Phase 3 Extension Study of Dexpramipexole in ALS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 3 Extension Study of Dexpramipexole in ALS (NCT01622088), a na phase 3 study. The primary outcome is Number of Subjects Who Reported an Adverse Event.

2. Clinical Question

The study also listed secondary outcomes concerning the slope of ALSFRS-R, the slope of Sniff Nasal Inspiratory Pressure (SNIP), death up to 6 months, and the percentage of participants with death or death equivalent up to 6 months. These are outcome topics in the registry, not evidence that their results were reported. The record lists 11 outcome measures overall, but no analyses. It does not report a concurrent control group or comparative estimate. The central interpretive question is therefore descriptive: what safety information is recorded for people exposed to dexpramipexole in this open-label extension, and what conclusions are limited by the absence of reported outcome analyses and a comparator?

3. Trial Design

This was a Phase 3, open-label, multicenter extension study of dexpramipexole in ALS. The official title describes its aim as evaluating long-term safety and efficacy in subjects with ALS, while the brief summary emphasizes collection of long-term safety data from exposed subjects. The registry lists a single-group model, allocation as NA, and masking as none. The intervention was dexpramipexole, described as 300 mg/Day.

The study record lists an enrollment of 616. It gives a start date of 2012-06 and a primary completion date of 2013-02, and its status is terminated. The primary adverse-event endpoint was defined from baseline through the end of the study, with a maximum timeframe of 226 days (approximately 32.2 weeks). That endpoint timeframe should be distinguished from the broader description of the study as an extension intended to collect long-term safety information.

Because the design is single-group and open-label, the posted safety counts describe events among participants exposed to the study treatment; they do not estimate a contrast against a concurrent control. The registry record does not report a randomized allocation, a masked assessment, or a control arm. It also does not report why the study was terminated or whether termination changed the planned follow-up or outcome collection.

The listed secondary outcomes cover functional measures, respiratory function, death, and death-equivalent events. Their presence in the record indicates that they were specified as outcomes, but it does not establish that results for them were analyzed or posted. The registry lists no analyses. Protocol details beyond the recorded design features, including how participants entered the extension and any rules governing treatment or follow-up, are not reported in the registry record.

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: The safety population is defined as all subjects who received at least 1 dose of study treatment

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: This open-label extension study consisted of a Baseline Visit, a treatment period of up to 36 months, and a Safety Follow-Up Visit. Subjects who completed either Study CL211 or Study 223AS302 were eligible to participate in this study. If possible, the last visit of the lead-in study was used the Baseline. Otherwise, subjects were required to enroll within 14 days of their last visit in the lead-in study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects Who Reported an Adverse Event, measured over Baseline through end of study (maximum 226 days: approximately 32.2 weeks).

The primary endpoint is the number of subjects who reported an adverse event. It is a participant count: it concerns whether a participant was recorded as having an event during the specified period, not how many separate event episodes occurred. The stated period runs from baseline through the end of the study, with a maximum of 226 days (approximately 32.2 weeks). The safety population is defined as all subjects who received at least 1 dose of study treatment.

Participant counts are useful in safety reporting because they describe how many people experienced an event, rather than allowing someone with repeated events to dominate an event tally. The endpoint can help characterize the safety experience recorded during exposure. In general, such counts are descriptive: without a comparator and a specified analysis, they do not establish whether events occurred more or less often than they would have under another condition.

The registry record does not report a separate analyzed result for this primary endpoint. Its safety summary reports 152 participants with serious adverse events and 215 with other adverse events, each against 616 at risk. These categories should not be combined into a new total: the record does not state whether participants could appear in both categories, and the posted counts are not presented as a single, deduplicated primary-endpoint count. Nor does the record provide an adjusted estimate or uncertainty interval for the endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary endpoint is defined as the number of subjects who reported an adverse event. A participant count answers how many people were recorded with an event during the endpoint period. It differs from a count of event episodes: if a participant experiences repeated events, a participant-based measure ordinarily counts that person once for the relevant endpoint, whereas an episode count could count each occurrence. The registry describes the endpoint as a participant count, but does not provide a separate analyzed result for it.

The safety population is defined as all subjects who received at least 1 dose of study treatment. This definition matters because enrollment and safety populations are not automatically interchangeable. The safety summary lists 616 at risk, and the registry lists enrollment of 616, but the record does not provide participant-level accounting or explain any exclusions between the defined population and the reported safety figures.

Why does the design matter?

This study is listed as single-group, open-label, with allocation NA and masking none. In general, a single-group safety description can show which events were recorded among exposed participants. It cannot, by itself, distinguish the contribution of treatment from the condition under study, other health circumstances, or events that might also occur without the treatment. A concurrent comparator can support a relative comparison when the design and analysis justify it; no such comparator is described in this record.

Open-label status means the registry does not describe masking of treatment assignment. In general, knowledge of treatment can affect reporting, assessment, or decisions about whether an event is recorded. The record does not state whether particular outcome assessments were independently adjudicated or whether any safeguards were used to reduce assessment bias. Those details are not reported in the registry record.

What can term-level safety percentages tell the reader?

