Safety and Efficacy of VEC-162 on Circadian Rhythm in Healthy Adult Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of VEC-162 on Circadian Rhythm in Healthy Adult Volunteers (NCT00490945), a randomized phase 2 study. The primary outcome is Circadian Phase Shift.

2. Clinical Question

3. Trial Design

The registry record describes a randomized, double-blind, placebo-controlled, multi-center, parallel-group study. Its official title identifies the study population as healthy subjects, while the study title specifies healthy adult volunteers. The record lists Circadian Rhythm Sleep Disorders as a condition. It does not provide further details about eligibility criteria, recruitment sites, or participant characteristics.

The study is listed as Phase 2 and completed. Enrollment is recorded as 45. The recorded study start is 2004-07, and primary completion is recorded as 2005-03. Vanda Pharmaceuticals is identified as the sponsor. These administrative details describe the registry entry; they do not establish how many participants contributed data to every endpoint or analysis.

The listed intervention is VEC-162. Posted primary endpoint summaries are available for placebo and the 10 mg, 20 mg, 50 mg, and 100 mg VEC-162 groups. The number of participants contributing to the primary endpoint varies across these groups: placebo n=6.0, 10 mg n=8.0, 20 mg n=7.0, 50 mg n=4.0, and 100 mg n=5.0. The record does not explain how participants came to be included in each endpoint summary or why these numbers differ from total enrollment.

The randomized and double-blind labels describe important design features, but the registry record does not report the sequence-generation procedure, allocation concealment, or how masking was maintained. It also does not report the protocol’s statistical analysis plan or sample-size justification. The planned study purpose included safety, circadian phase shift, and sleep parameters. The posted primary endpoint is circadian phase shift; the secondary outcomes include sleep measures and pharmacokinetic measures.

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: Number of Enrolled Subjects = 45 Number of Enrollment Failures = 6

Overall Study

Reasons for not completing this period:

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 Circadian Phase Shift, measured over Night 3 and Night 4.

The primary endpoint is titled Circadian Phase Shift and is reported in hours as a mean with a standard deviation. The record defines it as the exposure response to VEC-162 on induction of circadian phase shift, measured by Dim Light Melatonin Onset (DLMO). The change is taken between Night 3 and Night 4, at the time melatonin production reaches 25% of the maximum melatonin concentration. Samples below the melatonin assay’s limit of quantification (LOQ) were assigned 5 pg/ml.

DLMO is a timing measure based on the rise in melatonin under dim-light conditions. As a general measurement concept, using a biological timing marker can help describe circadian phase without relying only on a person’s reported sleep schedule. A change in the timing of the marker between the specified nights is therefore used as an indicator of phase shift. The registry record does not provide further details about the measurement setting, collection schedule, or processing beyond the endpoint definition and the rule for samples below LOQ.

The endpoint summaries are group means and standard deviations. A mean describes the average observed change within a group; a standard deviation describes the spread of individual observations around that group’s mean. Neither statistic alone gives the precision of a difference between groups. No confidence intervals or inferential comparisons for this endpoint are reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record reports the primary endpoint as a continuous measure summarized by a mean and standard deviation. It does not report the statistical methods used to compare groups. The explanations below describe general statistical concepts and should not be read as a claim that any particular method was used in this trial.

What does the mean describe?

For a continuous endpoint, the mean is the arithmetic average of the observed values in a group. In this study, those values are changes in DLMO timing between Night 3 and Night 4, measured in hours. A group mean condenses a set of observations into one location summary. It does not show the full distribution, and it can be influenced by unusually high or low observations. With limited group sizes, individual observations can have substantial influence on a mean.

The sign and size of a mean need interpretation in light of the endpoint’s definition and direction. The registry record labels the measure as time change between the specified nights, but it does not provide a separate statement explaining how positive and negative values should be interpreted in relation to a desired direction. Statistical descriptions should therefore preserve the posted signs rather than assign an unreported favorable direction.

