A Phase 2 Study to Evaluate AL001 in C9orf72-Associated ALS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 2 Study to Evaluate AL001 in C9orf72-Associated ALS (NCT05053035), a randomized phase 2 study. The primary outcome is Evaluation of Safety and Tolerability of AL001 Measured by Number of Subjects With Adverse Events.

2. Clinical Question

The clinical question is primarily about safety and tolerability. It is not a direct comparison of whether AL001 changes ALS symptoms or function. The registry record also lists change from baseline in plasma neurofilament light chain and change from baseline in CSF neurofilament light chain as secondary outcomes. These are distinct from the primary adverse-event endpoint. The record does not provide posted analyses for those secondary outcomes, so they cannot be used to draw conclusions about treatment effects.

3. Trial Design

This was a phase 2, multicenter, randomized, double-blind, placebo-controlled study of AL001 in C9orf72-associated ALS. The design was parallel group, with AL001 and placebo as the two interventions. Both were administered every 4 weeks. Masking is recorded as quadruple. The registry record does not describe which roles were masked or provide further details about the randomization procedure.

The record lists enrollment of 5 participants. The posted primary outcome uses the safety population, with 3 participants in the AL001 group and 2 in the placebo group. The study status is terminated. Its recorded start date is 2021-09-02, and its primary completion date is 2022-10-28. The reason for termination is not reported in the registry record; the status alone does not establish why the study ended.

The primary outcome was the number of participants with adverse events during the 24-week study treatment period. The record lists two secondary outcomes: change from baseline in plasma neurofilament light chain and change from baseline in CSF neurofilament light chain. It also records 8 outcome measures, but only 2 secondary outcomes are listed in the posted results summarized by the record. The registry record reports 0 analyses. It does not report a sample-size justification, a detailed statistical analysis plan, or further design assumptions. The randomized and masked design describes how the trial was organized, but the very small enrollment limits how much can be learned from the posted group counts.

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 population

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 Evaluation of Safety and Tolerability of AL001 Measured by Number of Subjects With Adverse Events, measured over 24 weeks.

The primary endpoint counts participants who had one or more adverse events during the 24-week study treatment period. It is reported for the safety population, separately for AL001 and placebo. This kind of endpoint is a binary participant-level outcome: each person is counted according to whether an adverse event occurred, rather than counting the total number of separate events experienced by that person.

Counting participants with adverse events is a way to describe the occurrence of harm during treatment and to compare the observed safety experience between groups. It is not, by itself, a complete description of event severity, duration, recurrence, or relationship to treatment. The registry record separately reports serious adverse events and deaths, which provide additional safety context.

The posted primary result is 2 participants with adverse events among 3 in the AL001 group, and 2 among 2 in the placebo group. These are counts from a small study, not precise estimates of how often adverse events would occur in a broader population. The registry record does not post an inferential comparison for this endpoint. The endpoint therefore supports a descriptive account of the events recorded during the study period, not a definitive comparative conclusion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary endpoint counts participants with at least one adverse event during the treatment period. This differs from a count of all adverse-event episodes. If one participant experienced multiple events, a participant-level endpoint would still count that person once. The reported endpoint is therefore a binary outcome at the participant level, summarized as counts within each group. The registry record does not provide further detail about event definitions or how repeated events were handled for this endpoint.

For binary outcomes, a group count should be read alongside its denominator. The posted results give 2 participants with adverse events among 3 in the AL001 group and 2 among 2 in the placebo group. Those denominators matter: the same event count can represent a different share of a group when group sizes differ. No additional percentage, relative measure, or comparative estimate is posted, and none should be treated as an inferential result from these counts.

Why is a comparative estimate important?

A trial comparison aims to quantify how the observed outcome differs between treatment groups while accounting for uncertainty. A confidence interval is a general statistical tool for showing a range of values compatible with the data and analysis assumptions. Its width conveys precision: wider intervals indicate greater uncertainty. A p-value is another general tool that evaluates how compatible data are with a specified null hypothesis under a statistical model. Neither a confidence interval nor a p-value is posted for this primary outcome in the registry record.

