Safety, Efficacy, and Pharmacokinetics of SKY0402 Administered as a Nerve Block in Subjects Undergoing Bunionectomy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Efficacy, and Pharmacokinetics of SKY0402 Administered as a Nerve Block in Subjects Undergoing Bunionectomy (NCT01206595), a randomized phase 2 study. The primary outcome is Time to First Use of Supplemental Pain Medication Postoperatively for Surgical Pain.

2. Clinical Question

The trial asked whether different doses of SKY0402, administered as a nerve block, could be evaluated for postoperative pain management following bunionectomy. The registry record reports the time to first use of supplemental pain medication as the primary efficacy outcome. That outcome captures the interval between dosing and a patient’s first use of opioid or non-opioid medication for surgical pain; it is not a direct measure of pain intensity.

The posted results give arm-level medians and inter-quartile ranges. They do not report a formal statistical comparison among the groups, an effect estimate for a pairwise contrast, or a confidence interval for such a contrast. The registry record therefore supports a description of the observed outcome values, but not a claim that one group differed statistically from another. The trial’s stated objective was to determine an appropriate SKY0402 dose; the posted primary-outcome values alone do not establish which dose should be selected.

3. Trial Design

This was a phase 2, multicenter, randomized, double-blind, parallel-group study. Its official title describes a dose-escalating/de-escalating design, and the record lists three SKY0402 dose groups alongside a bupivacaine HCl group. Enrollment was 58. The registry record marks the study as completed and gives the study start as 2005-03 and primary completion as 2006-03.

The three SKY0402 groups are identified as low dose (175 mg), low-mid dose (225 mg), and mid dose (350 mg). Bupivacaine HCl served as the comparator; the arm description identifies Marcaine with epinephrine 1:200,000 as the reference-listed drug. Random allocation and double masking are recorded, but the registry record does not report the allocation sequence method, concealment procedures, or exactly who was masked. It also does not report the operational details of dose escalation or de-escalation.

For the primary outcome, the reported group counts are 20 for bupivacaine HCl, 12 for SKY0402 low dose, 12 for SKY0402 low-mid dose, and 14 for SKY0402 mid dose. The primary endpoint is time to first use of supplemental pain medication for surgical pain, measured through 96 hours postdose. The outcome is presented as a median with an inter-quartile range for each arm.

These design features frame the interpretation: the record contains multiple dose groups and a comparator, while the posted primary results are descriptive arm-level summaries. The registry record does not report a statistical analysis plan, the intended primary comparison, or an inferential analysis of the primary endpoint. It also does not report whether any planned interim analyses were conducted. As a result, the design description can be stated, but details about how the investigators planned to test dose differences cannot be inferred from 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

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 Time to First Use of Supplemental Pain Medication Postoperatively for Surgical Pain, measured over Through 96 hours postdose.

The primary endpoint is the time from dosing to the first use of supplemental pain medication for surgical pain after bunionectomy. The record specifies opioid or non-opioid medication and a follow-up window through 96 hours postdose. A longer time to first use represents a later observed request or use of additional medication, while the endpoint does not directly quantify the intensity, duration, or character of pain.

Time to first use is a time-to-event measure: the event is the first use of supplemental medication, and the recorded time is when that event occurs. This type of outcome can be useful when the timing of an event is clinically relevant, rather than only whether the event occurred. In general, time-to-event analyses can account for participants whose event time is not observed during the study window, but the registry record does not say whether or how censoring was handled in this trial.

The posted summaries report the median time and inter-quartile range for each group. The median is the central value of the observed distribution; the inter-quartile range describes the middle half of that distribution. It is a measure of variability among observed times, not a confidence interval for the median or for a difference between groups. The registry record does not report a separate estimate of the treatment contrast or its precision.

