Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial (NCT03836716), a na phase 3 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period.

2. Clinical Question

The clinical question concerns longer-term safety and efficacy observations during open-label arimoclomol treatment among people with amyotrophic lateral sclerosis who completed the ORARIALS-01 trial. This extension did not assign participants to a comparison treatment: all participants received arimoclomol, and treatment was not masked. As a result, the record can describe events observed during treatment, but it cannot isolate the effect of treatment from the course of the disease or other influences.

The registry also lists changes in ALS Functional Rating Scale - Revised and percentage predicted slow vital capacity as secondary outcomes. The slow vital capacity outcome applies to subjects who did not meet the survival endpoint in ORARIALS-01. The record gives no results for these secondary outcomes in the registry record presented. Accordingly, the central interpretive task is to describe the safety observations and the amount of treatment exposure without treating an uncontrolled extension as evidence of a causal treatment effect.

3. Trial Design

This was a multicenter, non-randomized, open-label extension trial, registered as phase 3 and titled as an extension for participants who completed ORARIALS-01. The planned enrollment was 120. The registry lists the study status as terminated. Its start date was 2019-09-19, and its primary completion date was 2021-07-02. The reason for termination is not reported in the registry record.

There was a single treatment group: arimoclomol. The listed regimen was 248 mg arimoclomol base, equivalent to 400 mg arimoclomol citrate, 3 times daily. Since participants and investigators were not masked and there was no randomized allocation, event reporting and treatment exposure occurred without a blinded control condition. The record does not describe a separate comparator or a planned statistical comparison with another group.

The primary outcome was the number of participants with treatment-emergent adverse events during the open-label treatment period. That period was described as extending from Day 1 in ORARIALS-02 to early termination, with an average duration of approximately 28 weeks. The registry says adverse-event data were collected until early termination. It also gives an average exposure of 198.7 days, standard deviation 99.57 days, minimum 16 days, and maximum 494 days. No participant was treated for 76 weeks.

The registry lists 19 outcome measures, but the analysis details and results for most are not reported in the registry record. The specific reason for termination, the rationale for enrollment size, and the protocol’s analysis plan are also not reported in the registry record. These omissions make it important to distinguish the registered aims from the subset of results described in the 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: Safety analysis set: All enrolled patients who received at least one dose of arimoclomol.

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 Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period, measured over From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks.

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs) during the open-label treatment period. It is a participant count: it records whether participants experienced events, rather than measuring the severity of illness on a continuous scale or the rate of events per unit of exposure. The registry defines an on-treatment TEAE as an event in a period beginning with the first dose and ending 14 days after the last preceding administration. A participant could have multiple on-treatment periods separated by interruptions.

In general, safety endpoints of this kind are used to characterize events observed while people are receiving an intervention. Participant counts can make the breadth of event occurrence understandable, but they do not by themselves show when events occurred, how long they lasted, how severe they were, or whether treatment caused them. A participant may experience more than one event, while a participant-level count does not represent the total number of events.

The registry record reports an average exposure of 198.7 days and notes that no participant was treated for 76 weeks. Thus, the endpoint reflects follow-up that ended at early termination rather than a complete 76-week treatment period for all participants. The record’s outcome title identifies TEAEs, while its adverse-event summary separately lists participants in serious and other adverse-event categories. A single overall primary TEAE count is not reported in the registry record in the registry record presented.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical context. A single-group study describes outcomes within a treated cohort. Counts and proportions can show how many participants had recorded events, but there is no concurrent untreated or alternative-treatment group against which to estimate a treatment contrast. This limitation is especially important for outcomes that can occur as part of the underlying condition or for reasons unrelated to study treatment. The open-label design also means treatment assignment was known, so the record does not provide a blinded comparison to address possible differences in observation or reporting.

What a participant count represents. A participant-level event count asks how many people experienced at least one event in a category during the defined period. It is distinct from counting every event: one participant may have multiple events, and repeated events may contribute to an event total without changing the number of participants who experienced an event. The primary endpoint is framed as a participant count. The record also describes on-treatment periods separated by interruptions, with the on-treatment definition ending 14 days after the last preceding administration. The method for combining events across such periods into the posted categories is not reported in the registry record.

Exposure and observation time. Follow-up duration affects the opportunity to observe an adverse event. A person treated longer may have a greater chance of having an event recorded, even if the underlying event rate is similar. General statistical practice may address unequal observation time with exposure-adjusted rates or time-to-event methods, but the use of such methods is not reported in the registry record. The reported exposure summaries show that durations varied, and no participant was treated for 76 weeks. The number of participants with an event should therefore not be treated as a rate over a common duration or as a complete account of the intended longer observation period.

Uncertainty and confidence intervals. In general, a confidence interval expresses the statistical uncertainty around an estimated quantity under a specified method and assumptions. It is not a guarantee that the true value lies within its limits, and its interpretation depends on the design and analysis. No confidence intervals are reported in the registry record for the adverse-event counts. Even if an interval were available for a single-group event proportion, it would not remove the lack of a control group or establish that treatment caused or prevented events.