When outcomes are binary and group sizes are very small, estimates can be unstable and uncertainty can be substantial. Methods that work well with larger samples may behave poorly with sparse counts. In general, small-sample methods or exact methods may be considered for sparse binary data, but the registry record does not report which inferential method, if any, was planned or used. No method should be attributed to the trial without that information. The registry record reports 0 analyses, and values are not estimable for a two-arm comparison of this binary endpoint in the posted results.

What do the design features contribute?

Randomization is used in general to assign participants to groups in a way intended to reduce systematic differences at allocation. Masking is intended to limit the influence of treatment knowledge on participant experience, care, or outcome assessment. The record identifies the study as randomized, double-blind, and quadruple-masked. These labels describe the design; they do not establish that all potential sources of bias were eliminated. Details of the randomization sequence, allocation concealment, and the roles covered by masking are not reported in the registry record.

A parallel-group design assigns participants to one intervention group for the comparison rather than describing a crossover. The groups were AL001 and placebo, each administered every 4 weeks. The registry record does not provide further operational details about treatment adherence or the handling of treatment interruptions.

How should planning illustrations be understood?

General sample-size calculations ask how many participants may be needed to detect a specified effect under stated assumptions. The planning assumptions described for the illustrations use a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. Such calculations are hypothetical planning illustrations, not evidence that the trial had that design target. They are not observed power, and they do not supply evidence that a treatment effect exists.

The registry record does not report the trial's own sample-size justification. Because the posted two-arm binary comparison is not estimable, any planning illustration based on an observed effect must be interpreted cautiously and cannot substitute for a valid comparative analysis. No numerical planning result is described in this explanation.

Why can over-dispersion matter?

Over-dispersion is a general concern when observed variability is greater than a statistical model assumes. It is especially relevant to some count outcomes, where event counts may vary more across participants than a simple model allows. The primary endpoint is a participant count with an adverse event, rather than a total count of event episodes. The registry record does not report a model for over-dispersion or a model-based analysis. This concept therefore provides general context, not a claim about an analysis performed in this study.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("AL001", "Placebo")
n      <- c(3, 2)
events <- c(2, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  AL001  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2
ARM  Placebo  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 8 outcome measures and identifies two secondary outcomes: change from baseline in plasma neurofilament light chain and change from baseline in CSF neurofilament light chain. It reports 0 analyses. The presence of multiple outcomes raises a general multiplicity question: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses that issue. The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified testing strategy, so it is not possible to describe how multiplicity was handled.

The primary endpoint is identified as applying to the safety population. The record does not provide further definitions of analysis populations, such as an intention-to-treat population, or explain how participants were included in each outcome analysis. It also does not report how missing observations were handled, whether any outcome data were missing, or whether any imputation or sensitivity analysis was used. Those details are important because missingness and analysis-population choices can affect the interpretation of a trial result.

The study status is terminated, but the reason for termination is not reported in the registry record. The record also does not describe interim analyses, stopping rules, or changes to outcome definitions. Without these details, readers cannot assess whether the posted outcomes and analyses correspond to the original analysis plan. Because no analyses are posted, there are no reported adjusted or unadjusted secondary-outcome results to interpret.

12. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious-adverse-event figures count participants with at least one serious adverse event. The posted results record 0 of 3 participants in the AL001 group and 0 of 2 in the placebo group with serious adverse events. Deaths are recorded as 0 in both groups. The record lists no top serious-event terms.

These are observed counts among the participants in the safety results, not proof that the risk of a serious event is absent. The groups are small, and the primary outcome timeframe is 24 weeks. Rare events may not appear in a study of this size, and the registry record does not provide a longer-term safety estimate. The absence of recorded serious events should therefore be read as a description of what was reported for these participants, not as a guarantee about other participants or future use.

The primary adverse-event result is distinct from the serious-event count: 2 of 3 participants in the AL001 group and 2 of 2 in the placebo group had adverse events. An adverse event need not meet the definition of a serious adverse event. The registry record does not provide event-level detail for the listed overall adverse-event counts.

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

The result means that the registry record reports adverse events in 2 of 3 participants in the AL001 group and 2 of 2 participants in the placebo group during the 24-week study treatment period. It also reports no participants with serious adverse events and no deaths in either group. These are descriptive observations from a five-participant study, not precise estimates of event frequency in a larger population.

