Ibudilast (MN-166) in Subjects With Amyotrophic Lateral Sclerosis (ALS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ibudilast (MN-166) in Subjects With Amyotrophic Lateral Sclerosis (ALS) (NCT02238626), a randomized phase 2 study. The primary outcome is Safety and Tolerability of MN-166 60 mg/d Versus Placebo When Administered With Riluzole in Subjects With ALS.

2. Clinical Question

The clinical question is therefore about comparative safety and tolerability during the 6-month double-blind treatment period, not whether ibudilast improves ALS. The registry record also describes secondary measures concerning function, respiratory function, muscle strength, ventilation, quality of life, and clinical global impression. These measures provide additional clinical context, but their presence does not change the primary outcome’s safety focus.

3. Trial Design

The registry record describes a Phase 2, randomized, parallel-group, triple-masked, placebo-controlled trial conducted at a single center. The double-blind phase lasted 6 months and was followed by an open-label extension for placebo participants. The record gives the study start as 2014-09, primary completion as 2017-08, and status as completed. The enrollment field reports 70, while the brief summary describes a study in 60 subjects; the registry record does not explain this difference.

Two treatment arms were planned: MN-166 with riluzole, and matching placebo with riluzole. The brief summary states that randomization was planned in a 2:1 ratio for MN-166 to placebo. The posted outcome groups are separated into early and advanced ALS cohorts. The record does not report how cohort assignment was made, whether cohort status was part of randomization, or how the posted subgroup comparisons were prespecified.

For the double-blind phase, the arm descriptions specify up to 60 mg/day of MN-166 or matching placebo, with 50 mg riluzole twice daily, for 6 months. The summary describes screening for up to 3 months, a 6-month open-label phase for placebo participants, and follow-up approximately 2 weeks after the final dose. Clinic visits were scheduled at Months 3 and 6, with telephone contacts at Months 1, 2, 4, and 5 to collect information about side effects and new or concomitant medications.

Safety monitoring included treatment-emergent adverse events, serious adverse events, discontinuations due to adverse events, laboratory values, vital signs, ECGs, medical history, and physical and neurological examinations. The registry record does not report the detailed randomization method, allocation concealment procedures, or the statistical analysis plan.

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: Safety analysis population included all randomized subjects who received at least one dose of study drug and had at least one post-dose safety assessment.

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: Early ALS Cohort: Patient ALS symptom onset 5 years or less before screening. Advanced ALS Cohort: Patient ALS symptom onset between 5 and 10 years before screening.

6. Primary Endpoint

The registry lists the primary outcome as Safety and Tolerability of MN-166 60 mg/d Versus Placebo When Administered With Riluzole in Subjects With ALS, measured over 6 months.

The primary outcome is titled as a comparison of the safety and tolerability of MN-166 60 mg/day versus placebo, each administered with riluzole, over 6 months. The description says safety was assessed by monitoring treatment-emergent adverse events, including serious adverse events and discontinuations due to adverse events. It also lists hematology, blood chemistry, urine values, vital signs, ECGs, medical history, and physical and neurological examinations.

Monitoring these outcomes is used to characterize potential harms and tolerability during treatment. Adverse-event reporting can describe the kinds of events observed, while laboratory and clinical assessments can identify other safety changes. The primary outcome’s posted unit is participants and its parameter is a count of participants. The values therefore give participant counts for the outcome groups, rather than a detailed breakdown of each safety event or a single clearly specified adverse-event rate.

The posted primary comparisons show a risk difference of 0.0 with a confidence interval from 0.0 to 0.0 for each listed comparison. The associated posted proportions are 1.0 in both comparison arms. Because the primary outcome is described broadly but the numeric result is a participant count, the record does not make clear which safety event or assessment those proportions represent. The primary result should be read with that reporting limitation in mind, rather than as a complete account of comparative safety.

7. Results Posted in the Registry

• MN-166: 100.0% (34/34) versus 100.0% (17/17) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.
• MN-166 (Advanced ALS Cohort): 100.0% (11/11) versus 100.0% (17/17) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.

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.

Mean Change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Total Score From Baseline to Month 6

• 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:
  • MN-166 (Early ALS Cohort): mean -4.50 versus -3.80 on control; difference -0.70 (95% CI -3.23 to 1.83), standardized effect d = -0.15; z-test p = 0.587.
  • MN-166 (Advanced ALS Cohort): mean -4.80 versus -3.80 on control; difference -1.00 (95% CI -4.45 to 2.45), standardized effect d = -0.23; z-test p = 0.570.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MN-166 (Early ALS Cohort) 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 MN-166 (Advanced ALS Cohort) and the control. The interval gives the range of effects that remain compatible with the data.

