Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) (NCT05683860), a na phase 1, phase 2 study. The primary outcome is Number of Occurrences of Participants With Adverse Events (AEs) Severe AEs, Serious Adverse Events (SAEs), and Withdrawals Due to AEs.

2. Clinical Question

In practical terms, the record addresses whether adverse events were observed during the extension’s stated follow-up period in the enrolled treatment group. It also lists secondary outcomes concerning clinical function, pulmonary function, dementia rating, patient-reported symptoms, and a cerebrospinal-fluid biomarker. The clinical question is limited by the design: an open-label, single-group extension can describe observations among participants, but it cannot establish how those observations compare with an untreated or separately treated group. The registry record does not report results for the listed secondary outcomes.

3. Trial Design

This was a Phase 1 and Phase 2, multicenter, open-label extension study of WVE-004. It used a single-group model, with allocation recorded as NA and masking recorded as NONE. The intervention is listed as WVE-004 10 mg Q12W, and the arm is named WVE-004 (Dose A). The registry reports enrollment of 8 participants.

The study was intended for adults with ALS, FTD, or a mixed ALS/FTD phenotype associated with a documented C9orf72 mutation. Participation required successful completion of the earlier Phase 1b/2a WVE-004-001 study. This eligibility requirement means the extension population consisted of people who had already taken part in that study, not a broadly recruited group of people with these conditions.

The registry gives a study start date of 2022-12-14 and a primary completion date of 2023-06-27. Its status is TERMINATED. The reason for termination is not reported in the registry record, so the status alone does not establish why the study ended or whether the planned follow-up was completed for every participant.

The primary outcome concerns counts of participants with adverse events, severe adverse events, serious adverse events, and withdrawals due to adverse events. Its timeframe is Day 1 to Week 24 (early termination cutoff). The listed secondary outcomes include changes in CDR Plus NACC FTLD, ALSFRS-R, handheld dynamometry, forced vital capacity, ALSAQ-5, and CSF Poly-GP. Although these outcomes are listed, results for them are not reported in the registry record. The record also does not report a detailed statistical analysis plan, a sample-size justification, or a reason for selecting the stated follow-up period.

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 will include all enrolled participants who have received at least 1 dose of study medication in the OLE.

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: Safety Population- All participants who received at least 1 dose of WVE-004 or placebo.

6. Primary Endpoint

The registry lists the primary outcome as Number of Occurrences of Participants With Adverse Events (AEs) Severe AEs, Serious Adverse Events (SAEs), and Withdrawals Due to AEs, measured over Day 1 to Week 24 (early termination cutoff).

The primary endpoint is a count of participants with specified safety events: adverse events, severe adverse events, serious adverse events, and withdrawals due to adverse events. The unit is participants, the parameter is NUMBER, and the registry specifies follow-up from Day 1 to Week 24 with an early termination cutoff. The safety population is defined as enrolled participants who received at least 1 dose of study medication.

The registry defines a treatment-emergent adverse event as an event absent before exposure to study treatment, or an event already present that becomes more intense or frequent after exposure. This definition focuses on events occurring or worsening during treatment exposure; it does not by itself establish that treatment caused an event.

Safety event counts are used to describe the types and frequency of events observed during a study, and can help characterize what was recorded in the treated group. Counts are especially direct to interpret when the endpoint’s unit is participants: they indicate how many people had an event in the specified category, rather than the total number of event episodes. However, the record does not provide event-level descriptions for the reported non-serious category, nor does it report a breakdown of severity beyond the outcome’s stated categories. The endpoint therefore supports a limited descriptive account, not an estimate of comparative risk or a causal conclusion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods are not reported in the registry record. The record identifies a single-group, open-label design and gives a primary safety endpoint measured as the number of participants with events. It does not describe an inferential model, a planned hypothesis test, confidence intervals, or an analysis population beyond the safety-population definition. The concepts below are general explanations of how such features are typically interpreted; they are not claims about analyses performed in this study.

What does a participant count represent?

For an outcome whose unit is participants, the count indicates how many people in the risk group had at least one event in the category being described. It is not necessarily the number of event episodes, because a participant may experience more than one event. Counts are often useful for safety description, but the meaning depends on the event definition, observation period, and denominator. Here, the registry lists the number at risk alongside the number affected for serious events and other adverse events.

A count should not be mistaken for a comparative treatment effect. A comparative effect requires a suitable basis for comparing outcomes, usually a control group or another design that supports a defined contrast. This extension has no comparator group. The posted counts therefore describe events in the treated group and cannot show what would have occurred in the same participants under a different treatment condition.

Why does an open-label design matter?

In an open-label study, participants and investigators know which treatment is being given. General statistical interpretation recognizes that awareness can influence reporting, event assessment, and decisions about follow-up or withdrawal, depending on the outcome and study procedures. Masking can reduce some such influences, but the registry records masking as NONE. The record does not describe additional procedures for independent event adjudication or blinded assessment, so those procedures should not be assumed.