Use of supplemental medication can reflect both postoperative pain and decisions about whether and when to take additional medication. The endpoint therefore gives information about medication use over time, but it should not be treated as a direct pain score or as a complete account of postoperative pain.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a median with an inter-quartile range. This is a distribution-focused way to summarize a time measure. The median identifies the central point in the observed ordering of times. The inter-quartile range runs from the lower to the upper quartile and describes the spread of the middle portion of the observations. Unlike a mean and standard deviation, these summaries are less dependent on assumptions that the outcome has a symmetric distribution. Time-to-event observations can be skewed, so a median and inter-quartile range can communicate the center and spread without requiring a symmetric shape.

What does the inter-quartile range tell us?

In general, the inter-quartile range describes variation in participant-level outcomes, not the precision of an estimated treatment effect. A narrow or wide range is not, on its own, a test of whether two groups differ. It also does not show how uncertain the median is. A confidence interval for a median or a group contrast answers a different question by expressing uncertainty about an estimated quantity under a statistical model or procedure. The registry record reports inter-quartile ranges, but does not report confidence intervals for the primary endpoint.

Each group’s median and range should be read together. For example, the reported median for bupivacaine HCl is 9.4 hours, with an inter-quartile range of 6.1 to 11.2 hours. The SKY0402 low-dose group has a median of 1.9 hours and an inter-quartile range of 0.3 to 9.0 hours. These summaries convey the locations and spreads of the observed group distributions, but do not directly estimate a difference between those groups. The record does not give a contrast estimate or its standard error.

Why does time-to-event analysis matter?

In general, time-to-event methods are designed for outcomes where both the occurrence and timing of an event matter. They can make use of observed event times while accounting for participants whose event has not occurred by the end of observation or whose follow-up ends earlier. Such incomplete event-time information is often called censoring. The registry record does not report whether participants had censored times, how such times were handled, or whether the posted medians were generated with a time-to-event estimator. Those methodological details should not be assumed from the endpoint name alone.

The primary endpoint has an event defined as first use of supplemental medication, with a follow-up window through 96 hours postdose. The record does not state how medication use at the boundary of that window was handled, whether all participants completed the full window, or how events outside the window were treated. It also does not give a statistical test or model. Consequently, the endpoint definition and descriptive summaries are clear, but the analysis method behind the reported values is not fully documented in the registry record.

How should randomized group summaries be compared?

In general, randomization supports comparisons between groups by assigning participants to study arms through a chance-based process. It does not make the groups identical, and it does not remove the need for an appropriate statistical analysis. A formal comparison would need to specify the contrast of interest, the outcome model or test, and the treatment of incomplete observations. The registry record states that allocation was randomized and masking was double, but it does not report the planned primary contrast, the statistical method, or any adjustment for baseline factors.

The arm-level medians can therefore be described, but subtraction of these values would not by itself constitute a complete analysis. No new difference is calculated in this interpretation. In general, estimating a contrast requires attention to the distribution and censoring of event times, the allocation structure, and the analysis population. The registry record contains no reported analysis for the primary outcome, so those elements cannot be reconstructed from the summary values alone.

What do the planning assumptions mean?

In general, a sample-size planning illustration asks how much information might be needed to detect a specified effect under stated assumptions. It is not a measure of power achieved by the completed trial. The registry record describes planning assumptions based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not a report of the trial’s original design justification. The record does not report the trial’s own sample-size justification or the effect fraction used for any particular illustration.

For time-to-event planning, a common approach focuses on the total number of events needed, because event information is central to the precision of a comparison. The planning description states that time-to-event tables give the total number of events, while other tables give participants per arm. Such calculated planning quantities are illustrative and should not be confused with observed enrollment, observed event counts, or observed power. The registry record does not report a primary-outcome event count or a trial-specific power calculation.

Multiplicity is another methodological concern when several doses or outcomes are considered. In general, testing multiple contrasts can increase the chance of at least one false-positive finding if tests are interpreted without an appropriate plan. The registry record does not report a multiplicity strategy, a hierarchy of comparisons, or which dose contrast was designated primary. Since no inferential results are posted, multiplicity-adjusted or unadjusted conclusions cannot be assessed.