Respiratory Function

• 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:
  • MN-166 (Early ALS Cohort): mean -10.10 versus -6.10 on control; difference -4.00 (95% CI -9.97 to 1.97), standardized effect d = -0.41; z-test p = 0.189.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MN-166 (Early ALS Cohort) and the control. The interval gives the range of effects that remain compatible with the data.

Muscle Strength

• 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:
  • MN-166 (Early ALS Cohort): mean -4.90 versus -3.90 on control; difference -1.00 (95% CI -4.40 to 2.40), standardized effect d = -0.18; z-test p = 0.564.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MN-166 (Early ALS Cohort) and the control. The interval gives the range of effects that remain compatible with the data.

The registry record lists secondary outcomes spanning functional rating, respiratory function, muscle strength, non-invasive ventilation, quality of life, and clinical global impression. The posted numeric details include several continuous outcomes, with recalculated mean differences and confidence intervals for selected comparisons. Across those comparisons, the estimates are uncertain, and the intervals extend across values representing different possible directions or magnitudes of difference.

This broad pattern does not resolve the limitations in the primary safety result. Functional and clinical measures address different questions from adverse events and tolerability. They can add context about the course of ALS during follow-up, but they cannot define or replace the primary safety outcome. Nor can the available secondary results establish a treatment effect when the registry record provides no sponsor-reported analyses for them.

Secondary findings generally carry less inferential weight when many outcomes are examined without a reported plan for controlling multiplicity. With multiple outcomes and comparisons, some apparently notable results can arise by chance. The registry record does not report whether multiplicity adjustments were planned or applied, nor does it identify a hierarchy among the secondary outcomes. The recalculated comparisons are unadjusted, so their p-values and intervals should be treated as exploratory rather than as confirmatory evidence.

The registry also does not report how missing observations were handled for each secondary measure. Outcome-specific group sizes vary, which is relevant to precision and may reflect different availability of measurements; the record does not explain the reasons. The secondary outcomes are therefore best read as descriptive signals with substantial uncertainty, not as a coherent demonstration of benefit or lack of benefit.

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

• Mean Change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Total Score From Baseline to Month 6
• Respiratory Function
• Muscle Strength
• Use of Non-invasive Ventilation
• The Mean Change in Baseline to Month 6 in Quality of Life as Measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire - 5
• Clinical Global Impression of Change (CGIC)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a risk difference describe?

A risk difference compares the proportion of participants with an outcome in one group with the proportion in a comparison group. A value of 0.0 indicates that the posted proportions are equal in that comparison. The registry’s primary outcome values are counts of participants, and its calculated comparisons report proportions of 1.0 in each arm and risk differences of 0.0. Those figures describe the count outcome as it is encoded in the record; the broad safety outcome description does not establish which specific event or assessment is represented by that count.

A risk difference is generally easier to interpret when the event definition and the number of participants with and without the event are clear. Without that detail, a reader cannot determine what the equality of the posted proportions means for a particular harm. It should not be taken to mean that all safety outcomes were identical, or that no adverse events occurred. The separate serious adverse event record documents events in the groups.

How should the continuous comparisons be read?

For continuous outcomes, a mean change summarizes the average change in a measured score or quantity within a group. A mean difference compares those group averages. The posted functional score, respiratory function, and muscle strength results each include a mean change and standard deviation for the reported groups. Standard deviation describes variation among individual observations; it is not the same as uncertainty in the group mean.

The recalculated mean differences are simple, unadjusted comparisons from the posted summary statistics. They are not sponsor-reported analyses: the registry record lists no reported analyses for these secondary outcomes. The recalculated confidence intervals describe uncertainty under the calculation used, but do not account for any unreported adjustment, covariates, or trial-specific analysis choices. The record does not report a statistical plan that would establish which analysis should be considered primary for each secondary outcome.

For the early ALS comparison on mean change in the ALS Functional Rating Scale-Revised total score, the recalculated mean difference is -0.7 and the confidence interval ranges from -3.229 to 1.829. For the advanced ALS comparison, the recalculated mean difference is -1.0 with a confidence interval from -4.451 to 2.451. These intervals include values on either side of no difference. The other recalculated continuous comparisons also have confidence intervals spanning values in both directions. This degree of uncertainty means the point estimates alone should not be treated as conclusive.

What do the planning illustrations mean?

The sample-size illustrations are planning calculations based on the observed effect, not the trial’s original design assumptions. The registry record states that they use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The rows describe planning for 100%, 75%, or 50% of the observed effect, and the entries are participants per arm for 80% or 90% power.

These illustrations are not observed power, and they do not show what the completed study was designed to detect. Planning from a small study’s observed effect can be unstable, because that estimate may be imprecise. The record does not report the trial’s own sample-size justification, so these calculations should be treated only as illustrative planning scenarios.

Why do analysis choices matter?

