BIIB033 In Acute Optic Neuritis (AON): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BIIB033 In Acute Optic Neuritis (AON) (NCT01721161), a randomized phase 2 study. The primary outcome is Change in Full-field Visual Evoked Potential (FF-VEP) Latency at Week 24: Intent-to-treat (ITT) Population.

2. Clinical Question

3. Trial Design

This completed phase 2 study compared BIIB033 with placebo in people experiencing a first episode of acute optic neuritis. The registry describes the design as randomized, double-blind, and parallel-group. Enrollment was 82. The posted primary outcome groups each included 41 participants, while the analysis populations for secondary measures vary according to the specific outcome.

The intervention schedule was once every 4 weeks for 20 weeks, with a total of 6 doses in each group. Placebo was administered by intravenous infusion; the registry describes BIIB033 as an anti-LINGO-1 monoclonal antibody. The trial began in 2012-12 and primary completion was recorded in 2014-10. The overall study status is completed.

The primary outcome was change in full-field visual evoked potential latency at Week 24 in the intent-to-treat population. Its analysis population was defined as all randomized participants who received at least one dose of BIIB033 or placebo. If Week 24 data were missing, the registry says last observation carried forward was used. The endpoint description also states that the estimate was adjusted for the baseline latency of the unaffected fellow eye.

Secondary outcomes included retinal nerve fiber layer thickness, retinal ganglion cell layer/inner plexiform retinal layer measurements, low-contrast letter acuity, adverse events, and BIIB033 concentration. The registry record does not report the trial's original sample-size justification or the detailed procedures used to generate the random allocation or maintain 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population: all randomized subjects who received at least 1 dose of study treatment (BIIB033 or placebo). Last observation carried forward (LOCF) imputation was used if Week 24 data were missing.

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 in Full-field Visual Evoked Potential (FF-VEP) Latency at Week 24: Intent-to-treat (ITT) Population, measured over Baseline, Week 24.

The primary endpoint was change in full-field visual evoked potential latency at Week 24, measured in msec. The registry describes the analysis as an adjusted mean change for the affected eye, using the baseline latency of the unaffected fellow eye as the reference and adjusting for that fellow-eye baseline latency. The primary analysis population was the registry-defined intent-to-treat population: randomized participants who received at least one dose of study treatment.

As a general explanation, a visual evoked potential records an electrical response associated with visual stimulation. Latency describes the time taken for that response to occur. Because the study used this measure to assess optic nerve conduction, a change in latency offers a physiological measure alongside the clinical and retinal outcomes listed as secondary endpoints. It is not itself a direct measure of every aspect of vision or daily function.

The registry reports the endpoint as a mean, with standard error as the measure of dispersion. Week 24 was the assessment time for the primary comparison, with baseline measurement also used in the endpoint definition and adjustment. For participants without Week 24 primary data, the specified approach was last observation carried forward. That imputation carries an earlier observed value forward; it does not recover an unobserved Week 24 measurement, so the estimate depends in part on how missing values were handled.

7. Results Posted in the Registry

• BIIB033: mean 17.34 versus 20.83 on control; difference -3.49 (95% CI -10.50 to 3.52), standardized effect d = -0.22; z-test p = 0.329.

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.

Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 24: ITT Population

• 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:
  • BIIB033: mean -15.66 versus -11.77 on control; difference -3.89 (95% CI -9.59 to 1.81), standardized effect d = -0.30; z-test p = 0.181.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between BIIB033 and the control. The interval gives the range of effects that remain compatible with the data.

Percentage Change in SD-OCT Average RNFL Thickness at Week 24: Per-protocol Population

• 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:
  • BIIB033: mean -16.98 versus -12.22 on control; difference -4.76 (95% CI -11.12 to 1.60), standardized effect d = -0.36; z-test p = 0.143.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between BIIB033 and the control. The interval gives the range of effects that remain compatible with the data.

