A Study To Assess the Safety of OnabotulinumtoxinA (BOTOX) Intramuscular Injection in Adult Participants With Platysma Prominence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study To Assess the Safety of OnabotulinumtoxinA (BOTOX) Intramuscular Injection in Adult Participants With Platysma Prominence (NCT05134649), a na phase 3 study. The primary outcome is Number of Participants With Adverse Events.

2. Clinical Question

The study addressed long-term safety during repeat treatment in adults who had already completed a lead-in study and qualified for the extension. That entry pathway defines a particular study population; the results do not describe all people with platysma prominence. The registry record does not report the detailed eligibility criteria.

The primary safety timeframe was 371 days, from enrollment in lead-in study M21-309 through the end of extension study M21-323. The record reports counts of participants with adverse events, including serious adverse events, as well as deaths. These counts describe events observed in the study group. Without a comparator, they cannot show whether the counts would have been different under another treatment or without treatment.

3. Trial Design

This was a Phase 3, multicenter, open-label extension study of onabotulinumtoxinA. It used a single-group design: participants received BOTOX, and there was no randomized comparison group. The study was completed. The registry lists enrollment of 292 participants and planned enrollment of approximately 270.

Enrollment was open to participants who completed lead-in Phase 3 Study M21-309 and met eligibility requirements. Once enrolled, participants could receive up to 3 administrations if they met treatment criteria. Study entry on Day 1 coincided with the lead-in study's Day 120 or exit visit. The first administration could take place at Day 1, and the final administration could take place at Day 180, 60 days before the extension's Day 240 exit. Monthly follow-up visits were planned after enrollment.

Open-label means participants and study staff were not masked to the assigned study treatment. The registry lists no masking and no allocation to separate groups. These features fit a safety extension that follows participants from an earlier study, but they also limit what can be concluded from the results: there is no concurrent control group to help distinguish treatment-related events from events that might occur in the absence of study treatment.

The registry record does not report further details about the operational conduct of the study, such as how many participants completed follow-up or received each number of administrations. The safety outcome timeframe begins with enrollment in the lead-in study, rather than only with entry into the extension.

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.

Before assignment: Safety analyses were carried out for the Safety Analysis Set (Safety Population), which consisted of all participants who received study drug in both the lead-in study and in this study (N=292).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set

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: ITT Population

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events, measured over 371 days (from enrollment in the lead-in study M21-309 through end of study M21-323).

The primary endpoint was the number of participants with adverse events. An adverse event was defined as an untoward medical occurrence in a participant administered a pharmaceutical product; it did not necessarily have to be causally related to that product. The endpoint therefore records whether participants experienced an event, not whether the study established that BOTOX caused it.

Counting participants with events is a straightforward way to describe how many people in a safety population experienced an adverse event during a specified observation period. It differs from counting all event episodes: one participant may have more than one event, while a participant-level count records that person as having experienced an event. The posted primary measure is a count, and the registry identifies the Safety Analysis Set as its population.

The stated timeframe was 371 days, from enrollment in lead-in study M21-309 through the end of extension study M21-323. Including the lead-in period matters when interpreting the time window: it is not described as a period beginning only at the first extension-study injection. The registry record does not report a separate primary outcome for event timing, duration, severity beyond the serious-event classification, or causal attribution.

This endpoint is useful for describing safety experience, but a count alone does not convey the full clinical context of each event. It does not indicate how long an event lasted, whether it recurred, or whether investigators judged it related to treatment. Those details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a count of participants with adverse events. For a binary participant-level outcome, each person is classified according to whether the event occurred during the defined period. This is different from a count of event episodes: repeated events in one person need not correspond to multiple participants in the outcome count. The posted safety figures should therefore be read as participant counts, not as a tally of every episode.

The registry identifies the Safety Analysis Set as the primary outcome population and reports 292 participants at risk in the BOTOX group. A denominator gives context to a count by identifying the group from which it was drawn. However, the registry record does not give a separate denominator for every event term, nor does it describe how exposure or incomplete follow-up was handled in constructing the analysis population. The reported percentages for cellulitis and hyponatraemia are quoted as recorded; no additional percentage is calculated.

General statistical context: a confidence interval is a range constructed by a statistical method to express uncertainty around an estimate. Its width depends on the data and method, and its interpretation depends on the assumptions used. The registry record does not report a confidence interval for the primary count. Without one, the displayed count alone does not show the range of values compatible with sampling uncertainty under a specified model. A confidence interval would not, by itself, resolve the design limitation that there is no comparison group.

