary Endpoint

The registry lists the primary outcome as Part B: Rate of Development of New Active Lesions Over 24 Weeks, measured over Baseline (Week 0) to Week 24.

The primary endpoint is the rate of development of new active lesions over 24 weeks, expressed in lesions per week. A new active lesion was defined as either a gadolinium-enhancing lesion or a new or newly enlarging T2-hyperintense lesion that did not enhance, as seen on cranial MRI. The endpoint therefore combines lesion activity identified using two MRI features rather than counting only one lesion type.

For each participant, the rate was calculated as the ordinary least squares slope of cumulative new active lesions over time. In general, a slope describes the rate at which a measure changes across repeated observations; using a participant-level slope gives a rate measure rather than a single scan count. The registry reports the group mean and standard deviation for this continuous outcome.

This endpoint was selected to address Part B’s stated primary efficacy question about MRI lesion activity over the assessment period. It is a radiological outcome, not a direct measure of symptoms or disability. The registry also lists clinical and other MRI outcomes as secondary measures, but those do not replace the primary endpoint. The posted endpoint description states that missing lesion values were imputed by linear interpolation between adjacent non-missing values; for participants who discontinued, the method reduced to last observation carried forward.

7. Results Posted in the Registry

• Double-Blind Natalizumab: mean 0.06 versus 0.35 on control; difference -0.29 (95% CI -0.46 to -0.13), standardized effect d = -0.73; z-test p = <0.001.

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.

Part B: Cumulative Number of New Active Lesions Over 24 Weeks

• 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:
  • Double-Blind Natalizumab: mean 1.50 versus 8.50 on control; difference -7.00 (95% CI -10.86 to -3.14), standardized effect d = -0.73; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Double-Blind Natalizumab than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks

• 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:
  • Double-Blind Natalizumab: mean 1.20 versus 7.40 on control; difference -6.20 (95% CI -9.71 to -2.69), standardized effect d = -0.71; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Double-Blind Natalizumab than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks

• 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:
  • Double-Blind Natalizumab: mean 0.30 versus 1.10 on control; difference -0.80 (95% CI -1.39 to -0.21), standardized effect d = -0.55; z-test p = 0.008.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Double-Blind Natalizumab than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary MRI summaries generally point in the same direction as the primary result: the natalizumab group has lower reported mean lesion counts than the placebo group for the cumulative new-active-lesion outcome, Gd+ lesions, and new or newly enlarging non-enhancing T2-hyperintense lesions. The registry also lists clinical and participant-reported secondary outcomes, including adjusted annualized relapse rate, relapse-free participants, and global well-being assessed with a visual analog scale. The results described in the available summaries do not establish the pattern for every listed secondary endpoint.

These MRI measures are related to the primary endpoint because the primary measure combines Gd+ lesions and new or newly enlarging non-enhancing T2 lesions and expresses their development as a rate. The secondary cumulative measures describe counts over the assessment period, separating lesion categories or reporting a cumulative count. Their general direction can therefore provide context for the primary MRI finding, but they are not independent confirmations of a different clinical outcome.

Unadjusted secondary results carry less weight when several outcomes are examined. General statistical explanation: when many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for multiple comparisons. A multiplicity adjustment or hierarchy can help control that issue, but the procedure used for secondary outcomes is not reported in the registry record. The listed secondary p-values should therefore be interpreted as individual, unadjusted evidence rather than as a single confirmatory family of tests.

The registry lists 17 posted secondary outcomes and reports analyses for some, but the record does not provide a complete multiplicity strategy or full analysis details for every endpoint. These limitations mean the secondary findings are best treated as supportive descriptions of the posted outcome pattern, not as proof of effects across all clinical, imaging and participant-reported measures.

