Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS) (NCT00424463), a randomized phase 3 study. The primary outcome is Change From Baseline in Revised ALS Functional Rating Scale (ALSFRS-R) Score in Full Analysis Set (FAS) Population at 24 Weeks.

2. Clinical Question

The clinical question is therefore about the later treatment period among participants whose preceding treatment included MCI-186. It does not directly ask whether starting MCI-186 is better than starting placebo in an otherwise untreated population. The posted results also include a comparison with the sequence placebo of MCI-186 followed by MCI-186, but that is distinct from the primary comparison. The registry record identifies the study as a long-term extension of NCT00330681 and describes the preceding study as a 24-week phase 3 trial. It does not report a broader claim about the treatment’s effects beyond the outcomes and period described in this record.

3. Trial Design

The registry identifies this as a completed phase 3, randomized, quadruple-masked, parallel-group study of MCI-186 and placebo of MCI-186 in people with ALS. The listed enrollment is 181. The sponsor is Shionogi. The study start is recorded as 2007-01-31, and primary completion as 2009-05-31. The stated objective was to assess efficacy and safety of long-term intermittent therapy with 60 mg MCI-186. The record describes the study as an extension of NCT00330681, which it characterizes as a randomized, double-blind, placebo-controlled, parallel-assignment study lasting 24 weeks.

The primary analysis concerns the treatment period from Cycle 7 to Cycle 12, after six cycles of earlier treatment. The listed sequences are MCI-186 followed by placebo of MCI-186, MCI-186 followed by MCI-186, and placebo of MCI-186 followed by MCI-186. For the primary endpoint, the first sequence is the reference group for comparisons with the other sequences. The registry’s primary endpoint description explicitly emphasizes comparison of the two groups that received MCI-186 during the first six cycles. It does not report detailed arm descriptions beyond the treatment sequence names.

The primary outcome is assessed over 24 weeks, with baseline defined at the seventh cycle and the endpoint at the twelfth cycle. The posted analysis is reported as a mean and standard deviation in the FAS. The registry does not report the original sample-size justification, a detailed allocation ratio, or the full operational details of masking. It also does not report the protocol’s planned statistical model or a complete account of how participants were handled in each analysis population. These omissions limit how fully the design and analysis can be reconstructed from the registry record alone.

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: "1 patient with diseases other than ALS" and "4 patients with missing data" were excluded from the FAS in the MCI-186 - Placebo of MCI-186group. "5 patients with missing data" were excluded from the FAS in the MCI-186 - MCI-186 group. "14 patients with missing data" were excluded from the FAS in the Placebo of MCI-186 - MCI-186 group.

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 Baseline in Revised ALS Functional Rating Scale (ALSFRS-R) Score in Full Analysis Set (FAS) Population at 24 Weeks, measured over baseline (seventh cycle) and at 24 week (twelfth cycle).

The primary endpoint is change from baseline in the Revised ALS Functional Rating Scale (ALSFRS-R) score in the Full Analysis Set at 24 weeks. The registry specifies baseline at the seventh cycle and the follow-up assessment at the twelfth cycle. ALSFRS-R is reported in units on a scale where 0 is worst and 48 is best. The endpoint is summarized as a mean change with a standard deviation, so the posted group values describe average change and the spread of individual changes around that average.

A functional rating scale is used to quantify functioning over the assessment period. Change from baseline focuses the comparison on movement in scores during the specified period rather than on the endpoint score alone. In this record, the endpoint is tied to the question of whether effects were sustained after six cycles of MCI-186, comparing continued MCI-186 with switching to placebo of MCI-186 among participants who had received MCI-186 earlier.

Interpretation depends on both the direction and size of the mean changes, as well as their uncertainty. A negative mean change indicates that scores declined on a scale for which higher scores represent better function. The group average does not describe every participant’s experience, and a mean difference does not establish how an individual’s score changed. The registry record does not state a threshold for a clinically important difference on ALSFRS-R, so the posted group estimates alone cannot establish whether a particular difference would be clinically meaningful.

7. Results Posted in the Registry

• MCI-186 - MCI-186: mean -4.20 versus -5.50 on control; difference 1.30 (95% CI -0.56 to 3.16), standardized effect d = 0.30; z-test p = 0.171.
• Placebo of MCI-186 - MCI-186: mean -5.40 versus -5.50 on control; difference 0.10 (95% CI -1.66 to 1.86), standardized effect d = 0.02; z-test p = 0.911.