Finally, the record lists zero analyses and does not give a statistical analysis plan. That absence limits what can be said about estimation, hypothesis testing, missingness, censoring, and population selection. It is not evidence that no analysis was performed outside the registry; it means those details are not reported in the registry record. Interpretation should remain anchored to the arm-level summaries that are actually posted.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan, a prespecified hierarchy of dose comparisons, or a method for controlling multiplicity. With three SKY0402 dose groups and a bupivacaine HCl comparator, multiple possible contrasts could be considered. In general, when several comparisons are tested, the interpretation of p-values depends on whether and how multiplicity is addressed. Because the record reports no inferential analysis for the primary endpoint, it is not possible to determine whether any adjustment was planned or used.

The record lists one secondary outcome: number of patients with adverse events. It does not report a broader outcome-testing plan or identify a sequence in which primary and secondary hypotheses were tested. The presence of several arms and outcomes does not itself establish that all possible contrasts were tested.

Missing-data and analysis-population details are also not reported in the registry record. It does not state whether all randomized participants were included in the primary analysis, how missing medication-use times were handled, whether any participants were excluded, or how participants without an observed event through the follow-up window were treated. These details matter because they determine which observations contribute to an estimate and how incomplete follow-up affects it.

In general, an intention-to-treat analysis includes participants according to their randomized group, while other analysis populations may apply additional criteria. The registry does not identify which approach was used. It also does not report an accounting of missing primary outcome data or a sensitivity analysis. As a result, the posted medians and ranges can be described, but their relationship to the full randomized population and the robustness of the results to missing data cannot be assessed from the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: immobiliaztion prolonged (2.6%).

The registry reports serious adverse events for the SKY0402 group as 1 among 38 at risk and for the bupivacaine HCl group as 0 among 20 at risk. It also reports other adverse events as 15 among 38 at risk for SKY0402 and 6 among 20 at risk for bupivacaine HCl. These are counts with their reported denominators; they are not adjusted comparisons and do not establish that an event was caused by study treatment.

The serious-event listing includes “Immobiliaztion prolonged” at 2.6%. That term and percentage are presented as recorded. The record does not provide enough detail to interpret the event’s clinical circumstances, duration, relationship to treatment, or distribution beyond the listed term. Deaths are not reported in the registry record.

In general, safety counts are descriptive unless accompanied by a defined analysis and appropriate uncertainty estimates. The registry does not report confidence intervals or statistical tests for the adverse-event figures. Comparisons should therefore be read cautiously, particularly because the groups have different reported denominators. The counts do not by themselves measure severity across all possible events or rule out events that were not listed in the posted results.

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

The registry record documents a randomized, double-blind phase 2 study of SKY0402 nerve-block doses and bupivacaine HCl in subjects undergoing bunionectomy. It reports a primary endpoint focused on time to first use of supplemental pain medication for surgical pain and gives a median and inter-quartile range for each arm. The reported medians differ descriptively among the groups, and the ranges describe variability in the observed times.

Those findings do not establish that one treatment or dose is superior, equivalent, or inferior. The registry record does not report a formal statistical comparison, confidence interval, p-value, or adjusted estimate for the primary outcome. It also does not report the analysis method or clarify how missing or censored event times were handled. Without that information, the size and precision of any between-group effect cannot be determined from the posted summaries.

The outcome is time until use of additional medication, not a direct measure of pain intensity. It reflects an event that involves medication use and therefore does not fully describe the experience of postoperative pain. The registry does not report a pain-score result in the listed primary outcome. It is important to keep the endpoint’s meaning distinct from broader claims about pain relief or clinical benefit.

The safety findings are likewise descriptive. Counts of serious and other adverse events are posted by group, but the record does not provide inferential safety comparisons or detailed context for the events. They should not be interpreted as establishing a causal relationship or as a complete safety profile.

The trial’s stated objective was to determine an appropriate SKY0402 dose. The posted arm-level results alone do not identify an appropriate dose: the record does not report a dose-selection analysis, a dose-response test, or a prespecified method for choosing among the doses. The appropriate conclusion is limited to what is recorded: the study compared several groups, and the registry presents descriptive outcome and adverse-event information, without the inferential details needed to support broader comparative conclusions.