Change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 24: ITT Population

• 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:
  • BIIB033: mean -11.05 versus -9.90 on control; difference -1.15 (95% CI -1.67 to -0.63), standardized effect d = -0.97; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for BIIB033 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes broaden the assessment beyond the primary visual evoked potential measure. The listed domains include retinal structure, low-contrast letter acuity, adverse events, and BIIB033 concentration. The detailed numerical results include retinal nerve fiber layer thickness and retinal ganglion cell layer/inner plexiform retinal layer measurements, with both intent-to-treat and per-protocol populations represented for the nerve fiber layer outcome. These results involve different measures and populations, so they should be considered in their own context rather than treated as interchangeable evidence about the primary endpoint.

Overall, the secondary results do not provide a consistent, independently confirmatory pattern that resolves the uncertainty in the primary comparison. The detailed sponsor-reported analyses and recalculated comparisons can also differ because the sponsor's analyses use ANCOVA while the recalculations use posted summaries. Numerical results for the other listed secondary outcomes are not reported in the registry record's detailed results summarized in the outcome data.

Unadjusted secondary comparisons carry less weight because several outcomes were assessed. As a general statistical concern, examining many outcomes can increase the chance of observing an apparently notable result even when no corresponding effect exists. The registry record does not report a multiplicity adjustment or hierarchy for interpreting secondary outcomes. It is therefore more appropriate to view these results as supportive or exploratory context, not as stand-alone proof or as a substitute for the primary analysis.

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

• Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 24: ITT Population
• Percentage Change in SD-OCT Average RNFL Thickness at Week 24: Per-protocol Population
• Change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 24: ITT Population
• Change in SD-OCT Average RGCL/IPL at Week 24: Per-protocol Population
• Change in Low-contrast Letter Acuity (LCLA) at Week 24: ITT Population
• Change in LCLA at Week 24: Per-protocol Population
• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
• Summary of BIIB033 Concentration

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary mean difference represent?

The posted group values are means of a continuous outcome. A mean difference compares the average outcome in the BIIB033 group with the average in the placebo group. For the recalculation, the difference is expressed as BIIB033 minus placebo, so a negative estimate corresponds to a lower mean in the BIIB033 group. Here, the recalculated unadjusted estimate is -3.49 msec. This arithmetic comparison does not account for covariates beyond the posted group summaries.

The sponsor's reported primary analysis used ANCOVA, an analysis of covariance. In general, ANCOVA compares groups while adjusting for one or more baseline measurements or other specified covariates. The registry states that the primary endpoint was adjusted for baseline latency of the unaffected fellow eye. This makes the sponsor's adjusted comparison distinct from a simple difference between the posted means. The registry record does not report the complete model specification, including all details needed to reproduce that analysis.

What does the standard error describe?

The primary endpoint is reported as a mean with standard error. In general, a standard error describes the estimated uncertainty of a sample mean as an estimate of a population mean. It is not the same as the spread of individual participant measurements. The posted primary group values each have a standard error of 2.53 msec. The recalculation uses the posted summary statistics to estimate an unadjusted comparison and its uncertainty; it does not recreate participant-level modeling.

For the secondary outcomes, the registry uses different dispersion measures in different records. Some are reported with standard error and another with standard deviation. In general, standard deviation describes variation among observations, while standard error describes uncertainty in an estimated mean. These quantities answer different questions and should not be read interchangeably.

How should a confidence interval be read?

In general, a confidence interval gives a range of values reasonably compatible with the observed data under the analysis assumptions. Its width reflects precision: a wider interval indicates greater uncertainty about the size of the effect. The primary recalculated interval extends from -10.5 to 3.523 msec. Because it includes zero, it is compatible with no mean difference as well as with negative or positive differences. The sponsor's ANCOVA interval also includes zero.

A confidence interval is not a guarantee that the true effect lies within the particular reported range, and it is not a probability statement about the treatment hypothesis. It is interpreted through the statistical procedure that generated it. Differences between the recalculated interval and the sponsor interval are expected to be possible because one is an unadjusted calculation from summaries and the other comes from ANCOVA.

What do the p-values add?

As a general explanation, a p-value measures how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It does not measure effect size, clinical importance, or the chance that a result is due to chance. The recalculated primary p-value is unadjusted, while the sponsor's p-value comes from the ANCOVA result. Both are consistent with the confidence intervals that include no difference. The registry record does not report the full statistical plan for the primary analysis.

Why do analysis populations matter?