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 Baseline in % Forced Vital Capacity (%FVC) in Full Analysis Set (FAS) Population at 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:
  • MCI-186 - MCI-186: mean -12.91 versus -10.60 on control; difference -2.31 (95% CI -8.40 to 3.78), standardized effect d = -0.16; z-test p = 0.457.
  • Placebo of MCI-186 - MCI-186: mean -10.54 versus -10.60 on control; difference 0.06 (95% CI -5.07 to 5.19), standardized effect d = 0.00; z-test p = 0.982.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MCI-186 - MCI-186 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Placebo of MCI-186 - MCI-186 and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes spanning disease progression, respiratory function, adverse events, adverse drug reactions, laboratory changes, and sensory examination changes. The posted continuous secondary result is change from baseline in %FVC at 24 weeks. Across the treatment-sequence comparisons, its point estimates do not show a consistent pattern of separation that independently resolves the uncertainty in the primary ALSFRS-R comparison. The estimates and intervals should be interpreted as additional context, not as a replacement for the primary endpoint.

The registry record lists six secondary outcomes, but it posts numerical results for only some of them in the information described. It reports no endpoint analyses in the analyses listing. The presence of an outcome in the registry does not itself show that a result was analyzed or reported, and the record does not establish how the other outcomes were handled. The overall secondary pattern therefore has to be read with attention to both what is posted and what is not reported in the registry record.

Secondary outcomes commonly serve different purposes. Some provide information about function or respiratory status, while others describe safety or other clinical events. These measures may support a broader understanding of a study, but they can have different scales, distributions, missing-data patterns, and analysis populations. A result on one measure cannot be assumed to confirm another measure, especially when the registry does not provide a complete analysis plan.

Unadjusted secondary results carry less weight when many outcomes or comparisons are considered. With multiple opportunities to observe an apparently notable result, chance findings become more likely unless the analysis accounts for multiplicity or the results are interpreted as exploratory. The registry record does not report a multiplicity adjustment, a hierarchy of secondary hypotheses, or a correction strategy. Accordingly, secondary findings should be treated as supportive or exploratory evidence rather than as independent proof of a treatment-sequence effect.

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

• Number of Participants With Death or a Specified State of Disease Progression
• Change From Baseline in % Forced Vital Capacity (%FVC) in Full Analysis Set (FAS) Population at 24 Weeks
• Percentage of Participants With Adverse Events
• Percentage of Participants With Adverse Drug Reactions
• Percentage of Participants With Laboratory Tests for Which the Incidence of Abnormal Changes Was 5% or Higher in Either Group
• Percentage of Participants With Abnormal Changes in Sensory Examinations

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: it records a numerical score change, rather than whether a participant did or did not experience a particular event. The registry reports group means and standard deviations. A mean gives the average change in each treatment-sequence group; a standard deviation describes how spread out participant-level changes are around that group mean. The standard deviation is not the uncertainty in the estimated mean difference. Confidence intervals address that uncertainty by giving a range of values compatible with the estimate under the method used.

What does the mean difference represent?

The primary recalculated contrast subtracts the mean change in the MCI-186-then-placebo group from the mean change in the MCI-186-then-MCI-186 group. The resulting estimate is 1.3 ALSFRS-R units. Because higher scores indicate better function, a positive contrast means the average change was less negative, or more positive, in the continued-MCI-186 sequence than in the reference sequence. It is a difference between group averages, not a change experienced by every participant. The separate comparison against placebo followed by MCI-186 uses the same reference sequence but answers a different question.

What does an unadjusted comparison assume?

The recalculated comparisons use the posted group means, standard deviations, and group sizes without adjustment for other variables. This is a straightforward way to contrast the posted summaries. It does not account for possible baseline imbalances, repeated measurements, or other features that a prespecified analysis might address. The registry record does not report the sponsor’s detailed statistical analysis for these endpoints, and it lists no reported endpoint analyses. Accordingly, these recalculations should be understood as simple summaries rather than as a reconstruction of an undocumented formal model.

Randomization is intended to make treatment groups comparable on average, but it does not guarantee that every measured or unmeasured characteristic is balanced in a particular trial. An adjusted analysis can account for selected variables according to a prespecified plan. Without the trial’s statistical plan and analysis results, the posted summary statistics cannot establish whether adjustments were planned or how they would affect the estimates.

Why are confidence intervals useful?

A point estimate is the single best estimate produced by a particular calculation, but it does not convey its precision on its own. A confidence interval adds information about sampling uncertainty. A broad interval indicates that the estimated difference is not tightly pinned down; an interval spanning zero includes both a possible advantage for either sequence and no difference. An interval that includes zero does not prove exact equality. Conversely, a point estimate away from zero does not by itself establish a reliable difference.