13. Why This Trial Matters Statistically

This trial illustrates an important distinction in clinical-trial interpretation: arm-level outcome summaries are not the same as a statistical comparison. Medians and inter-quartile ranges describe the location and spread of observed times within groups. They can help readers understand the data’s distribution, but they do not quantify the uncertainty in a contrast between groups. A separate inferential analysis is needed to support claims about between-group differences.

The endpoint also highlights why outcome definitions matter. Time to first supplemental medication captures when additional medication was first used, rather than directly measuring pain intensity. Statistical interpretation depends on understanding exactly what counts as the event, how observation ends, and how participants without an observed event are handled. The registry specifies the event and follow-up window, but does not report the analysis details needed to evaluate censoring or missing observations.

Multiple dose groups create a further interpretive challenge. A dose-selection objective can involve several possible comparisons and a decision rule, yet the registry record does not report a prespecified contrast, dose-response method, or multiplicity approach. Without those elements, descriptive differences among dose-group medians should not be converted into a selection claim.

The safety results show another general statistical lesson: counts and denominators are informative descriptions, but they are not adjusted measures of comparative risk. The posted counts do not include uncertainty estimates or detailed event attribution. Readers should distinguish what was observed from what can be inferred about treatment effects.

More broadly, this record demonstrates the value of transparent reporting. Randomization and masking are important design features, but evaluation also depends on the analysis plan, analysis population, handling of incomplete data, and reporting of estimates with their uncertainty. Those details are not reported for the primary endpoint in this registry record, which limits the statistical conclusions available from the posted results.

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 registry record provides arm-level medians and inter-quartile ranges for the primary outcome, but no formal comparison among groups. It does not report a confidence interval, p-value, effect estimate, or model for time to first supplemental medication use. The precision of a group contrast therefore cannot be evaluated from the posted primary results.

The record does not describe the statistical analysis plan or identify the analysis population. It does not report how incomplete follow-up, missing outcome times, or participants without an observed event during the follow-up window were handled. It also does not state whether the reported summaries were based on a time-to-event estimator or another method.

Although the study is described as randomized, double-blind, multicenter, and parallel-group, the registry record does not report the randomization procedure, concealment details, masking roles, or practical dose-escalation/de-escalation procedures. The record does not provide baseline characteristics for evaluating the groups’ observed composition.

The primary endpoint concerns time to medication use, not a direct pain-intensity score. The registry record does not provide further primary-outcome measures that would allow a broader assessment of postoperative pain. Nor does it report a dose-response analysis or the decision criteria for selecting an appropriate dose.

Safety information is also limited to the posted counts and a listed serious-event term. The record does not provide event-level context, statistical comparisons, or a detailed account of causality. These limitations constrain interpretation of both the efficacy summaries and safety counts; they do not show that unreported analyses or information were absent from other study materials.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety, Efficacy, and Pharmacokinetics of SKY0402 Administered as a Nerve Block in Subjects Undergoing Bunionectomy — NCT01206595.
• Registry record last updated 2021-01-25; status last verified 2021-01.
• Results first posted 2012-05-15.
• 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

NCT01206595 is a completed phase 2, multicenter, randomized, double-blind, parallel-group study of SKY0402 administered as a nerve block for postoperative pain following bunionectomy. The record reports 58 enrolled and describes three SKY0402 dose groups and a bupivacaine HCl comparator.

The primary outcome was time to first use of supplemental opioid or non-opioid medication for surgical pain through 96 hours postdose. Results are reported as arm-level medians and inter-quartile ranges. The registry record does not report a formal primary-outcome comparison, analysis method, statistical analysis plan, or details of missing-data handling.

Adverse-event counts are posted for SKY0402 and bupivacaine HCl, including serious-event counts and one listed serious-event term. The registry record does not report inferential safety comparisons or deaths. Overall, the posted results support descriptive reading of the outcome and safety summaries, while important details for comparative inference are not reported in the registry record.