What does the standard deviation describe?

The standard deviation describes how spread out observed values are around their group mean. A larger standard deviation indicates greater spread in that sample; a smaller one indicates that the observations were more concentrated around the mean. It is not the same as a standard error or a confidence interval. The standard deviation concerns variability among observations, while a standard error or confidence interval concerns precision in an estimated quantity.

Standard deviations are useful for understanding the variation underlying an average, but they do not show whether group means differ beyond what sampling variability might produce. That question ordinarily calls for an estimate of a contrast and its uncertainty, such as a confidence interval, together with an inferential procedure appropriate to the design and analysis plan. No such inferential results are reported in the registry record for the primary endpoint.

Why are confidence intervals useful?

As a general statistical concept, a confidence interval is a range of values constructed by a specified procedure to express uncertainty about an estimate. For a trial comparison, an interval around the estimated contrast can show both the direction and the precision of the estimated difference. A narrow interval indicates greater precision than a wide interval, under the assumptions of the method. An interval does not eliminate uncertainty, and its interpretation depends on the design, data, and analysis method.

The registry record does not report confidence intervals for the posted group means or for comparisons with placebo. It is therefore not possible to use the posted endpoint summaries alone to judge the precision of a treatment contrast. The group standard deviations cannot substitute for a confidence interval around that contrast.

Why can an unadjusted comparison differ from a planned analysis?

In general, an unadjusted comparison uses observed outcome summaries without accounting for additional variables or design features. A prespecified adjusted analysis may account for baseline values, stratification, repeated measurements, or other factors, depending on the trial protocol. Such adjustments can affect the estimate and its uncertainty. The registry record does not report whether any adjusted analysis was planned or performed, which covariates might have been included, or how repeated observations were handled.

No recalculated two-group estimate is reported for this continuous endpoint. The registry record states that values were missing or not estimable for a two-arm comparison. There is therefore no posted sponsor comparison to set alongside an unadjusted recalculation, and no basis for presenting a new treatment contrast from these summaries.

What does over-dispersion mean in general?

Over-dispersion is a general concept used when observed variability is greater than a statistical model expects. It is especially relevant in analyses of counts or other outcomes where a model makes assumptions about variability. The primary endpoint in this record is continuous and summarized by a mean and standard deviation. The record does not report a model-based analysis or identify over-dispersion as an issue. It would be inappropriate to claim that over-dispersion was assessed or present as a finding in this trial.

How should the planning illustrations be read?

The record’s sample-size assumptions describe planning illustrations computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated effect to detect is a specified share of the observed effect. These assumptions characterize illustrations, not the trial’s original design or actual statistical power. The registry record does not report the trial’s own sample-size justification, and sample-size illustrations should not be described as observed power.

In general, a planning calculation estimates how many participants per arm might be needed under chosen assumptions to detect a target effect with a chosen power. It depends on the effect size, variability, significance level, allocation, and analysis method. Changing assumptions can change the resulting estimate. Such planning results are not evidence that a trial had a particular chance of success after it was conducted, nor do they replace the actual observed results and their uncertainty.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Placebo", "10 mg VEC-162", "20 mg VEC-162", "50 mg VEC-162", "100 mg VEC-162")
n   <- c(6, 8, 7, 4, 5)
m   <- c(-0.48, 0.18, -1.14, -0.5, -2.74)
sp  <- c(0.84, 2.48, 0.46, 0.32, 1.95)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  6  -0.480  0.840  -1.362  0.402
CARM  10 mg VEC-162  8  0.180  2.480  -1.893  2.253
CARM  20 mg VEC-162  7  -1.140  0.460  -1.565  -0.715
CARM  50 mg VEC-162  4  -0.500  0.320  -1.009  0.009
CARM  100 mg VEC-162  5  -2.740  1.950  -5.161  -0.319

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures and four secondary outcomes. The secondary outcomes named include Wake After Sleep Onset (WASO) and Latency to Persistent Sleep (LPS), along with VEC-162 AUC, Cmax, and Tmax. The primary endpoint is Circadian Phase Shift. Multiple outcomes and dose groups create a general multiplicity concern: when many questions are examined, the chance of obtaining an apparently notable result by chance can increase. General approaches can include prespecifying a primary comparison, adjusting inference, or clearly separating confirmatory from exploratory questions. The registry record does not report a multiplicity strategy, hierarchy of tests, or analysis plan.

