Effects of Vortioxetine (Lu AA21004) on the Concentrations of Selected Neurotransmitters in Healthy Male Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of Vortioxetine (Lu AA21004) on the Concentrations of Selected Neurotransmitters in Healthy Male Adults (NCT01299805), a randomized phase 1 study. The primary outcome is Area Under the Effect Curve From Time Zero to 24 Hours Postdose of 5-hydroxytryptamine (5-HT) in Plasma.

2. Clinical Question

This is a pharmacodynamic question: it concerns a measured biological response over time, rather than a clinical benefit or harm outcome. The endpoint focuses on plasma serotonin and is assessed at baseline, after a single dose and after multiple doses. The study also aimed to describe pharmacokinetics and safety and tolerability, but the registry record does not give numerical results for those aims in the record.

The question is limited to the population and treatment schedule studied. Healthy male adults do not represent every population in which a medicine might be studied, and this short Phase 1 design does not by itself answer questions about longer-term outcomes. Because the endpoint results and analyses are not reported in the registry record, the direction and size of any difference between vortioxetine and placebo cannot be determined from the information available.

3. Trial Design

The registry describes a Phase 1, single-center, randomized, single-blind, placebo-controlled, multiple-dose study. It used a parallel-group design, with participants assigned to vortioxetine or matching placebo. Enrollment was 17. The record names Takeda as sponsor and records the study as completed. The recorded start was 2011-03 and primary completion was 2011-06.

Participants assigned to vortioxetine received 20 mg orally once daily for up to 14 days; the placebo group received matching capsules on the same schedule. The record does not report how many participants were assigned to each group in the design description, although the posted safety figures list 12 at risk in the vortioxetine group and 5 in the placebo group. The identity of the person or people masked by the single-blind procedure is not reported in the registry record.

The primary endpoint was the area under the effect curve from time zero to 24 hours after dosing for plasma 5-hydroxytryptamine. Measurements were planned at baseline on Day -1, after a single dose on Day 1 and after multiple doses on Day 14. Blood sampling included a predose sample and samples at 1, 2, 4, 8, 12, 16 and 24 hours after dosing. The registry record lists 12 outcome measures overall, but does not provide the results for the primary endpoint in the record.

The study’s parallel design means that the intervention groups are distinct rather than the same participants receiving both treatments. Random assignment is intended, in general, to support a fair comparison by reducing systematic differences between groups at the outset. The registry record does not describe the randomization method, allocation concealment, protocol deviations or the detailed statistical analysis plan. Those design details are not reported in the registry 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.

Before assignment: In this study, 17 healthy men were enrolled and randomized to receive an oral dose of vortioxetine 20 mg or placebo in a 2:1 ratio.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The pharmacodynamic (PD) set consisted of all participants in the safety set with sufficient plasma or serum or CSF data for derivation of at least 1 PD parameter. If a patient's concentration profile contained ≤3 data points, the PD parameter results were not included. "n" indicates the number of patients with available data at each time point.

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 Area Under the Effect Curve From Time Zero to 24 Hours Postdose of 5-hydroxytryptamine (5-HT) in Plasma, measured over Day -1 (Baseline), Day 1 and Day 14. Blood samples were taken predose (up to 15 minutes prior) and at 1, 2, 4, 8, 12, 16 and 24 hours post-dose..

The primary endpoint is the area under the effect curve from time zero to 24 hours after dosing for 5-hydroxytryptamine (5-HT, or serotonin) in plasma. It is expressed in pg*hr/mL and summarized as a mean with a standard deviation. The registry description specifies measurements at baseline on Day -1, after a single dose on Day 1 and after multiple doses on Day 14.

In general, an area-under-the-curve measure combines information across repeated measurements over a defined time window. It can represent overall exposure during that interval rather than relying on one concentration at one sampling time. The listed blood-sampling schedule runs from predose through 24 hours after dosing, giving measurements across the interval used for the endpoint.