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

• Part B: Cumulative Number of New Active Lesions Over 24 Weeks
• Part B: Adjusted Annualized Relapse Rate Over 24 Weeks
• Part B: Cumulative Number of Gd+ Lesions Over 24 Weeks
• Part B: Cumulative Number Of New Or Newly Enlarging, Non-Enhancing T2-Hyperintense Lesions Over 24 Weeks
• Part B: Number of Participants Who Were Relapse Free Over 24 Weeks
• Part B: Change From Baseline to Weeks 12 and 24 in the Global Assessment of Well-Being As Assessed by Participants Using a Visual Analog Scale (VAS)
• Part A: Concentration of Natalizumab in Serum
• Part B: Concentration of Natalizumab in Serum

9. Statistical Interpretation

10. Statistical Methods Explained

What does the mean describe?

The registry reports a mean for the continuous primary endpoint. A mean is the arithmetic average of participant-level values; in this study those values are rates of new active lesions per week. The posted mean is therefore a group summary, not an individual participant’s result and not a count of lesions in every participant. The standard deviation describes how dispersed participant values are around the group mean. A larger standard deviation indicates more spread in the observed values, while a smaller one indicates values closer together. It is not the same as the uncertainty in the estimated group mean.

What does the recalculated mean difference add?

The recalculated contrast is the natalizumab mean minus the placebo mean. It is a simple, unadjusted comparison based on the posted group summaries. The estimate of -0.294 lesions per week expresses the direction and size of the difference on the endpoint’s original scale. A negative value means the natalizumab group’s posted mean is lower. This recalculation is useful for describing magnitude, but it is not a replacement for the sponsor’s own analysis. The registry reports a Wilcoxon (Mann-Whitney) test for the primary outcome, rather than a mean-difference analysis.

General statistical explanation: a rank-based test orders observations and compares their ranks across groups. It can be useful when an analysis is based on distributional ordering rather than assumptions about normally distributed observations. Its p-value addresses evidence of a group difference under the test; it does not directly give the mean difference or its clinical meaning. The registry does not post further details of the primary test implementation.

How should the confidence interval be read?

The interval from -0.457 to -0.131 is the recalculated 95% confidence interval for the unadjusted mean difference. General statistical explanation: a confidence interval conveys uncertainty around an estimate. A narrower interval indicates greater precision than a wider interval, all else equal. The interval is compatible with a range of negative mean differences on this scale; it does not mean that 95% of individual participants had results within those limits. Nor is it a probability statement about the true value after the data have been observed.

The interval is based on a simple recalculation from the posted summaries, whereas the registry’s reported primary p-value comes from a rank-based test. These are different statistical summaries and need not be numerically interchangeable. The registry record does not report an interval for the sponsor’s rank-based analysis, so the recalculated interval should not be presented as if it were the sponsor’s test-based interval.

Why can lesion counts be dispersed?

General statistical explanation: count outcomes can be unevenly distributed, with many small values and some larger values. When variability exceeds what a simple model expects, that feature is often called over-dispersion. It can affect the precision and suitability of methods that rely on a particular distributional model. The posted standard deviations for the lesion outcomes describe substantial variation in the observed groups, but the registry does not report an over-dispersion assessment or a count-model analysis for the primary endpoint. The primary endpoint is a participant-level rate, and the registry reports its mean and standard deviation.

In general, a rank-based method does not require interpreting the outcome as normally distributed in the same way as a simple mean-based test; however, it answers a different question from a direct comparison of means. The record does not give enough detail to infer all assumptions checked or all sensitivity analyses performed.

What do the reported p-values mean?

A p-value describes how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the test assumptions held. It is not the probability that a treatment effect is real, nor the probability that the observed result occurred “by chance.” The primary registry analysis reports p < 0.001. The recalculated estimate and interval add information about direction, magnitude and precision that a p-value alone cannot convey.

The registry also reports rank-based tests for some secondary outcomes. The Van Elteren test is generally a stratified rank-based method, while the Wilcoxon rank sum test compares ranked observations between groups. These general descriptions do not establish what strata or implementation details were used in this trial; those details are not reported in the registry record.

11. Confidence Intervals and Precision

The recalculated primary mean difference is -0.294 lesions per week, with a 95% confidence interval from -0.457 to -0.131. The interval remains below zero, matching the negative direction of the estimated contrast. It conveys uncertainty about the unadjusted mean difference, not about every participant’s rate and not about a clinical threshold. No threshold for a clinically important difference is reported in the registry record.