Randomization can support a fair comparison when outcomes are analyzed as planned and participants are handled consistently. However, subgrouping, incomplete follow-up, outcome definitions, and multiple testing can affect interpretation. The registry record does not report details of the statistical analysis plan, adjustment for multiple comparisons, or methods for handling missing data in the secondary outcomes. The safety population is defined as randomized participants who received at least one dose and had at least one post-dose safety assessment; the record does not provide a corresponding analysis-population definition for each secondary outcome.

11. Confidence Intervals and Precision

A confidence interval gives a range of values compatible with the data under the calculation and assumptions used. It expresses uncertainty around an estimate; it does not guarantee that the true effect lies in the interval, and it does not replace careful consideration of the outcome definition or analysis method.

For the primary comparisons, the posted risk difference is 0.0 and the confidence interval runs from 0.0 to 0.0 in both the early and advanced ALS comparisons. The associated posted proportions are 1.0 in both arms. This apparently exact result reflects the posted participant-count representation and comparison. Because the record does not clarify which specific safety event or assessment the primary count represents, the narrow interval should not be interpreted as proof of precise knowledge about all safety outcomes.

The continuous secondary comparisons have wider intervals. For the ALS Functional Rating Scale-Revised outcome, the early-cohort recalculated mean difference is -0.7, with a confidence interval from -3.229 to 1.829; the advanced-cohort estimate is -1.0, with a confidence interval from -4.451 to 2.451. The respiratory function and muscle strength comparisons also have intervals that extend to both sides of no difference. Their width indicates that the posted estimates do not pin down a single direction or magnitude of difference with precision.

Precision is affected by the amount of information in each comparison, including the group sizes and variability. Some outcome-specific groups are smaller than others, and the standard deviations show that individual results varied. The registry record does not report sponsor analyses for the secondary comparisons, so the recalculated intervals should be understood as unadjusted illustrations from summary data, not as substitutes for a prespecified trial analysis.

12. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan describing how the primary and secondary outcomes were to be tested, whether an outcome hierarchy was prespecified, or whether multiplicity adjustments were planned. It lists several secondary measures, but does not report analyses for them. The recalculated comparisons are unadjusted. When several outcomes or subgroup comparisons are examined, the chance of observing a seemingly notable result by chance can increase; without a reported multiplicity strategy, secondary p-values should not be treated as confirmatory.

Missing-data methods are also not reported in the registry record for the secondary outcomes. The record provides outcome-specific group sizes that differ across measures, but does not explain whether these differences reflect unavailable assessments, withdrawals, measurement eligibility, or another reason. It does not state whether analyses used observed cases only, imputation, or another approach. As a result, readers cannot assess how missing measurements may have influenced the reported means or comparisons.

The safety analysis population is defined as randomized participants who received at least one dose of study drug and had at least one post-dose safety assessment. That definition clarifies who could contribute to the primary safety population, but it is not the same as a full intention-to-treat population. The registry record does not report a detailed accounting of participants excluded from that population or the reasons for exclusion. It also does not give analysis-population definitions for each secondary outcome.

These reporting gaps do not establish that an analysis was improperly conducted; they mean its methods cannot be evaluated from the registry record. The enrollment field reports 70, while the brief summary says the study was designed for 60 subjects. The record does not explain the difference or connect either figure to the outcome-specific analysis populations. Together, the missing analysis details and population information limit reproducibility and confidence in inferential interpretations.

13. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

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: pneumonia (12.5%), amyotrophic lateral sclerosis (12.5%), pneumonia aspiration (9.1%), aspiration (9.1%), ankle fracture (5.9%).

The serious adverse event summaries should be read as descriptive counts within the listed groups. The record reports 1 serious adverse event in the early ALS placebo group and 5 in the early ALS MN-166 group; it reports 2 in the advanced ALS placebo group and 3 in the advanced ALS MN-166 group. The serious-event terms listed include pneumonia, amyotrophic lateral sclerosis, pneumonia aspiration, aspiration, ankle fracture, and dysphagia.

These counts do not by themselves establish that treatment caused an event or explain its severity, timing, duration, recurrence, or relationship to study drug. The record’s term list includes event labels and percentages, but it does not provide enough detail in this summary to interpret each event’s clinical context. The deaths field reports 0 for the early ALS placebo group and 1 for each of the other listed groups; these descriptive entries should not be interpreted as treatment-attributable deaths.

Serious adverse events are not interchangeable with all adverse events. The primary outcome description also mentions treatment-emergent adverse events, discontinuations, laboratory monitoring, and other safety assessments, while the posted primary count does not provide an event-by-event breakdown. The serious adverse event counts therefore add safety information, but they do not supply a complete comparative safety profile.