In general, a mean describes the central value of a continuous measurement, while a standard deviation describes how spread out individual measurements are around that mean. These summaries can help characterize the distribution within a group, but a mean alone does not show how precise a group estimate is or whether groups differ. Precision for a treatment comparison would ordinarily require the group-level results and an appropriate uncertainty estimate, such as a confidence interval. Those results are not reported in the registry record.

The endpoint is a pharmacodynamic measure of plasma serotonin exposure. It is not itself a direct measure of a clinical outcome. The record does not provide a numerical AUEC value, a treatment contrast, or an estimate of uncertainty for any of the listed measurement days.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods describe how measurements are summarized and compared, and what assumptions are used to quantify uncertainty. The registry record contains some information about the measurement and analysis population, but does not report the statistical test, model, covariate adjustment, missing-data method or multiplicity procedure for the primary endpoint. General explanations below describe common statistical ideas; they should not be read as a statement that this study used a particular method.

What does an area-under-the-curve endpoint represent?

The primary outcome is an area under the effect curve from time zero to 24 hours after dosing. In general, an area-under-the-curve endpoint summarizes repeated measurements across a defined interval. A concentration at an individual sampling time can be affected by the timing of that sample, whereas an area summarizes the measured profile over the interval. The interpretation remains tied to the specified analyte, biological sample and time window. In this study, those are plasma serotonin and the first 24 hours after dosing.

The registry lists predose sampling and samples at 1, 2, 4, 8, 12, 16 and 24 hours after dosing. It also identifies baseline on Day -1, Day 1 and Day 14 as assessment occasions. These measurements can describe the profile at different stages of dosing, but the record does not provide the calculated AUEC values or explain how values between sampling times were handled. That computational detail is not reported in the registry record.

What do mean and standard deviation tell the reader?

The endpoint is described as a mean of a continuous measure, with standard deviation as its dispersion summary. In general, a continuous measure can take values across a scale rather than being restricted to categories. A mean is a compact description of the group’s central value. A standard deviation describes the spread of participant measurements around that mean. It is not the same as a confidence interval: standard deviation describes variability among observations, while a confidence interval describes uncertainty around an estimated quantity.

For a comparison between randomized groups, readers generally need to know both the estimated contrast and its uncertainty. Separate group means may be informative, but they do not alone give the precision of the between-group difference. The registry record does not report group means, standard deviations, a treatment contrast or a confidence interval for this endpoint.

Why does randomization matter?

In general, random assignment aims to make treatment groups comparable at the start of a study with respect to measured and unmeasured characteristics, apart from chance differences. This supports interpretation of group contrasts as comparisons of assigned interventions, subject to adherence, missingness, outcome measurement and other design considerations. The record identifies the study as randomized, but does not describe the allocation sequence or concealment procedures. No further details about how randomization was implemented are reported in the registry record.

A parallel-group design assigns participants to distinct groups for the study comparison. In general, analysis must account for the actual design and the participants contributing outcome data. The registry record identifies a parallel design, but does not specify the primary analysis model or whether the analysis used a particular adjustment for baseline measurements.

What does single-blind mean for interpretation?

The record describes the study as single-blind. Masking can, in general, reduce the influence of expectations on participant reports, study conduct or outcome assessment, depending on who is masked and how the outcome is measured. The registry record does not state who was blinded or how masking was maintained. Because the primary endpoint is a laboratory measurement, the role of masking cannot be fully assessed from the record alone; no further claim about its implementation is warranted.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variation is greater than a statistical model expects. It is particularly relevant to some count-data models, where ignoring extra variation can make uncertainty estimates too small. The primary endpoint in this study is described as a continuous mean, not a count outcome. The record does not report the statistical model or any diagnostic checks, so there is no basis for saying whether over-dispersion was assessed or relevant to a particular analysis. This general concept does not establish that it affected the study.

What can be inferred from the analysis record?