Open-label status does not make a recorded event count meaningless. It does affect how confidently one can interpret subjective or assessment-sensitive outcomes, particularly when there is no concurrent comparison group. For the safety endpoint, the event definitions and the completeness of follow-up matter alongside the count itself.

How should a zero count be understood?

General statistical interpretation treats a zero observed count as evidence that no event of that category was recorded in the observed group during the relevant observation period. It does not establish that the event is impossible or that its underlying probability is zero. The smaller the group and the shorter or less complete the observation, the less information a zero count can provide about uncommon events. This distinction is important for the posted serious adverse event count: it is a study observation, not a guarantee about risk outside the observed group.

A confidence interval, when reported, can express uncertainty around an estimated quantity. The registry record does not report confidence intervals for these event counts. Without them, and without a comparison group, the displayed counts remain descriptive rather than a precise comparative estimate.

What is the role of the registry’s outcome definition?

The treatment-emergent definition includes events that begin after exposure and pre-existing events that worsen in intensity or frequency. This helps specify which events are considered for the endpoint. It is a temporal definition, however, and temporal ordering alone does not prove that treatment caused an event. Causal interpretation would require a suitable design and analysis, together with consideration of other explanations. The record does not report a causal analysis.

The primary outcome title includes adverse events, severe adverse events, serious adverse events, and withdrawals due to adverse events. These are related but distinct categories. Severity and seriousness are not interchangeable concepts: seriousness typically describes outcomes or consequences defined by safety criteria, while severity describes intensity. The posted results give a serious-event count and a count for other adverse events, but separate results for severe events and withdrawals due to adverse events are not reported in the registry record. The available counts should not be used to fill in those missing categories.

What analysis details are unavailable?

The registry does not report a statistical analysis plan, a sample-size justification, interim analyses, a method for handling missing outcome data, or inferential analyses. The number of analyses reported for the outcomes is 0. That does not establish that no analyses were conducted outside the registry; it means that analyses are not reported in the registry record. Similarly, the enrollment of 8 is a reported study characteristic, not evidence of a particular power calculation or design target.

In general, small studies are often primarily descriptive, and their estimates can be imprecise. Precision is the degree to which an estimate is constrained by the available data; more observations can generally reduce uncertainty, while incomplete follow-up or sparse outcomes can leave substantial uncertainty. No precision interval is reported for this safety result. Statistical significance, power, or an effect size should not be inferred from the counts.

The study’s secondary outcomes include clinical rating scales, physical and pulmonary measures, a questionnaire, and CSF Poly-GP. These outcomes are named in the record, but results and statistical methods for them are not reported in the registry record. Thus, no claim about their direction, magnitude, uncertainty, or multiplicity adjustment can be made.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes: changes in CDR Plus NACC FTLD, ALSFRS-R, handheld dynamometry, forced vital capacity, ALSAQ-5, and CSF Poly-GP. It also identifies several categories within the primary safety outcome. The results and analysis details for the secondary outcomes are not reported in the registry record, and the record does not describe a plan for controlling multiplicity.

In general, multiplicity refers to the statistical challenge created by evaluating several outcomes or hypotheses. When many comparisons are tested, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for the number and relationship of tests. This is a general concern, not evidence that any particular adjustment was or was not used in this study. The registry record does not report a multiplicity procedure.

Missing-data methods are also not reported in the registry record. The study is marked TERMINATED, and the primary outcome timeframe is described as Day 1 to Week 24 (early termination cutoff). These details make follow-up duration relevant to interpretation, but the record does not state whether participants had complete follow-up, why the study terminated, or how missing observations were handled. No assumptions about imputation, censoring, or exclusion should be made.

The safety population includes enrolled participants who received at least 1 dose of study medication. The record does not provide a participant flow account or a fuller description of analysis populations. It therefore does not clarify whether every enrolled participant received a dose, how many completed follow-up, or whether a separate population was used for any secondary analysis. These omissions limit assessment of completeness and potential selection effects.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry’s adverse-event record lists 8 participants at risk for serious adverse events, with 0 affected, and 8 at risk for other adverse events, with 3 affected. It also reports 0 deaths in the WVE-004 (Dose A) group. These figures describe participants, not the total number of event episodes. The record does not provide the specific terms for the other adverse events; the serious-event terms are not listed.

The primary outcome also names severe adverse events and withdrawals due to adverse events. Separate counts for those categories are not reported in the registry record. They should not be inferred from the serious-event count or from the count for other adverse events. The registry’s definition of a treatment-emergent adverse event is based on occurrence or worsening after exposure, which does not by itself show that treatment caused the event.

The serious adverse event count is zero among the listed at-risk participants, but this is not evidence that serious events cannot occur. The study has no control group, and its enrollment is 8. The registry does not clarify the amount of follow-up contributed by each participant before the early termination cutoff. The counts should therefore be read as a limited description of the recorded safety experience, not as a complete estimate of risk or a comparison with another treatment.

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

The posted record documents a small, open-label extension in which WVE-004 was given to participants in a single group. In the safety results, 3 participants are listed as affected by other adverse events, while 0 are listed as affected by serious adverse events; the record also lists 0 deaths. Those counts describe what was recorded in this group and within the registry’s stated follow-up framework.