Over-dispersion in general. Over-dispersion occurs when observed variability in count data is greater than expected under a chosen statistical model. It can arise when participants differ in their underlying event tendency or exposure, among other reasons. A model that ignores over-dispersion can understate uncertainty. The record does not report a count model, an assessment of over-dispersion, or model-based estimates. No such analysis should be inferred from the descriptive counts.

Missingness and incomplete follow-up. Early termination and different exposure durations mean that participants did not all contribute the same observation period. General analyses of longitudinal outcomes may need to account for incomplete measurements, but the approach depends on why observations are missing and on the assumptions made. The registry record does not report the amount or pattern of missing outcome data, reasons for individual discontinuation, or a missing-data method. It also does not describe an imputation approach or sensitivity analyses. Therefore, the consequences of incomplete follow-up for any outcome cannot be quantified from the record.

Multiplicity and outcomes. When a study evaluates multiple outcomes or repeated time points, testing many hypotheses can increase the chance of at least one apparently notable result by chance. General approaches include prespecifying a hierarchy or adjusting inference for multiple testing. The record lists 19 outcome measures, but a multiplicity strategy is not reported in the registry record. There are 0 reported analyses in the registry record presented, so there is no basis to characterize a set of statistical tests, their adjustment, or any hierarchy of confirmatory outcomes.

Sample-size planning versus evidence. A sample-size calculation is a planning exercise based on assumptions; it is not an outcome and does not demonstrate that a study had a particular probability of detecting an effect after results are observed. The registry record does not report the study’s sample-size justification, assumptions, or a power analysis for its own design. Any planning illustration based on an observed effect would not replace a prespecified design rationale and would not create a treatment comparison where none exists.

Analysis populations. The registry describes the safety analysis set as all enrolled patients who received at least one dose of arimoclomol. This defines the stated safety population. The record does not report a separate efficacy analysis population or explain how participants with missing measurements were handled for secondary outcomes. General interpretation should keep the population used for an analysis distinct from all individuals who may have enrolled or been screened; screening and exclusion details are not reported in the registry record.

Overall, the reported information is descriptive. There is no reported inferential analysis, adjusted estimate, or controlled comparison. These are not merely technical omissions: they determine which questions the results can answer. The counts characterize events documented during observed exposure, while causal attribution, comparative safety, and efficacy require information and design features not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures, including the primary TEAE endpoint and secondary outcomes concerning ALSFRS-R and predicted SVC. A plan for managing multiplicity across outcomes or time points is not reported in the registry record. In general, evaluating many outcomes can make isolated findings difficult to interpret unless the testing strategy and outcome hierarchy are specified. Here, no inferential analyses are reported, so the record does not describe a family of tests or any multiplicity adjustment.

The registry defines the safety analysis set as all enrolled patients who received at least one dose of arimoclomol. The registry entries presented do not describe a separate analysis population for efficacy outcomes. The reasons for any exclusions from particular analyses, if applicable, are not reported in the registry record.

The adverse-event collection continued until early termination, and exposure ranged from 16 days to 494 days. The registry does not report participant-level reasons for stopping treatment, the amount or pattern of missing outcome assessments, or methods for handling missing data. It also does not report imputation or sensitivity analyses. In general, incomplete observations can affect summaries, particularly for outcomes measured over time; the direction and extent of any effect depend on why data are missing and the analysis assumptions. No specific missing-data mechanism can be inferred from the record.

The unequal exposure durations and the absence of treatment for 76 weeks are relevant to interpreting follow-up completeness. However, the record does not describe an analysis that adjusts event summaries for time at risk. These limits should be kept separate from the reported participant counts, which remain descriptive of the categories and follow-up summarized in the registry.

11. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (5.8%), pneumonia aspiration (2.5%), acute respiratory failure (1.7%), pulmonary embolism (1.7%), clostridium difficile infection (0.8%).

The registry’s adverse-event summary lists 21 participants in the serious adverse-event category and 91 in the other adverse-event category, among 120 at risk in the single arimoclomol group. It also lists 23 deaths. These values describe the categories as recorded; they do not indicate that the serious-event count, other-event count, and death count are mutually exclusive. A participant can experience more than one type of outcome, and the record does not explain overlap among these categories.

The listed serious-event terms are Pneumonia (5.8%), Pneumonia aspiration (2.5%), Acute respiratory failure (1.7%), Pulmonary embolism (1.7%), Clostridium difficile infection (0.8%), and Corona virus infection (0.8%). The registry reports the percentages but does not state the denominator or explain whether a participant with repeated events contributes once or more than once to a term’s percentage. No counts should be derived from these percentages.

In general, a serious adverse event is a classification of an event, not proof that treatment caused it. The open-label, uncontrolled design does not allow comparison with an alternative treatment or an estimate of excess risk attributable to arimoclomol. Exposure also varied, and no participant was treated for 76 weeks. The event summaries should therefore be read as observations during the recorded treatment and follow-up, not as comparative safety estimates or causal findings.