Precision depends on both the amount of information and the variability in the outcome. General statistical explanation: more variable measurements tend to make estimates less precise when other aspects of the design are unchanged. The posted primary group standard deviations are 0.565 for placebo and 0.075 for natalizumab, while each group has 47 participants in the primary comparison. The interval summarizes uncertainty for a mean difference derived from these posted summaries; it is distinct from the sponsor’s rank-based test result.

The registry’s primary analysis reports p < 0.001 but no confidence interval or effect estimate for that analysis. Therefore, the recalculated interval should be read as an unadjusted estimate based on the posted group means and dispersion, not as a confidence interval reported by the sponsor. The registry record does not state whether the sponsor’s primary analysis used an interval-based estimation procedure.

Confidence intervals do not account automatically for every source of uncertainty. They do not resolve questions about missing-data assumptions, analysis populations, endpoint selection, or multiplicity. The primary endpoint description does report linear interpolation for missing lesion values and last observation carried forward for participants who discontinued, but the record does not provide a sensitivity analysis showing how alternative missing-data approaches would affect precision. These considerations matter when judging how robustly the interval represents uncertainty in the treatment comparison.

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 figures are planning illustrations based on the observed effect, not the trial’s original design justification. The registry record does not report the trial’s own sample-size assumptions or justification. For the continuous outcomes in this analysis, the figures are participants per arm, not total events. The listed planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect.

The 80% power column gives the planned participants per arm for a design with an 80% chance of detecting the assumed effect under those planning assumptions, if that effect and the assumptions held. The 90% power column gives the per-arm planning figure for a 90% chance under the same framework. These are design probabilities used for planning, not guarantees about the results of a future study. This is not observed power.

Rows that plan for 100% of the observed effect use the full estimated contrast as the assumed effect; rows for 75% and 50% use smaller fractions of that observed contrast. Smaller effects are harder to detect at a given sample size, so the illustrations require more participants per arm for smaller assumed effects. For example, the primary endpoint illustration lists 30 participants per arm for 80% power at 100% of the observed effect, 53 at 75%, and 118 at 50%. The corresponding 90% figures are 40, 71 and 158 participants per arm.

These calculations are sensitive to the observed effect used as their starting point. Because the effect comes from this trial’s posted result, the figures should not be treated as independent evidence that a future study will reproduce that effect. They are comparative planning aids, not a reconstruction of the study’s original recruitment target or a substitute for a protocol-based design.

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 = -0.294; pooled standard deviation σ = 0.403.
2. n = 2 × (1.96 + 0.842)² × 0.403² / -0.294² = 29.5, rounded up to 30 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 <- -0.294                      # observed difference in means
sigma <- 0.402861067863352                     # 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(1440101)
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 = 30 (80% power), 40 (90% power)
 75% of observed effect: n per arm = 53 (80% power), 71 (90% power)
 50% of observed effect: n per arm = 118 (80% power), 158 (90% power)
power.t.test: 30.5 
Simulated power at n = 30 per arm: 0.794 (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

For the primary endpoint, the registry reports the sponsor’s analysis as a Wilcoxon (Mann-Whitney) test with p < 0.001. It does not post an effect estimate or confidence interval from that test. The accompanying recalculation is a simple, unadjusted difference between the posted group means: -0.294 lesions per week, with a 95% confidence interval from -0.457 to -0.131.

The reported test and the recalculation answer related but not identical statistical questions. The rank-based test compares ranked observations, while the recalculated contrast quantifies the difference in group means on the original endpoint scale. The latter helps describe magnitude and precision, but it should not be attributed to the sponsor’s analysis. The registry record indicates no discrepancy between the posted results and the recalculation, but that does not make the methods interchangeable.

For the secondary outcome of cumulative Gd+ lesions, the registry reports a Van Elteren test with p < 0.001. For new or newly enlarging non-enhancing T2-hyperintense lesions, it reports a Wilcoxon rank sum test with p = 0.006, while the unadjusted recalculation has p = 0.008. The registry does not post a sponsor-reported test for the cumulative number of new active lesions. The distinction between registry analyses and simple summary-statistic recalculations should be kept clear throughout interpretation.

15. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity adjustment, a testing hierarchy, or another procedure for controlling the chance of false-positive findings across the primary and secondary outcomes. This matters because the record lists numerous secondary outcomes, including several MRI measures, relapse outcomes, a participant-reported assessment, and serum concentration measures. The primary endpoint is clearly identified, but the registry does not state how testing across the wider outcome set was handled.

General statistical explanation: multiplicity arises when more than one hypothesis is tested. Without an adjustment or prespecified hierarchy, a small p-value for an individual secondary outcome does not necessarily have the same confirmatory interpretation as a primary test planned as the principal question. The reported secondary p-values are informative about their individual analyses, but they should not be treated as if the full family of tests had been controlled.

The primary endpoint description states that missing lesion values were imputed using linear interpolation between adjacent non-missing values. For participants who discontinued, the approach reduced to last observation carried forward. These are relevant details because conclusions can depend on how missing outcomes are handled. The registry record does not provide sensitivity analyses comparing this approach with alternatives, or enough detail to assess the robustness of the result to the imputation assumptions.

The exact analysis populations, handling of other missing secondary outcomes, and detailed analysis plan are not reported in the registry record. The posted group sizes describe the results, but they do not by themselves specify every inclusion, exclusion, or analysis-population rule. The original sample-size justification, interim analyses, and additional statistical-plan details are also not reported in the registry record. Their absence should be read as an information limit, not as evidence that a procedure was or was not used.

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: multiple sclerosis relapse (21.3%), retinal detachment (8.3%), pyelonephritis (2.1%), basal cell carcinoma (2.1%), asperger's disorder (2.1%).

The adverse-event record gives serious adverse events by study group. In the open-label natalizumab group, 2 of 12 participants at risk were affected. In the double-blind placebo group, 11 of 47 were affected, and in the double-blind natalizumab group, 7 of 47 were affected. These are counts of participants affected in the listed groups; they are not an adjusted comparison and do not establish that treatment caused or prevented an event.

The record also lists other adverse events affecting 8 of 12 participants in the open-label natalizumab group, 32 of 47 in the placebo group, and 21 of 47 in the double-blind natalizumab group. The open-label group is a different study part and is not directly comparable with the randomized groups without further design and analysis details. The registry lists serious adverse-event terms including Multiple Sclerosis Relapse, Retinal Detachment, Pyelonephritis, Basal Cell Carcinoma, Asperger's Disorder, and Somatoform Disorder, with the posted percentages varying by term. Death counts are not reported in the registry record.

These summaries do not provide event timing, exposure-adjusted rates, or a full causal assessment. They should be read as descriptive safety counts from the registry record, not as a complete benefit-risk evaluation.

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

The posted results show that, in the randomized Part B groups, the mean rate of MRI-defined new active lesions was lower in the natalizumab group than in the placebo group over the stated 24-week assessment period. The recalculated unadjusted mean difference is -0.294 lesions per week, and its 95% confidence interval ranges from -0.457 to -0.131. The registry’s reported rank-based primary test gives p < 0.001.

This result concerns a specific radiological endpoint in Japanese participants with RRMS. It does not directly answer whether participants experienced fewer relapses, improved disability, or better overall well-being. Those outcomes are distinct, and the registry lists some as secondary measures. A lower mean MRI lesion rate should not be translated into a claim about every participant or every aspect of the condition.

The result also does not establish the size of a clinically important benefit. The registry record does not state a threshold for meaningful change in the primary endpoint. Statistical evidence of a group difference and clinical importance are separate questions. The confidence interval helps describe uncertainty in the unadjusted mean difference, but it does not resolve that clinical interpretation.

The study’s duration and population also define the scope of inference. The primary outcome covers Baseline (Week 0) to Week 24, and the study concerns Japanese participants with RRMS. The result alone does not determine what would occur over longer follow-up, in other populations, or with a different regimen. The trial record also does not provide all details needed to assess the analysis plan, multiplicity handling, or sensitivity to missing-data assumptions.