They do not establish that WVE-004 caused or prevented any event. Without a comparator, there is no direct estimate of how the observed events differ from what might have occurred without treatment or under another treatment. The treatment-emergent definition establishes a timing relationship to exposure, not causality. The open-label design is another reason to interpret the observations as descriptive rather than as a controlled comparison.

The absence of a reported serious event in this group does not establish an absence of serious risk. The small enrollment limits the amount of information available about uncommon events, and the registry does not report confidence intervals or participant-level follow-up completeness. The termination status and early termination cutoff are relevant context, but the reason for termination and the duration of follow-up for each participant are not reported in the registry record.

The record lists clinical and biomarker outcomes, including functional ratings, pulmonary function, a questionnaire, and CSF Poly-GP. Their results are not reported in the registry record. Therefore, the safety counts cannot answer whether clinical function, symptoms, or biomarker measures changed. Nor can the listed outcome names alone establish benefit or harm.

Statistically, the main contribution of the posted results is a descriptive account of selected adverse-event counts in this extension group. The record does not support comparative efficacy conclusions, a precise estimate of event risk, or generalization to all people with C9orf72-associated ALS or FTD. It also does not provide enough detail to evaluate the analysis of missing data or the handling of multiple outcomes.

13. Why This Trial Matters Statistically

This study illustrates the difference between recording safety events and estimating a comparative treatment effect. A registry can report the number of participants with events, but when a study has one open-label group, those counts do not show how the experience compares with a control condition. Keeping that distinction clear prevents descriptive observations from being overstated.

The extension setting is also statistically important. Participants had to complete the Phase 1b/2a WVE-004-001 study before entering, so the population reflects people who reached and qualified for the extension. That eligibility context limits how directly the results can represent a broader population with ALS, FTD, or a mixed phenotype.

Safety endpoints require careful attention to categories and definitions. The primary outcome names adverse events, severe adverse events, serious adverse events, and withdrawals due to adverse events, but the posted record gives counts for serious adverse events and other adverse events. Separate values for severe events and withdrawals are not reported in the registry record. Those distinctions matter because categories with similar everyday language can have different statistical and regulatory meanings.

The study is marked TERMINATED, and the primary outcome includes an early termination cutoff. Without reported follow-up completeness or a reason for termination, readers cannot determine how much observation each participant contributed or why the study ended. These are not details that can be recovered from the event counts alone.

Finally, the registry lists several clinically relevant and biomarker outcomes without reporting their results. This highlights why an outcome’s presence in a protocol record is not the same as an available finding. The study is statistically informative as a focused description of a small group and as an example of the limits of single-group safety data; the available record does not establish comparative clinical effects.

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.

The most direct limitation is the enrollment of 8 participants, which constrains the amount of safety information available. In general, small groups provide limited information about uncommon events, and the registry does not report confidence intervals to express uncertainty around the event counts. A zero count should therefore be interpreted only as no recorded event in the listed group during the relevant observation, not as proof of zero underlying risk.

The single-group, open-label design provides no concurrent comparator. Allocation is recorded as NA and masking as NONE. As a result, the posted safety counts cannot be used to estimate a treatment-versus-control difference, and awareness of treatment may be relevant to reporting or assessment. The record does not report blinded event adjudication or other assessment procedures.

The extension eligibility requirement further narrows interpretation: participants had to have completed the earlier WVE-004-001 study. The record does not describe how many people were eligible but did not enter the extension, or how the extension group compares with the broader population with C9orf72-associated disease.

The study is marked TERMINATED, with the primary outcome timeframe ending at Week 24 using an early termination cutoff. The reason for termination, participant-level follow-up, and handling of missing data are not reported in the registry record. Separate results for severe adverse events and withdrawals due to adverse events are also not reported. Results for the listed secondary clinical and biomarker outcomes are absent, as are details of the statistical analysis plan, sample-size justification, and multiplicity handling. Together, these gaps limit evaluation of completeness, precision, and the scope of conclusions that can be drawn.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) — NCT05683860.
• Registry record last updated 2026-09-09; status last verified 2026-07.
• Results first posted 2026-09-09.
• 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

NCT05683860 is a Phase 1 and Phase 2, multicenter, open-label, single-group extension study of WVE-004 in adults with C9orf72-associated ALS, FTD, or a mixed ALS/FTD phenotype. Participants had to have completed the Phase 1b/2a WVE-004-001 study. The registry reports enrollment of 8 and lists the intervention as WVE-004 10 mg Q12W.

The study started on 2022-12-14, has a primary completion date of 2023-06-27, and is marked TERMINATED. Its primary safety outcome covers Day 1 to Week 24 (early termination cutoff). The posted adverse-event record lists 0 serious adverse events, 3 participants with other adverse events, and 0 deaths. Separate values for severe adverse events and withdrawals due to adverse events are not reported in the registry record.

Several secondary clinical and biomarker outcomes are listed, but their results are not reported in the registry record. The record does not report a comparator, detailed statistical methods, missing-data handling, or the reason for termination.