The registry lists percentages for selected serious adverse event terms. Each term is a category of reported events, and a participant may potentially be represented under more than one term. In general, term-specific percentages should not be summed as though each term belonged to a separate, non-overlapping group. The record does not report overlap among terms, the event-level coding rules, or a broader term summary that would support such a calculation. The serious-event participant count and individual term percentages answer different descriptive questions and should not be treated as interchangeable.

The figures also need to be interpreted in light of observation time. The primary endpoint timeframe runs from baseline through end of study and has a maximum of 226 days (approximately 32.2 weeks). The record does not report participant-level time at risk or a time-to-event analysis for the serious-event summary. In general, counts observed over differing follow-up durations are not directly equivalent to rates that account for time under observation.

What is missing from the statistical reporting?

The registry lists 11 outcome measures and zero analyses. It does not report inferential tests, confidence intervals, adjusted estimates, or a statistical analysis plan. The primary endpoint is named and defined, but a separate result for the number of participants with any adverse event is not reported. The safety summary gives serious and other adverse-event counts, but does not report whether those categories overlap or how the primary endpoint result relates to them.

In general, a confidence interval communicates the uncertainty of an estimate under the selected statistical model and assumptions. A p-value, when reported, describes how compatible the observed data are with a specified null hypothesis under a model; it does not by itself establish causation or clinical importance. Neither a comparative estimate nor its uncertainty is reported for this single-group endpoint. Without an analysis and a defined comparison, an inferential claim about relative risk or treatment effect cannot be drawn from the counts.

The record includes a general sample-size planning description based on the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; time-to-event illustrations are described as total event counts using Schoenfeld, while other illustrations are participants per arm. These are planning conventions, not results from this single-group study. No numerical planning illustration is reported in the record, and no sample-size justification for the trial itself is reported. In general, planning calculations depend on the assumed effect and design; they are not observed power and cannot substitute for an analysis of the collected outcomes.

Over-dispersion is a general concern for count outcomes when the variability exceeds what a simple model assumes. It can affect standard errors and the reliability of inferential results if the model does not account for it. Here, the primary endpoint is a participant count and the record does not report a model-based analysis or dispersion estimate. It would therefore be inappropriate to claim that over-dispersion was tested, present a model result, or infer that it affected a reported conclusion. The statistical methods used for the posted safety counts are not reported in the registry record.

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("Dexpramipexole 150 mg BID")
n      <- c(616)
events <- c(454)
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  Dexpramipexole 150 mg BID  616  454  73.7  70.0  77.1  70.1  77.0  70.1  77.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including the primary adverse-event count and secondary outcomes concerning ALSFRS-R slope, SNIP slope, death, and death or death equivalent. It reports zero analyses. No multiplicity strategy is reported in the registry record. In general, when several outcomes are examined, the chance of at least one apparently notable result can increase if each is tested separately without accounting for the number or structure of the tests. A prespecified hierarchy or adjustment can address this issue, but the record does not say whether one was planned or used. Because no outcome analyses are posted, there is no basis for assessing how multiplicity affected reported inferences.

Missing-data handling is also not reported. The registry does not describe how missing outcome assessments, incomplete follow-up, or withdrawal were handled, nor whether imputation or a sensitivity analysis was used. This matters in general because an analysis based only on observed assessments can be affected if missingness is related to health status or outcomes. The record gives the primary endpoint timeframe and defines the safety population, but does not provide information sufficient to evaluate completeness of follow-up or missingness for the listed outcomes.

The safety population is defined as all subjects who received at least 1 dose of study treatment. Other analysis populations, their definitions, and their use are not reported in the registry record. The record does not state whether the listed safety counts include every participant meeting that definition, or describe exclusions or deviations. It also does not report a statistical analysis plan, interim analyses, or reasons for the terminated status. These omissions limit assessment of whether outcome selection, missing-data decisions, and analysis populations were set before results were known.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: respiratory failure (8.1%), dysphagia (2.6%), amyotrophic lateral sclerosis (2.6%), pneumonia (2.4%), pneumonia aspiration (0.8%).

The serious adverse event summary reports 152 participants with serious events among 616 at risk. It separately reports 215 participants with other adverse events among 616 at risk, along with 73 deaths. The registry does not report whether the serious and other adverse-event categories overlap, so these counts should not be added to create a combined number of participants with any event.

The listed serious-event terms are respiratory failure (8.1%), dysphagia (2.6%), amyotrophic lateral sclerosis (2.6%), pneumonia (2.4%), pneumonia aspiration (0.8%), and dyspnoea (0.6%). Each percentage is a term-specific figure as recorded. The record does not explain whether participants could contribute to more than one term, so the values should not be summed or interpreted as mutually exclusive portions of a whole.

These are descriptive safety figures from an open-label, single-group study. They do not compare event frequency with a control group, and they do not establish that treatment caused or prevented any listed event. The registry does not report uncertainty intervals or a detailed analysis method for these figures. Interpret them alongside the stated observation period and the limits of the recorded follow-up, rather than as comparative estimates.