General statistical context: a hypothesis test evaluates data against a specified null hypothesis using a statistical model. A p-value, when reported, measures how unusual the data would be under that model and null hypothesis; it is not the probability that a treatment caused an event. No analysis is listed for the primary outcome, and the registry record does not report a p-value or a hypothesis test for these adverse-event counts. Thus there is no reported inferential comparison to interpret.

General statistical context: rates and time-to-event methods can account for follow-up duration when participants contribute different amounts of observation time. A participant count over a stated period does not by itself show when events arose or how long each participant was observed. The registry record gives a 371-day timeframe but does not report person-time, event timing, or a time-to-event analysis for this endpoint. It is therefore not possible to infer an incidence rate or event hazard from the posted counts alone.

The registry lists no analyses for the outcome. It does not report an adjusted model, a model for repeated events, or a method for handling competing events. Such methods may be relevant to other questions, but they should not be assumed to have been used in this study. The available description supports a descriptive reading of the participant counts, not reconstruction of an unreported analysis plan.

General statistical context: over-dispersion occurs when observed variability exceeds what a statistical model assumes. It can matter for count models because an inadequate variability assumption may make uncertainty appear too small. The primary outcome is a participant count, and no count-model analysis is listed. There is no basis in the registry record to say whether over-dispersion was assessed or relevant to an analysis performed for this outcome.

Any sample-size planning illustrations use a hypothetical two-arm framework with equal allocation, a two-sided significance level of 0.05, and a normal approximation, with the target effect specified relative to the observed effect. Such illustrations are planning calculations, not observed power and not evidence that the trial was designed with those assumptions. They do not turn this single-group extension into a randomized comparison. The registry record does not report the study's own sample-size justification or a statistical power calculation.

For safety interpretation, the most direct method is to keep the outcome definition, analysis population, and observation period together: participants with events in the Safety Analysis Set over the stated timeframe. A reader should not treat event counts as causal estimates, infer unreported precision, or substitute an assumed model for the analysis information absent from 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("Placebo (Lead-in)", "BOTOX (Cycle 1)", "BOTOX (Cycle 2)", "BOTOX (Cycle 3)", "BOTOX (Cycle 4)", "BOTOX (All Treatment Cycles)")
n      <- c(151, 292, 268, 177, 54, 292)
events <- c(33, 74, 46, 26, 11, 111)
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  Placebo (Lead-in)  151  33  21.9  15.5  29.3  16.0  29.1  16.0  29.1
ARM  BOTOX (Cycle 1)  292  74  25.3  20.5  30.7  20.7  30.6  20.7  30.6
ARM  BOTOX (Cycle 2)  268  46  17.2  12.8  22.2  13.1  22.1  13.1  22.1
ARM  BOTOX (Cycle 3)  177  26  14.7  9.8  20.8  10.2  20.7  10.2  20.7
ARM  BOTOX (Cycle 4)  54  11  20.4  10.6  33.5  11.8  32.9  11.8  33.0
ARM  BOTOX (All Treatment Cycles)  292  111  38.0  32.4  43.9  32.6  43.7  32.6  43.7

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity strategy. Multiplicity arises when several outcomes, comparisons, time points, or subgroups are tested: as the number of statistical tests grows, the chance of at least one apparently unusual result can increase. Methods to address this can include defining a hierarchy of outcomes or adjusting the threshold for interpretation. No such strategy is described for this outcome, and no inferential analyses are listed.

Missing-data handling is also not reported in the registry record. The record does not say whether all participants completed the planned follow-up, whether any safety observations were unavailable, or how participants with incomplete follow-up were treated in the analysis. The listed 292 participants at risk identify the reported safety group, but do not by themselves establish that every participant contributed the same amount of observation time.

The analysis population is named as the Safety Analysis Set. The registry record does not provide a detailed definition of that set or explain whether it differs from the enrolled group. It also does not report a separate population for an efficacy analysis. Because this study's stated focus was safety and its primary outcome is an adverse-event count, conclusions should remain tied to the stated safety population rather than being generalized to an undefined group.

These omissions matter because missing follow-up can affect the opportunity to observe events, while multiple analyses can affect how results should be interpreted. Without details on either issue, the posted counts remain descriptive and the extent of any resulting bias or uncertainty cannot be assessed from the registry record.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cellulitis (0.3%), hyponatraemia (0.3%).

The registry reports 2 participants with serious adverse events in the BOTOX group, with 292 participants at risk. It separately records 42 participants with other adverse events and 0 deaths. These are participant counts; they should not be interpreted as counts of every event episode. The registry lists cellulitis and hyponatraemia as serious adverse-event terms, each with a reported value of 0.3%.

The serious-event count does not establish that the events were caused by treatment. The study's adverse-event definition includes medical occurrences that do not necessarily have a causal relationship to the product. The record does not report the investigators' causality assessments, the details of individual cases, or the timing and duration of these events.