The registry defines the primary intent-to-treat population as randomized participants who received at least one dose, and says last observation carried forward was used for missing Week 24 primary data. This definition should be kept in view when interpreting the estimate: it is not simply a description of every person randomized regardless of treatment received. Secondary analyses also use different populations, including intent-to-treat and per-protocol groups for retinal nerve fiber layer thickness. As a general principle, population definitions affect which observations contribute to an estimate and can affect how well a comparison preserves the advantages of randomization.

Last observation carried forward is an imputation method. In general, it substitutes an earlier recorded value when a later measurement is missing. This can be consequential if the outcome would have changed after the last observation. The registry identifies the method but does not report the amount or pattern of missing primary endpoint data or analyses testing alternative missing-data assumptions.

Why can secondary findings be less conclusive?

Multiple outcomes create a multiplicity issue: when many comparisons are examined, the chance of at least one apparently unusual result can increase. In general, adjustment procedures or a prespecified hierarchy can address this, but the registry record does not report a multiplicity adjustment or testing hierarchy. Therefore, unadjusted secondary p-values should be interpreted cautiously, especially when they are considered separately from the primary endpoint.

The secondary outcomes also differ in measurement scale and analysis population. Some measure retinal structure, one assesses low-contrast letter acuity, and others cover adverse events and drug concentration. A finding on one measure is not automatically a finding on another. The numerical recalculations are unadjusted comparisons derived from posted summary statistics; sponsor-reported ANCOVA results, where posted, reflect the sponsor's model and should be distinguished from those recalculations.

11. Confidence Intervals and Precision

The primary unadjusted estimate is -3.49 msec, with a 95% confidence interval from -10.5 to 3.523. The interval crosses zero and extends to values on both sides of it. This means the observed data do not pin down the direction or magnitude of the underlying group difference with high precision. The point estimate is only one plausible estimate among the range compatible with the analysis.

The sponsor's ANCOVA result is -3.48 msec, with a 95% confidence interval from -10.61 to 3.65. It likewise includes zero and covers a broad range of possible differences. The closeness of the point estimates does not make the interval narrow: uncertainty about the effect remains substantial relative to the estimated difference. The p-values, 0.329 for the unadjusted recalculation and 0.334 for the sponsor analysis, are consistent with intervals that do not exclude zero.

In general, confidence intervals communicate both direction and precision. A range that includes zero does not prove there is no effect; it indicates that the estimate is not sufficiently precise to distinguish the observed data from no difference at the confidence level used. Conversely, the interval should not be used to claim that every value within it is equally likely or clinically equivalent.

The posted primary outcome groups each had 41 participants, but the width of an interval also depends on variability and the analysis method. The recalculated interval is based on summary statistics and is unadjusted; the sponsor interval comes from ANCOVA. The registry record does not report additional precision measures or a prespecified threshold for a clinically important difference, so statistical uncertainty cannot be translated into a conclusion about clinical importance from these results alone.

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 planning figures are participants per arm, not total participants or total events. They are illustrations based on the observed effect, rather than the trial's original design calculation. The 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 trial's own original sample-size assumptions are not reported in the registry record.

Each planning row asks how many participants per arm would be needed under the stated assumptions to have a specified chance of detecting a difference of the size being planned for, if that difference were the true effect and the assumptions held. The 80% power column corresponds to an 80% chance of detecting that target effect under the planning model. The 90% power column uses a higher target chance of detection, and therefore generally calls for more participants per arm. These are design probabilities, not probabilities that the observed result is correct.

The rows consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. Smaller effects are harder to distinguish from random variation and need more participants. The figures increase as the target effect becomes smaller, illustrating why planning around a more modest effect requires a larger study under otherwise fixed assumptions.

These figures are not observed power. Observed power is not an appropriate way to reinterpret the trial's result after the data have been collected. The planning display instead shows hypothetical future study sizes under specified assumptions. It should not be read as evidence that the original study was designed with these assumptions, or as a recommendation about the size of a future trial.