The safety counts are descriptive and should be considered separately from the efficacy comparison. Differences in recorded adverse-event counts do not on their own establish causation, and the open-label group is not equivalent to the randomized Part B groups. Together, the registry entries describe a bounded set of study outcomes; they do not amount to individualized medical advice or a complete account of treatment effects.

18. Why This Trial Matters Statistically

This trial is statistically informative because its primary endpoint turns repeated MRI lesion observations into a participant-level rate, then compares group summaries over a defined assessment period. That makes the distinction between a rate, a cumulative count, and a clinical outcome important: each represents a different statistical and clinical quantity. The registry’s endpoint description allows readers to understand how the rate was constructed, including the combination of Gd+ and new or newly enlarging non-enhancing T2 lesions.

The result also illustrates why estimates and tests are complementary. The reported Wilcoxon (Mann-Whitney) test gives a p-value, while the unadjusted recalculation supplies a mean difference and confidence interval on the endpoint scale. The p-value communicates evidence under a test; the estimate and interval convey direction, magnitude and precision. Keeping these quantities distinct avoids treating statistical significance as a measure of effect size.

The secondary MRI measures provide related context, while the registry’s broader list of outcomes raises the importance of multiplicity. Without a reported procedure for handling multiple tests, individual secondary p-values have a more limited confirmatory role. Similarly, the explicit missing-data approach is useful information, but the lack of posted sensitivity analyses leaves uncertainty about how dependent results may be on that approach.

Finally, the record separates an open-label safety and pharmacology part from a randomized placebo-controlled efficacy part. Recognizing that distinction is essential when reading group counts and deciding which comparisons support which questions. These features make the study a useful example of reading a clinical trial through endpoint definition, effect estimation, analysis methods, and limits of registry reporting.

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 primary comparison is based on 47 participants in each Part B group, and the outcome is an MRI-derived measure assessed from Baseline (Week 0) to Week 24. The record does not establish how far these results extend beyond that population, endpoint, or period. The overall enrollment of 106 includes the full study, while the primary comparison is a Part B result; the registry does not provide enough information in this record to reconstruct every analysis-population decision.

The primary outcome description specifies linear interpolation for missing lesion values and last observation carried forward for participants who discontinued. The registry does not report sensitivity analyses for these assumptions. It also does not report detailed handling of missing values for all secondary outcomes, or a complete statistical analysis plan. These omissions limit assessment of robustness.

The sponsor-reported primary analysis is rank-based, while the mean difference and confidence interval are unadjusted recalculations from posted summaries. This provides a useful effect-scale description but is not the same as a sponsor-reported estimate from the rank-based method. The record does not give the sponsor’s primary effect estimate or confidence interval.

The registry does not report a multiplicity procedure for the numerous secondary outcomes, so secondary p-values should not be read as if a familywise strategy were documented. The original sample-size justification and interim-analysis details are not reported in the registry record. Finally, adverse-event counts alone do not provide event timing, exposure-adjusted comparisons, or causal attribution; the open-label Part A safety group also differs in design from the randomized Part B groups.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Natalizumab (BG00002, Tysabri) Study in Japanese Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) — NCT01440101.
• Registry record last updated 2014-10-21; status last verified 2014-10.
• Results first posted 2014-10-21.
• 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.

23. Record Summary

NCT01440101 is a completed study of natalizumab in Japanese participants with RRMS, sponsored by Biogen. The record lists phase 2 and phase 3, a parallel randomized design, and quadruple masking. It describes an open-label safety and pharmacology Part A and a randomized, double-blind, placebo-controlled Part B.

The primary Part B endpoint was the rate of new active MRI lesions over 24 weeks. Posted mean rates were 0.352 lesions per week for placebo and 0.058 for natalizumab. The registry reports a Wilcoxon (Mann-Whitney) test with p < 0.001; the recalculated unadjusted mean difference is -0.294, with a 95% confidence interval from -0.457 to -0.131.

The record also lists secondary outcomes and adverse-event counts. Multiplicity handling, the original sample-size justification, and several analysis-plan details are not reported in the registry record.