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

The registry record gives a description of a dexpramipexole exposure study in ALS: a Phase 3, open-label, single-group extension with a safety-focused primary endpoint. The posted safety summary lists counts for serious and other adverse events, a death count, and percentages for selected serious-event terms. These data can inform a descriptive account of the events recorded during the study.

They do not establish whether dexpramipexole caused an event, reduced its likelihood, or changed the course of ALS. Without a concurrent comparator, the observed counts cannot be interpreted as a treatment-versus-control difference. The record also does not report a separate analyzed result for the primary endpoint, statistical uncertainty for a comparative effect, or analyses of the listed functional and death outcomes.

The absence of a reported analysis is not evidence that no events occurred; the safety summary does report events. Nor does the presence of outcome names establish that each outcome was analyzed or that a particular finding was obtained. The record lists 11 outcome measures and zero analyses, so conclusions should remain limited to the descriptive details actually recorded.

The reported timeframe for the primary endpoint extends from baseline to the end of the study, with a maximum of 226 days (approximately 32.2 weeks). That period should not be mistaken for uniform observation of every participant. The registry does not report individual follow-up duration, missing-data handling, or detailed accounting of the safety population.

In general, conclusions about treatment effects require a design and analysis that support a comparison and quantify uncertainty. The recorded counts alone do not provide that basis. They describe the study's safety experience, while questions about causation, relative risk, efficacy, and the completeness of outcome follow-up remain unresolved in the registry record.

14. Why This Trial Matters Statistically

This study matters statistically because it illustrates the difference between a safety description and a comparative treatment-effect analysis. A single-group, open-label extension can record adverse events among people exposed to treatment. Its counts may be useful for describing what was observed, but they do not isolate the contribution of treatment from other possible causes. The design features listed in the registry—single group, no masking, and allocation NA—define important limits on what can be inferred.

The endpoint is a participant count, not a count of event episodes or a comparative rate. The registry's safety summary separates serious from other adverse events, but does not report overlap between categories or a deduplicated count for the primary endpoint. This makes it important to keep the recorded measures distinct rather than combining them into a new figure.

The record also lists multiple outcome measures while reporting zero analyses. This highlights why outcome specification and outcome results are not the same thing. Without reported estimates, uncertainty measures, missing-data methods, or a multiplicity strategy, readers cannot evaluate the statistical evidence for the listed outcomes. The absence of these details should not be replaced by assumptions about what the protocol or analysis plan may have contained.

Finally, a planning illustration based on an observed effect is conceptually different from an analysis of trial outcomes. Planning assumptions can describe hypothetical design requirements, but they do not establish observed power or answer whether a treatment effect was present. The record's sparse analysis reporting makes this distinction especially relevant: the available safety counts support descriptive reading, not a claim of efficacy or a causal safety comparison.

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 principal limitation is the single-group, open-label design. There is no concurrent comparator in the registry record, so the posted counts cannot show how event occurrence differed from another treatment or a control condition. The record does not describe masked assessment or an adjusted comparative analysis.

The registry does not report an analyzed result for the named primary endpoint, despite listing safety counts by serious and other event categories. It does not explain whether those categories overlap, how the listed term percentages were calculated, or whether event terms were independently reviewed. The record also does not provide confidence intervals or other measures of uncertainty for the safety summary.

Although the record defines the safety population as subjects who received at least 1 dose, it does not provide detailed accounting of eligibility for the reported counts, exposure duration, or participant-level follow-up. The endpoint timeframe has a maximum of 226 days (approximately 32.2 weeks), but the observation period for each participant is not reported. Missing-data procedures, withdrawal handling, and sensitivity analyses are not reported.

The record lists 11 outcome measures but zero analyses. It does not report statistical methods for the outcomes, a multiplicity approach, a statistical analysis plan, or a sample-size justification for the trial. It also does not report why the study was terminated. These gaps prevent assessment of whether all planned outcomes were collected and analyzed, and whether the posted safety summary reflects a prespecified analysis. The limitations do not invalidate the descriptive counts, but they restrict the conclusions that can be drawn from them.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 3 Extension Study of Dexpramipexole in ALS — NCT01622088.
• Registry record last updated 2022-05-03; status last verified 2022-04.
• Results first posted 2022-04-07.
• 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 describes a Phase 3, open-label, multicenter, single-group extension study of dexpramipexole in ALS. The intervention is listed as 300 mg/Day, with enrollment of 616. The record gives a start date of 2012-06, a primary completion date of 2013-02, and a status of terminated.

The primary endpoint is the number of participants reporting an adverse event from baseline through the end of study, with a maximum timeframe of 226 days (approximately 32.2 weeks). The safety population is defined as subjects who received at least 1 dose. The safety summary reports 152 participants with serious adverse events, 215 with other adverse events, and 73 deaths, with 616 at risk. Selected serious-event terms and their percentages are listed in the registry.

The record lists 11 outcome measures and zero analyses. It does not report a comparator, an analyzed primary-endpoint result, inferential methods, missing-data handling, or a multiplicity strategy. The posted information therefore supports a descriptive account of recorded safety events, not a comparative or causal treatment conclusion.