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 = -3.490; pooled standard deviation σ = 16.200.
2. n = 2 × (1.96 + 0.842)² × 16.200² / -3.490² = 338.2, rounded up to 339 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 <- -3.49                      # observed difference in means
sigma <- 16.1999043207051                     # 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(1721161)
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 = 339 (80% power), 453 (90% power)
 75% of observed effect: n per arm = 602 (80% power), 805 (90% power)
 50% of observed effect: n per arm = 1,353 (80% power), 1,812 (90% power)
power.t.test: 339.2 
Simulated power at n = 339 per arm: 0.800 (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 sponsor-reported primary analysis used ANCOVA and estimated a difference of -3.48 msec, with a 95% confidence interval from -10.61 to 3.65 and p = 0.334. The recalculation from the posted group summary statistics gives an unadjusted difference of -3.49 msec, a 95% confidence interval from -10.5 to 3.523, and an unadjusted p-value of 0.329. These are similar point estimates, but the confidence limits and p-values are not identical.

The distinction is methodological: the recalculation is a simple unadjusted comparison based on summary statistics, whereas the registry's reported analysis is ANCOVA and the endpoint description specifies adjustment for baseline latency of the unaffected fellow eye. The sponsor's analysis is the relevant reported adjusted analysis for the primary endpoint. The registry record does not provide enough detail to reproduce the full ANCOVA model from participant-level data. Both analyses show considerable uncertainty, with confidence intervals that include zero; neither establishes a clear group difference on this endpoint.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study assesses several endpoints or makes several comparisons. As a general statistical principle, the more tests considered, the greater the opportunity for at least one result to appear unusual by chance under a null model. Researchers can address this with prespecified approaches such as adjustment procedures or a testing hierarchy. The registry record does not report whether such a strategy was prespecified or used for the secondary outcomes. Consequently, unadjusted secondary p-values should not be interpreted as if each were the only test performed.

The registry lists a broad set of secondary measures, including structural retinal outcomes, low-contrast letter acuity, adverse events, and BIIB033 concentration. The posted detailed results include only some of these measures. Results for listed secondary outcomes without detailed numerical results are not reported in the registry record. The absence of a reported result does not establish that an outcome was not measured; it means the registry record does not give the result in the information available for this analysis.

Missing data also matter. For the primary endpoint, the registry states that last observation carried forward was used if Week 24 data were missing. In general, this method assumes that an earlier measurement can stand in for the missing later value. If the outcome changes over time, carrying the last value forward can misrepresent the value that would have been observed at Week 24. The registry record does not report the number or pattern of missing primary measurements, nor sensitivity analyses using alternative assumptions.

The primary population is described as all randomized participants who received at least one dose of study treatment. This registry-defined population should not be silently equated with every randomized participant regardless of treatment received. Secondary analyses also include different analysis populations, such as intent-to-treat and per-protocol populations. The registry record does not report enough detail to assess all consequences of those population choices or how missing secondary measurements were handled.

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: hypersensitivity (4.9%), liver disorder (2.4%), viral pericarditis (2.4%), alanine aminotransferase increased (2.4%), aspartate aminotransferase increased (2.4%).

The registry reports serious adverse events for 2 participants in the placebo group and 5 participants in the BIIB033 100 mg/kg group, with 41 participants at risk in each group. It also reports participants with other adverse events: 25 in the placebo group and 27 in the BIIB033 group, again with 41 at risk in each group. These counts describe reported events in this trial; they do not by themselves establish that treatment caused an event or that the groups differ reliably in safety.

The serious-event terms listed include hypersensitivity at 4.9%, and liver disorder, viral pericarditis, alanine aminotransferase increased, aspartate aminotransferase increased, and cytomegalovirus test positive at 2.4% each. These are registry-listed terms and percentages; they should not be interpreted as comparative risk estimates without further detail about event definitions, timing, and attribution. Death counts are not reported in the registry record.

Safety comparisons in a study of this size can be imprecise, particularly for individual serious-event terms. The figures should be read as descriptive counts rather than proof of a treatment-related safety difference.

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

The primary result is an estimate of the difference in Week 24 full-field visual evoked potential latency between BIIB033 and placebo, under the analysis methods described in the registry. The adjusted sponsor estimate is -3.48 msec, and the unadjusted recalculation is -3.49 msec. Both confidence intervals include zero, so the posted results do not establish a clear difference on the primary endpoint.