The registry lists zero analyses, and the primary continuous-outcome comparison is marked as skipped because values were missing or not estimable for a two-arm comparison. No inferential analysis for the primary endpoint is posted. The absence of an analysis result does not establish that no analysis occurred outside the registry; it means an analysis is not reported in the registry record.

The record does not describe missing-data amounts, reasons for missingness, imputation, or sensitivity analyses. The endpoint description says samples below LOQ were assigned 5 pg/ml; this is a specific assay-handling rule, not a general account of missing outcome data. It does not indicate how other missing observations, if any, were handled.

The registry record also does not define analysis populations, such as an intention-to-treat or per-protocol population, or explain whether the posted endpoint group sizes include all randomized participants who had usable measurements. The total enrollment is 45, while the primary endpoint summaries have group-specific participant counts. Without a participant flow or population definition, the relationship between enrollment, randomization, and endpoint inclusion cannot be fully assessed.

12. 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 non-serious adverse event terms

The posted serious adverse event summaries report zero affected participants in every listed group. The at-risk counts are placebo 8, 10 mg VEC-162 9, 20 mg VEC-162 8, 50 mg VEC-162 7, and 100 mg VEC-162 7. The registry record lists no top serious adverse event terms. These figures describe the serious adverse event information posted for the groups and the recorded at-risk denominators.

These safety denominators differ from the participant counts in the primary endpoint summaries. The registry record does not explain the relationship between those populations, so the endpoint and safety counts should not be treated as interchangeable. Zero affected participants in the posted serious-event summaries does not establish that an event was impossible or that the groups had equivalent risk; the group sizes are limited, and no comparative safety analysis is reported.

The record also lists participants affected by other adverse events: placebo 8 of 8 at risk, 10 mg 8 of 9, 20 mg 7 of 8, 50 mg 7 of 7, and 100 mg 7 of 7. These are not serious-event counts. Deaths are not reported in the registry record. The posted adverse-event information alone does not support a broader conclusion about safety.

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

The posted primary endpoint results describe the observed mean DLMO time change between Night 3 and Night 4 for placebo and the listed VEC-162 dose groups. The standard deviations describe within-group spread. Together, these statistics provide a basic account of the endpoint values represented in the registry, but they do not provide an estimate of the uncertainty around a comparison with placebo.

The record does not report a two-arm comparison, confidence interval, p-value, or analysis method for the primary endpoint. It therefore does not show whether any observed difference between group means is statistically distinguishable from random variation. Descriptive group means should not be read as proof of a treatment effect, and the absence of inferential results should not be read as proof that there is no effect.

The summaries also do not establish that results generalize beyond the participants represented in the endpoint groups. The study is described as involving healthy adult volunteers, and the record does not report detailed eligibility or participant characteristics. It does not provide an account of missing outcomes or a definition of the analysis population. These omissions limit interpretation of who the results represent.

The stated study purpose included safety and sleep parameters as well as circadian phase shift. The registry lists secondary sleep and pharmacokinetic outcomes, but does not post their results in the available record. The primary endpoint summaries therefore cannot answer those questions. The posted serious adverse event counts are also descriptive and do not constitute a comparative safety analysis.