The unadjusted p-value measures how compatible the observed contrast is with a specified no-difference model, under the assumptions of the calculation. It is not the probability that the no-difference model is true, nor does it quantify the size or clinical importance of a difference. In particular, a p-value should be read alongside the estimate and its interval. The registry does not report whether these unadjusted comparisons were the prespecified inferential tests.

Why does the analysis population matter?

The registry identifies the primary endpoint population as the FAS and notes exclusions for disease status and missing data. This means the posted endpoint summaries do not represent every person recorded as enrolled. The record does not give a complete description of the FAS exclusions: the final sentence of the population description is incomplete. Missing outcome values can affect the composition of the analyzed group, and conclusions may depend on how missingness was handled. The registry record does not report a detailed missing-data method, sensitivity analysis, or imputation approach.

The listed group sizes for the primary endpoint are 40, 43, and 74. These are analysis counts for the reported endpoint groups, not a substitute for the enrollment figure or a complete account of participant flow. The record does not explain all differences between enrollment and the endpoint analysis counts. It is therefore important to keep the analysis population in view when interpreting the means and uncertainty.

Why can over-dispersion matter in other outcome types?

Over-dispersion is a general statistical issue that arises when variability in count or event data exceeds what a simple probability model expects. If a model understates variability, its standard errors can be too small and its intervals too narrow. This concept is not a reported feature of the ALSFRS-R analysis, which is presented as a continuous outcome with means and standard deviations. It may be relevant in general to analyses of counts or event rates, but the registry record does not report a model for such data.

More generally, statistical methods should match the outcome and design. A continuous score is typically analyzed through its distribution and the comparison of group means or adjusted means. Repeated measurements may call for methods that account for the relationship between observations from the same participant. The registry’s brief endpoint description does not establish which approach was used in the sponsor’s formal analysis. No inference should be drawn about an unreported model simply from the summary format.

Finally, this is an extension study comparing sequences over a later period. Its results concern the specified follow-up and selected analysis population. They should not automatically be generalized to treatment initiation, different follow-up periods, or other populations. The posted statistics support a cautious reading of group averages and their uncertainty, not a complete account of every planned or performed analysis.

11. Confidence Intervals and Precision

The primary mean difference is 1.3 ALSFRS-R units for continued MCI-186 compared with switching to placebo after earlier MCI-186. Its confidence interval runs from -0.560 to 3.161. Because the interval includes zero, the estimate is not precise enough to rule out no average difference under this recalculated comparison. It also allows for values on either side of zero, so the direction of the underlying difference is uncertain. The unadjusted p-value is 0.171, which is consistent with the interval’s failure to establish a clear difference.

The interval is more informative than the point estimate alone. The point estimate suggests a less negative mean change in the continued-MCI-186 group, but the interval indicates that uncertainty remains about the size and direction of the difference. It should not be read as a range containing every participant’s individual response. It describes uncertainty in the estimated group contrast under the calculation, not the spread of participant outcomes.

For the comparison with placebo followed by MCI-186, the mean difference is 0.1, with a confidence interval from -1.656 to 1.856. This interval also includes zero. The estimate is close to zero, but that does not demonstrate equivalence: the registry does not report an equivalence margin or a noninferiority margin. A non-significant result is not evidence that groups are identical.

The registry record does not report a sponsor-generated confidence interval or the method used for a formal adjusted analysis. The intervals discussed are from simple unadjusted recalculations using posted summary statistics. They are useful for understanding the uncertainty around those contrasts, but they do not replace any formal analysis that may have been conducted outside the posted record.

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 illustrations based on the observed effect, not the trial’s original design assumptions. The registry record does not report the original sample-size justification or the assumptions used to choose enrollment. For the continuous outcomes, the figures are participants per arm, not total events. The planning illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It considers detecting the stated fraction of the observed effect.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the chosen effect under those assumptions, if that effect were the true one. The 90% power column gives the corresponding per-arm figure for a design targeting a 90% chance. These are design calculations and depend on the assumptions; they do not describe the chance that this completed trial detected an effect that was actually present.

Rows for planning for 100% of the observed effect use the full observed point estimate. Rows for planning for 75% or 50% of the observed effect illustrate progressively smaller effects. Smaller effects are harder to distinguish from random variation and therefore require more participants per arm under the same assumptions. Where the observed estimate is very close to zero, the resulting illustrative sample sizes become extremely large. That reflects the calculation’s dependence on the observed point estimate, not a claim about the size of a clinically important effect.

These figures are not observed power. They are planning illustrations based on posted summary statistics and should not be used to infer that the trial was adequately or inadequately designed without the original design rationale, prespecified target effect, and analysis plan.