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

The posted results describe a completed Phase 2 trial of ibudilast with riluzole compared with matching placebo with riluzole. They show the registry’s participant-count outcome and separate serious adverse event counts, along with selected secondary outcome summaries. The primary comparison reports equal posted proportions and a risk difference of 0.0 in each listed comparison. That result describes the encoded count comparison, but the record does not clarify which specific safety event or assessment the count represents.

The results do not establish that ibudilast is safe or unsafe overall. A broad safety assessment requires clear event definitions, event-level details, exposure and follow-up context, and appropriate comparative analyses. The record’s serious adverse event summaries are descriptive and cannot on their own show whether an event was caused by study treatment. Likewise, the secondary functional measures do not answer the primary safety question.

The available continuous comparisons are recalculated from summary statistics and are unadjusted. Their confidence intervals reflect uncertainty, while the registry record does not report the sponsor’s statistical analyses for those outcomes. The record also does not report how missing secondary data were handled or how multiple outcomes were addressed. These omissions make it inappropriate to treat the displayed comparisons as definitive tests.

Nothing in the posted results should be interpreted as medical advice or as a basis for an individual treatment decision. The trial’s outcomes apply to its enrolled study population and follow-up context, and the registry record does not supply the detail needed to generalize a complete benefit-risk conclusion. The most defensible reading is descriptive: the record documents group counts and selected changes, while important details needed for strong causal and statistical conclusions remain unreported.

15. Why This Trial Matters Statistically

This trial is statistically instructive because its primary outcome is described broadly as safety and tolerability, while the posted numeric result is a participant count. That mismatch highlights why an outcome’s label, operational definition, analysis population, and result format all matter. A count that produces identical proportions across groups may appear precise, but without a clear event definition it cannot answer which specific safety question the comparison addresses.

The record also separates early and advanced ALS cohorts in the posted results. Subgroup comparisons can be useful for describing possible variation, but they are generally less precise than a single well-powered comparison and need a clear rationale and prespecified analysis plan. The registry record does not report how these cohorts were defined or whether subgroup analyses were prespecified.

Another statistical lesson concerns secondary outcomes. Functional, respiratory, and strength measures address different dimensions of the disease, but multiple outcomes create multiple opportunities for chance findings. Without a reported multiplicity strategy and sponsor analyses, unadjusted recalculations remain exploratory. Their confidence intervals are important because they display uncertainty that point estimates alone can conceal.

Finally, the sample-size illustrations are based on observed effects rather than the original design, so they should not be mistaken for evidence of the study’s planned sensitivity. The registry record does not report the original sample-size justification. Together, these features show why transparent outcome definitions, prespecified analysis plans, and complete population and missing-data reporting are essential for interpreting a clinical trial record.

16. 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.

Several trial-specific limitations affect interpretation. The brief summary describes a study in 60 subjects, while the enrollment field reports 70; the registry record does not explain the difference. The posted outcomes are split between early and advanced ALS cohorts, but the cohort definitions and their role in the design are not reported. The record also does not explain how the posted primary participant counts map to the broad safety and tolerability description.

The study was conducted at a single center, and the posted groups are limited in size, with smaller group sizes for some outcomes. This constrains precision, particularly for subgroup comparisons and uncommon safety events. The different outcome-specific group sizes are not explained, and missing-data handling is not reported for the secondary measures.

The record does not report the detailed randomization procedures, allocation concealment, sample-size justification, or statistical analysis plan. It lists no sponsor-reported analyses for the secondary outcomes, and does not state whether multiplicity adjustments or subgroup analyses were prespecified. The continuous comparisons are recalculated and unadjusted, so they may not match an analysis using the trial’s intended methods.

Safety follow-up and monitoring are described, but the available summary does not provide event-level timing, duration, severity, or treatment attribution for the serious adverse event terms. The open-label extension is described for placebo participants, but the posted primary outcome timeframe is 6 months. The registry record does not give enough detail to use the extension as a comparative controlled assessment. These limitations call for cautious, descriptive interpretation of the registry results.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Ibudilast (MN-166) in Subjects With Amyotrophic Lateral Sclerosis (ALS) — NCT02238626.
• Registry record last updated 2021-11-05; status last verified 2021-10.
• Results first posted 2021-11-05.
• 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.

20. Record Summary

NCT02238626 is a completed Phase 2, randomized, triple-masked, parallel-group, placebo-controlled study of ibudilast with riluzole in people with ALS. The registry record describes a 6-month double-blind phase followed by an open-label extension for placebo participants. The primary outcome concerns safety and tolerability, but its posted numeric result is a participant count and does not identify a specific adverse event.

Posted serious adverse event counts and selected secondary outcome summaries provide additional descriptive information. The secondary comparisons are recalculated from summary statistics and are unadjusted; the registry record does not report sponsor analyses, multiplicity methods, or secondary-outcome missing-data methods. These reporting gaps, along with the unexplained difference between the enrollment field and the brief summary, limit the strength of conclusions that can be drawn from the record.