As a general statistical principle, a treatment conclusion requires more than observing that group averages differ. Interpretation depends on the design, completeness of outcome data, prespecified analysis, uncertainty estimates, and the relevance of the measure to the study question. Those elements are not fully reported for the primary endpoint. The appropriate reading is limited: the registry provides group-level descriptive results, but not the inferential evidence needed to characterize the precision of a placebo comparison.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between descriptive outcome summaries and a treatment comparison. The registry posts means and standard deviations for the primary endpoint across placebo and several VEC-162 dose groups. Those values summarize the observed data, but the record does not report the comparison estimates or uncertainty needed to assess how precisely the groups differ.

The variation in group sizes contributing to the endpoint is also important. Total enrollment is 45, while the primary endpoint summaries report group-specific counts. The record does not explain the flow from enrollment to endpoint analysis or define the population used. This illustrates why readers need both outcome summaries and clear information about who contributed data.

The record lists multiple outcomes and dose groups but does not report a multiplicity approach or statistical analysis plan. As a general matter, a prespecified plan helps readers distinguish the main confirmatory question from additional exploratory analyses and understand how the analysis accounts for multiple questions. Without that information, isolated descriptive patterns should be interpreted cautiously.

The study also demonstrates why outcome definitions matter. Circadian phase shift is defined using a change in DLMO timing between specified nights, with an assay rule for samples below LOQ. Knowing this operational definition clarifies what the measure represents, while the lack of inferential results limits what can be concluded from its group averages.

Finally, the record’s planning assumptions are not a substitute for the original sample-size rationale. Planning illustrations based on an observed effect are conditional calculations, not evidence of observed power. Separating those concepts helps prevent descriptive results or retrospective planning figures from being mistaken for a definitive assessment of efficacy or precision.

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 registry record does not report the statistical analysis plan, sample-size justification, allocation sequence method, or allocation concealment procedure. Although the design is identified as randomized, double-blind, and parallel, the record does not describe how randomization or masking was implemented. These omissions limit assessment of the planned analysis and safeguards against bias.

The primary endpoint has descriptive means and standard deviations, but no reported confidence intervals or inferential comparisons. The record marks the two-arm continuous-outcome comparison as skipped because values were missing or not estimable. No further explanation is given about the missing or non-estimable values, and there is no account of missing-data handling or sensitivity analyses.

Primary endpoint participant counts differ by group and are not the same as total enrollment. The record does not provide participant flow, analysis-population definitions, or reasons for exclusion from the endpoint summaries. It also does not report participant characteristics that would help assess the population represented by the results.

Six outcome measures are listed, with four secondary outcomes named, but results for the secondary outcomes are not posted. The registry record does not report how multiplicity was addressed or which analyses, if any, were intended to be confirmatory. The safety summaries are descriptive, and deaths are not reported in the registry record. Taken together, these limitations mean the posted information supports a description of selected endpoint and adverse-event counts, but not a complete evaluation of efficacy, precision, or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of VEC-162 on Circadian Rhythm in Healthy Adult Volunteers — NCT00490945.
• Registry record last updated 2014-08-26; status last verified 2014-08.
• Results first posted 2014-08-26.
• 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 record describes a completed, randomized, double-blind, placebo-controlled, multi-center, parallel Phase 2 study sponsored by Vanda Pharmaceuticals. It lists enrollment of 45 and records a study start of 2004-07 and primary completion of 2005-03. The population is described in the titles as healthy adult volunteers or healthy subjects; Circadian Rhythm Sleep Disorders is listed as a condition.

The primary endpoint is Circadian Phase Shift, measured in hours as the mean change in DLMO timing between Night 3 and Night 4. Group means and standard deviations are posted for placebo and the 10 mg, 20 mg, 50 mg, and 100 mg VEC-162 groups. The registry lists secondary sleep and pharmacokinetic outcomes, but does not post their results in the available record.

No primary endpoint comparison or confidence interval is reported, and the record lists zero analyses. The registry does not report the trial’s statistical plan, sample-size justification, analysis populations, or a full account of missing data. The available results therefore support descriptive reading rather than a precise inferential comparison.