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 = 1.300; pooled standard deviation σ = 4.299.
2. n = 2 × (1.96 + 0.842)² × 4.299² / 1.300² = 171.7, rounded up to 172 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 <- 1.3                      # observed difference in means
sigma <- 4.29935395663633                     # 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(424463)
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 = 172 (80% power), 230 (90% power)
 75% of observed effect: n per arm = 306 (80% power), 409 (90% power)
 50% of observed effect: n per arm = 687 (80% power), 920 (90% power)
power.t.test: 172.7 
Simulated power at n = 172 per arm: 0.799 (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. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity strategy for the primary and secondary outcomes. It lists several secondary outcomes covering functional, respiratory, safety, laboratory, and sensory measures, but does not state whether these were organized into a testing hierarchy or adjusted for multiple comparisons. When several hypotheses are examined, the chance of at least one apparently notable result can increase. Without a reported plan, isolated unadjusted secondary results warrant particular caution.

The record lists no reported endpoint analyses. Thus, the posted summary statistics and simple recalculations do not disclose a full prespecified analysis strategy, including whether the sponsor used covariate adjustment, repeated-measures methods, or another model. The record also does not report interim analyses or stopping rules. These features are not inferable from the phase, masking, or randomization labels.

The primary population is described as the FAS, and the registry notes exclusions for missing data and for a participant with diseases other than ALS in one treatment sequence. It also mentions missing data in the other sequence descriptions, but the final part of the population description is incomplete. A complete participant disposition and explanation of the analysis denominators are not reported in the registry record. The record does not specify whether missing outcomes were imputed, handled through a model, or excluded under another rule.

Missingness can matter if the likelihood of having an observed outcome is related to a participant’s health or treatment experience. An analysis limited to participants with available data can differ from an analysis that accounts for missing values, depending on the reasons for missingness and the methods used. The registry record does not provide enough information to assess those possibilities or to evaluate sensitivity to missing-data assumptions.

These omissions do not establish that the trial lacked a statistical plan or that a particular analysis was inappropriate. They mean that the registry record does not permit a full appraisal of multiplicity control, missing-data handling, or the formal analysis populations. The numerical comparisons should therefore be read as posted summaries and unadjusted recalculations, with those limits in mind.

15. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dysphagia (25.0%), musculoskeletal disorder (12.5%), respiratory failure (12.5%), gait disturbance (8.3%), dyslalia (6.8%).

The safety summaries distinguish serious adverse events from other adverse events and give the numbers at risk and affected for each treatment sequence. For serious adverse events, the registry lists 13 affected participants among 45 at risk in the MCI-186-then-placebo group, 25 among 48 in the MCI-186-then-MCI-186 group, and 39 among 88 in the placebo-then-MCI-186 group. For other adverse events, the corresponding figures are 43 among 45, 43 among 48, and 74 among 88. These are descriptive counts; they do not establish that treatment caused an event or explain its timing, severity, or duration.

The registry also lists serious adverse-event terms and percentages, including dysphagia at 25.0%, musculoskeletal disorder at 12.5%, respiratory failure at 12.5%, gait disturbance at 8.3%, dyslalia at 6.8%, and dyspnoea at 6.2%. These terms describe reported events in the registry; they are not estimates of comparative risk between treatment sequences. The record does not report deaths in the safety summary, so death counts are not reported in the registry record.

Safety counts should be interpreted with the group denominators and the study’s extension context in mind. The record does not provide enough detail to compare event timing, exposure duration, or adjusted safety rates. Nor does the presence of an event term establish a causal relationship to MCI-186.

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

The posted primary results describe average ALSFRS-R score changes during a defined 24-week extension period. Scores declined on average in both groups in the primary comparison. The recalculated mean difference was 1.3 units in favor of the continued-MCI-186 sequence numerically, but its interval includes zero and the unadjusted p-value is 0.171. The data therefore do not establish a clear average difference between the sequences in this comparison. They also do not prove that the sequences have identical effects.

The result addresses a specific treatment history: participants had received MCI-186 during the earlier cycles, and the comparison concerns continuing MCI-186 versus switching to placebo of MCI-186 for the later period. It is not a direct test of starting MCI-186 versus starting placebo in a treatment-naive population. The additional posted sequence comparison has a different treatment history and should be interpreted separately.

Statistical uncertainty is only part of interpretation. The registry record does not state a clinically important difference threshold for ALSFRS-R, so the mean difference cannot be classified from this record alone as clinically important or unimportant. Group means also conceal variation in individual outcomes. The registry summaries do not show how many participants had improvement, stability, or decline at the individual level.