The figures describe the study group over the stated 371-day timeframe, which begins with enrollment in the lead-in study and continues through the end of the extension. They do not provide a comparison with another group or a background event rate. A reader should therefore treat them as a record of observed safety events in this particular study, not as a comparative measure of risk.

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

The result provides a descriptive account of adverse events recorded in a selected group of adults who entered an open-label extension after completing a lead-in study and meeting eligibility requirements. The registry reports 292 participants at risk, including 2 participants with serious adverse events, 42 with other adverse events, and 0 deaths. It also identifies cellulitis and hyponatraemia among the serious-event terms, each at 0.3%.

These findings do not demonstrate that BOTOX caused the events. An adverse event is an untoward medical occurrence and need not be causally related to the product. The record does not provide case-level details or causality assessments. Nor do the counts establish how the observed experience compares with what would occur in a similar group without study treatment or with another intervention: there was no comparator group.

The findings also do not describe treatment benefit. The primary outcome was a safety count, not an efficacy measure. The registry record does not report a comparative efficacy analysis, and no such conclusion should be inferred from the adverse-event counts.

The degree of precision is limited by the information reported. There is no confidence interval or inferential analysis for the primary count, and details on incomplete follow-up and exposure time are not reported in the registry record. The results are most appropriately understood as observed participant counts over the specified timeframe in this extension-study population. They do not establish what would happen in other populations, with different follow-up, or under a different study design.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of a safety extension that follows people from a lead-in study. Its single-group structure and open-label conduct are important to interpretation, not minor details: they mean the posted safety counts have no concurrent control-group estimate to place them in comparative context.

The endpoint also illustrates the difference between a participant count and an event count. Counting participants with an event is useful for describing how many people experienced an adverse event, but it does not reveal the total number of episodes, recurrent-event burden, or timing. Those questions require information beyond a participant-level count, and the registry record does not report those details.

The stated observation period begins in the lead-in study and continues through the extension. This makes it especially important to keep the timeframe in mind when reading the safety outcome. The record also identifies the Safety Analysis Set, but does not explain its detailed construction or the handling of incomplete observation.

Finally, the absence of reported inferential analyses and confidence intervals limits assessment of statistical precision. Descriptive counts remain useful for documenting study experience, but they are not substitutes for a comparative estimate. This distinction helps readers avoid turning a safety description into a causal claim or a claim about treatment benefit.

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 main design limitation is the absence of a control group. Because the study was single-group and open-label, its adverse-event counts cannot estimate a difference relative to another treatment or no treatment. The registry record also does not report a causal analysis, so events cannot be attributed to study treatment based on these counts alone.

The population was limited to adults who completed lead-in Phase 3 Study M21-309 and met eligibility requirements. Detailed eligibility criteria are not reported in the registry record. The results therefore may not describe people who would not have qualified for or completed the lead-in study.

The primary endpoint counts participants with adverse events, rather than all event episodes. The record does not describe event timing, duration, recurrence, case-level details, or causality assessments. It also does not report how many participants received each number of administrations, how much time each participant contributed, or whether follow-up was complete.

The registry record identifies the Safety Analysis Set but does not provide its detailed definition. It does not report methods for handling missing safety observations, confidence intervals, hypothesis tests, an analysis plan for multiplicity, or a sample-size justification. These gaps limit assessment of precision, potential missing-data effects, and the reasoning behind the study's design. The posted counts should consequently be read as descriptive results for the stated group and timeframe, rather than as a complete comparative or causal assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study To Assess the Safety of OnabotulinumtoxinA (BOTOX) Intramuscular Injection in Adult Participants With Platysma Prominence — NCT05134649.
• Registry record last updated 2024-12-05; status last verified 2024-11.
• Results first posted 2024-12-05.
• 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.

19. Record Summary

NCT05134649 was a completed Phase 3, multicenter, open-label extension study of onabotulinumtoxinA for adults with platysma prominence. Participants who completed lead-in Study M21-309 and met eligibility requirements could enroll. The study had one treatment group, with up to 3 administrations for participants meeting treatment criteria, and planned monthly follow-up visits.

The primary outcome was the number of participants with adverse events over 371 days, from enrollment in the lead-in study through the end of the extension. The Safety Analysis Set is identified as the analysis population. The record lists 292 participants at risk, 2 with serious adverse events, 42 with other adverse events, and 0 deaths. Cellulitis and hyponatraemia are each listed at 0.3% among serious-event terms.

No comparator was used, and no inferential analyses are listed. Detailed reporting on missing data, precision, and causal assessment is not reported in the registry record.