This does not demonstrate that the groups are identical. The intervals remain compatible with a range of differences in either direction, and the estimates are not precise enough to rule out effects that differ from the point estimate. Nor does a result that includes zero prove that BIIB033 has no effect. It indicates that these data, analyzed in the stated ways, do not clearly distinguish the observed result from no group difference.

The primary endpoint is a physiological measure of visual pathway response time, not a complete measure of vision, daily functioning, or every consequence of acute optic neuritis. Secondary measures address some additional domains, but their differing populations, analyses, and multiplicity concerns make them insufficient to convert an uncertain primary result into a definitive overall conclusion.

The study also reports adverse-event counts, but those descriptive data do not establish causation or settle comparative safety. The registry record does not supply detailed missing-data sensitivity analyses, a multiplicity plan, or the original sample-size rationale. These omissions limit assessment of how robustly the reported estimates address alternative assumptions. Interpretation should therefore remain tied to the specific outcomes and analyses recorded rather than extended to unmeasured outcomes or broader populations.

18. Why This Trial Matters Statistically

This trial is statistically informative because it brings together a randomized, double-blind, placebo-controlled comparison and a physiological primary endpoint in acute optic neuritis. The registry reports both a sponsor ANCOVA analysis and enough summary statistics for an unadjusted recalculation. Comparing these results illustrates how an adjusted model and a simple summary-based calculation can yield similar estimates while retaining different uncertainty limits and p-values.

The example also emphasizes why a point estimate should be read alongside its confidence interval. The primary estimate is negative, but its interval includes zero and spans effects in either direction. A numerical direction alone is not enough to establish a reliable group difference. The reported uncertainty is central to interpreting the result.

The range of secondary measures highlights the complexity of a trial with structural, functional, pharmacokinetic, and safety outcomes. Different measures can address distinct aspects of a clinical question, but multiple analyses make careful interpretation important. Without a reported multiplicity strategy, secondary findings should be treated cautiously, especially when the primary result is uncertain.

Finally, the registry's account of last observation carried forward and its defined analysis population show why endpoint estimates depend not only on the treatment comparison but also on missing-data and population rules. These features matter when assessing what the trial establishes and what remains uncertain.

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 analysis population includes randomized participants who received at least one dose, rather than being described simply as all randomized participants. The registry record does not provide additional detail about treatment discontinuation or the relationship between this definition and any alternative analysis population.

The primary endpoint used last observation carried forward for missing Week 24 data. The record does not report how many measurements were missing, why they were missing, or whether alternative missing-data assumptions were examined. The robustness of the primary estimate to missing-data handling therefore cannot be assessed from the registry record.

The registry reports ANCOVA for the sponsor's primary analysis but does not give a complete model specification. The unadjusted recalculation cannot reproduce the adjusted analysis and should not be treated as an equivalent model-based result. The original sample-size rationale and detailed statistical plan are also not reported in the registry record.

Multiple secondary outcomes were listed, but a multiplicity adjustment or hierarchy is not reported. Detailed numerical results are not available in the registry record for every listed secondary outcome. The small group sizes and the breadth of outcomes also mean that estimates, particularly for less common safety events, may be uncertain. The registry data do not include a stated threshold for a clinically important primary-endpoint difference, limiting interpretation of the effect's clinical importance.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: BIIB033 In Acute Optic Neuritis (AON) — NCT01721161.
• Registry record last updated 2016-06-30; status last verified 2016-05.
• Results first posted 2016-06-30.
• 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.

23. Record Summary

NCT01721161 is a completed phase 2 randomized, double-blind, parallel-group, placebo-controlled study of BIIB033 in participants with a first episode of acute optic neuritis. Enrollment was 82. The primary endpoint was change in full-field visual evoked potential latency at Week 24 in the registry-defined intent-to-treat population.

The sponsor's ANCOVA estimate was -3.48 msec, with a 95% confidence interval from -10.61 to 3.65 and p = 0.334. The unadjusted recalculation was -3.49 msec, with a 95% confidence interval from -10.5 to 3.523 and p = 0.329. Both intervals include zero, leaving substantial uncertainty about the primary group difference. Secondary and safety outcomes provide additional descriptive context but do not remove that uncertainty.