The findings should not be extended automatically to other follow-up periods, populations, treatment regimens, or outcomes. The registry describes an extension study and provides incomplete information about the original statistical plan, missing-data handling, multiplicity, and formal analyses. The posted figures are best read as estimates with uncertainty for the measured outcomes and populations, rather than as definitive evidence about all possible effects of MCI-186.

Safety summaries add descriptive information about adverse events, but they do not establish causation. The numbers affected are not adjusted comparisons, and the registry record does not report event-level timing or exposure-adjusted rates in the information described. Overall, the result is a bounded statistical statement about group averages and reported events in this study record; it is not medical advice or a recommendation about treatment.

17. Why This Trial Matters Statistically

This trial is statistically interesting because its primary question concerns treatment sequence during an extension period rather than simply comparing initial treatment assignments. The two primary groups had both received MCI-186 during the first six cycles, after which one continued MCI-186 and the other received placebo of MCI-186. That structure makes the interpretation dependent on treatment history and the defined later assessment period.

The endpoint is a continuous functional score, and the registry reports group means and standard deviations. This makes it possible to examine both the direction of average change and the uncertainty around a mean difference. The primary recalculated estimate is modest relative to the reported uncertainty, and its interval spans zero. This illustrates why a point estimate alone should not carry the interpretation: a numerical difference can coexist with substantial uncertainty about its size and direction.

The record also illustrates the distinction between enrollment and endpoint analysis populations. The listed endpoint group sizes differ from the enrollment figure, while the population description notes exclusions and missing data but is incomplete. That makes transparent participant flow and missing-data methods important for evaluating the result. The registry record does not provide enough detail to reconstruct those processes fully.

Finally, the registry lists multiple secondary outcomes but does not report a multiplicity strategy or analyses for those endpoints. This highlights a general issue in interpreting a broad set of outcomes: secondary findings can add context, but unadjusted results should not be treated as independent confirmation without a clear analysis plan. The study’s statistical contribution is therefore best understood through its treatment-sequence contrast, its interval-based uncertainty, and the limits of the analysis information available in the registry record.

18. 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 an extension period following earlier treatment, so its interpretation is specific to the treatment sequences and follow-up described. It does not directly answer what would happen if MCI-186 were initiated in a different population or over a different period. The posted results do not provide a complete account of the preceding study or participant flow through the extension.

The registry identifies the FAS but gives an incomplete description of exclusions. Missing values are noted, yet the method used to address them is not reported in the registry record. This limits assessment of whether the analyzed participants represent those enrolled and whether missingness could have influenced the estimates. The endpoint group sizes are reported, but the complete reasons for differences among counts are not.

The statistical analyses discussed are unadjusted recalculations from posted summary statistics. The registry does not list formal analyses or specify the sponsor’s analysis model, prespecified covariates, or handling of repeated measurements. The original sample-size justification is also not reported. Planning illustrations based on observed effects should not be mistaken for the trial’s design rationale.

Multiplicity handling is not reported despite the presence of several secondary outcomes. The registry also does not report a clinical-importance threshold for ALSFRS-R, an equivalence margin, or a noninferiority margin. Consequently, the posted results cannot establish clinical equivalence or classify the observed difference against a prespecified threshold. Safety summaries are descriptive and do not provide event timing, exposure-adjusted comparisons, or causal attribution in the information described.

These limitations describe what can be assessed from the registry record; they do not establish that omitted methods or analyses were not performed elsewhere. They constrain how confidently the posted summary statistics can be interpreted as a complete account of the trial’s results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS) — NCT00424463.
• Registry record last updated 2026-07-21; status last verified 2026-06.
• Results first posted 2018-06-04.
• 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.

22. Record Summary

The registry record describes a completed phase 3, randomized, quadruple-masked, parallel-group study of MCI-186 and placebo of MCI-186 in ALS. It was designed as a long-term extension of NCT00330681 and focused on treatment during Cycles 7 to 12 after six earlier cycles. The primary endpoint was change in ALSFRS-R score in the FAS at 24 weeks.

In the primary comparison, the recalculated unadjusted mean difference for continued MCI-186 versus MCI-186 followed by placebo was 1.3, with a confidence interval from -0.560 to 3.161 and an unadjusted p-value of 0.171. The interval includes zero, leaving substantial uncertainty about the difference. The registry also posts a separate sequence comparison and secondary respiratory and safety information.

The record does not report formal endpoint analyses, the original sample-size rationale, a multiplicity plan, or a complete missing-data analysis. The posted statistics therefore support a cautious reading of the specified group averages and safety counts, not a complete reconstruction of the trial’s analysis.