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

The results describe adverse events recorded during an open-label extension in which participants received arimoclomol. The registry reports 120 participants at risk, 21 participants in the serious adverse-event category, 91 in the other adverse-event category, and 23 deaths. It also lists serious-event terms and their percentages. These observations are relevant as a record of what was documented during the study, but they do not alone establish why an event occurred.

The study does not provide a concurrent control group, randomization, or masking. In general, random assignment can help balance groups on measured and unmeasured factors, and a concurrent comparator can provide context for outcomes over the same period. Those features are absent. The observed event summaries cannot show whether the frequency of an event was higher or lower because of arimoclomol, nor can they distinguish treatment effects from underlying disease, background risks, or other influences.

Follow-up was also incomplete relative to the listed 76-week secondary outcome time point: no participant was treated for 76 weeks. Exposure varied from 16 days to 494 days, with a reported average of 198.7 days. This means participants had different opportunities for events to be observed. The record does not report an exposure-adjusted analysis, a missing-data strategy, or inferential uncertainty estimates for the adverse-event summaries.

The trial’s stated aim included long-term safety and efficacy, but the registry entries presented do not report results for changes in ALSFRS-R or predicted SVC. They also do not report a standalone overall count for the primary TEAE endpoint or any inferential analyses. Accordingly, the record supports descriptive statements about the adverse-event categories and duration of exposure; it does not establish efficacy, comparative safety, treatment causation, or the likely outcome for an individual.

13. Why This Trial Matters Statistically

This trial is statistically important because it illustrates the distinction between observing events during treatment and estimating an effect of treatment. A single-group extension can add descriptive information about participants who continue into follow-up and about the events recorded during their exposure. It cannot, without a concurrent comparison, separate those observations from what might have occurred under another treatment or without the study intervention.

The exposure summaries also make follow-up duration central to interpretation. Participants were observed for differing lengths of time, and none received treatment for 76 weeks. Participant counts remain useful descriptions, but they do not account for unequal time at risk. An exposure-adjusted analysis could address a different statistical question, although use of one is not reported in the registry record.

The record’s 19 outcome measures and 0 reported analyses highlight another general issue: outcome registration, analysis specification, and presentation of results are distinct. Without reported analysis methods, missing-data handling, multiplicity strategy, or uncertainty estimates, readers cannot determine how secondary outcomes were analyzed or how confidently estimates might be interpreted. The sample-size justification and the reason for termination are not reported in the registry record either.

These features do not make descriptive findings meaningless. They define their scope. The event categories and exposure durations can be read as observations in this enrolled cohort, while conclusions about comparative safety, efficacy, or causality require stronger comparative evidence and fuller reporting. Recognizing that boundary is a core part of sound statistical interpretation in clinical research.

14. 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 limitations specific to this extension constrain interpretation. It was non-randomized, open-label, and single-group, so there was no concurrent control condition. Participants and investigators knew the treatment, and the record does not offer a like-for-like comparison that could separate treatment-related events from background events or disease-related changes.

Exposure was variable and follow-up ended at early termination. The average duration was 198.7 days, with a standard deviation of 99.57 days, a minimum of 16 days, and a maximum of 494 days. No participant was treated for 76 weeks. Thus, the intended longer observation was not completed by any participant, and the opportunity to record events differed across participants. The reason the trial was terminated is not reported in the registry record.

The record does not report the sample-size justification, a statistical analysis plan, a missing-data method, an approach to multiplicity, or confidence intervals for the described outcomes. Although 19 outcome measures are listed, 0 analyses are reported in the registry record presented. Results for the secondary ALSFRS-R and predicted SVC outcomes are not reported in the registry record in the registry record presented.

The adverse-event summary gives participant counts and percentages for selected serious-event terms, but the denominator for those term percentages and the handling of repeated events are not reported in the registry record. The record also does not provide a standalone overall primary TEAE count in the registry record presented. These limitations prevent precise comparative or causal interpretation and restrict the conclusions to the recorded descriptive information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial — NCT03836716.
• Registry record last updated 2023-08-24; status last verified 2023-08.
• Results first posted 2023-08-24.
• 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.

18. Record Summary

NCT03836716 is a phase 3, multicenter, open-label, non-randomized extension trial of arimoclomol in people with amyotrophic lateral sclerosis who completed ORARIALS-01. The registry lists 120 enrolled participants, one treatment group, and a regimen of 248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily. The study is listed as terminated.

The primary outcome concerns the number of participants with treatment-emergent adverse events during the open-label treatment period. The registry reports 21 participants in the serious adverse-event category, 91 in the other adverse-event category, and 23 deaths. Average exposure was 198.7 days, and no participant was treated for 76 weeks. The listed secondary outcomes include changes in ALSFRS-R and predicted SVC, but their results are not reported in the registry record in the registry record presented.

No randomized comparison, inferential analyses, sample-size justification, missing-data method, or multiplicity strategy is reported in the registry record. The available safety information is descriptive and does not establish comparative effects or causation.