The results do not establish that AL001 increases, decreases, or has the same adverse-event risk as placebo. The registry record posts no statistical comparison, confidence interval, or p-value for the primary endpoint. With such small groups, the counts alone cannot distinguish a meaningful group difference from the substantial uncertainty expected when only a few participants contribute information.

The primary endpoint measures safety and tolerability through adverse-event occurrence; it does not measure improvement or worsening in ALS. Although change from baseline in plasma and CSF neurofilament light chain are listed as secondary outcomes, the registry record reports 0 analyses. No conclusion about those outcomes, disease progression, or treatment efficacy can be drawn from the posted analyses.

The terminated status is a record of study status, not an explanation for the result. The reason for termination is not reported in the registry record. The record also does not report the study's sample-size justification or detailed methods for missing data and outcome analysis. Those gaps further limit interpretation. The data are best read as a small descriptive safety record, rather than evidence for a broad comparative conclusion.

14. Why This Trial Matters Statistically

This trial illustrates a basic statistical distinction between recording outcomes and estimating a treatment difference. The posted safety counts show what happened among a very small number of participants, but they do not provide a precise comparison between AL001 and placebo. For binary outcomes, denominators are essential, and sparse data leave little information for estimating uncertainty or testing hypotheses.

It also illustrates why trial design features and statistical evidence answer different questions. Randomization and masking are important design features, but they cannot create precision when enrollment is limited. A randomized study with 5 participants can describe observations in those participants; its design labels alone do not make the observed counts broadly generalizable or establish a treatment effect.

The endpoint choice matters as well. Counting participants with adverse events addresses a safety question, while the listed neurofilament outcomes concern changes from baseline in plasma and CSF. Because the registry record reports 0 analyses, those outcome names do not constitute evidence of a measured treatment effect. Separating outcomes that are listed from outcomes that have analyzed results helps prevent an outcome description from being mistaken for a finding.

Finally, the terminated status and missing details about analysis planning highlight the value of transparent reporting. A reason for termination, a sample-size rationale, handling of missing data, and a prespecified approach to multiple outcomes would help readers assess the evidence. Those items are not reported in the registry record. Their absence does not explain the findings, but it constrains how much can be concluded from them.

15. 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 most immediate limitation is the very small enrollment: 5 participants, with 3 in the AL001 group and 2 in the placebo group. Counts from groups this small are highly sensitive to individual outcomes, and the record does not provide a comparative estimate or measure of precision. The primary endpoint is limited to participants with adverse events during the 24-week treatment period; the registry record does not give event-level descriptions for the overall counts.

The study is listed as terminated, but the reason for termination is not reported in the registry record. The record does not report the trial's sample-size justification, the statistical analysis plan, interim analyses, or stopping rules. It also does not describe missing-data handling, adherence, or detailed definitions for the analysis populations beyond identifying the primary outcome as using the safety population.

Two secondary outcomes are listed, but 0 analyses are reported. As a result, there are no posted secondary-outcome results to assess, and the record does not describe how multiplicity was addressed. The absence of an inferential result for the primary endpoint also means that its observed counts should not be interpreted as a precise treatment comparison. These limitations restrict conclusions to a description of the small set of recorded safety outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase 2 Study to Evaluate AL001 in C9orf72-Associated ALS — NCT05053035.
• Registry record last updated 2025-06-18; status last verified 2025-05.
• Results first posted 2025-06-18.
• 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.

19. Record Summary

The registry record describes a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of AL001 in C9orf72-associated ALS. It lists enrollment of 5 participants, a terminated status, a start date of 2021-09-02, and a primary completion date of 2022-10-28. AL001 and placebo were each administered every 4 weeks.

The primary endpoint was the number of participants with adverse events during 24 weeks. The posted results report 2 of 3 participants in the AL001 group and 2 of 2 in the placebo group. No serious adverse events or deaths were recorded in either group. The record lists plasma and CSF neurofilament light chain as secondary outcomes and reports 0 analyses. The reason for termination, sample-size justification, and detailed statistical methods are not reported in the registry record.