The registry reports zero analyses, and no endpoint estimate or inferential result is included in the registry record recorded for this study. The analysis plan, choice of statistical test, assumptions, handling of repeated measurements, any covariate adjustment and any sensitivity analyses are not reported in the registry record. General statistical concepts cannot fill in those missing details. Without the results and methods, the strength, direction and precision of a treatment comparison cannot be evaluated from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, and the primary outcome is described as having several categories or time points rather than being reduced to one comparison. The primary endpoint is assessed at baseline, Day 1 and Day 14. Considering multiple outcomes, time points or comparisons can raise a multiplicity issue: in general, the more hypotheses examined, the greater the chance that at least one apparently notable result arises by chance if each is assessed separately. Statistical plans may address this through prespecification, adjustment or a hierarchy of questions. The registry record does not report a multiplicity strategy, so it is not possible to determine how multiple comparisons were handled.

The record defines the pharmacodynamic set as safety-set participants with sufficient plasma, serum or cerebrospinal fluid data for derivation of at least one pharmacodynamic parameter. It also states that a participant’s pharmacodynamic parameter results were not included if the concentration profile contained three or fewer data points. This is a stated rule for including parameter results; it does not reveal how many participants met the rule for the primary endpoint on each assessment day. Those counts are not reported in the registry record.

In general, missing measurements can reduce the information available and may affect estimates if the reasons for missingness are related to outcomes or treatment. Appropriate handling depends on the design, the extent and pattern of missing data, and assumptions about why values are missing. The record does not describe imputation, a model for incomplete repeated measurements, or sensitivity analyses. It also does not report endpoint-specific analysis populations or the number of participants contributing data to each time point.

The pharmacodynamic-set definition is not the same as a complete description of the analysis population for every endpoint. The registry record does not report how many participants were randomized, treated or included in each primary endpoint analysis beyond the enrollment and safety figures recorded elsewhere. No further missing-data or analysis-population details are reported.

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 non-serious adverse event terms

The posted serious adverse-event figures list 12 participants at risk in the vortioxetine group and 5 in the placebo group. Serious adverse events affected zero participants in each group. The record lists no serious adverse-event terms. These are counts of participants affected, not counts of event episodes, and the registry record does not provide additional detail about event definitions or timing.

The separate other-adverse-event figures list 11 affected participants in the vortioxetine group and 4 in the placebo group, with 12 and 5 participants at risk, respectively. These figures describe what was posted for that category; the record does not provide a statistical comparison, event-level details or an assessment of causal relationship. They should not be treated as a substitute for the missing primary pharmacodynamic results.

Death counts are not reported in the registry record. A zero count for serious events in the posted groups is a descriptive finding for those recorded participants, not proof that no serious events could occur in other settings or populations. The small enrollment and short treatment schedule also limit how much can be inferred about uncommon or longer-term events. The safety figures should be read as registry counts, without extrapolating beyond the participants and period described.

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

The record establishes that this was a randomized, single-blind, placebo-controlled Phase 1 study in healthy male adults, with oral vortioxetine 20 mg once daily for up to 14 days. It specifies a primary pharmacodynamic endpoint: plasma serotonin AUEC over 24 hours, assessed at baseline, Day 1 and Day 14. It also posts participant counts for serious and other adverse-event categories. These details clarify what the study set out to assess and how its primary measurement was framed.

The record does not report numerical primary endpoint results, treatment contrasts, confidence intervals or p-values. As a result, it does not show the direction or magnitude of a difference in plasma serotonin exposure, nor how precisely such a difference might have been estimated. The study purpose and endpoint name cannot substitute for those missing results. Statistical significance and clinical importance cannot be inferred from the design description alone.

The posted serious adverse-event counts are zero affected participants in each group, while other adverse events are recorded for 11 participants in the vortioxetine group and 4 in the placebo group. Death counts are not reported in the registry record. These descriptive safety figures do not, by themselves, establish causation or support a comparative safety conclusion, and they do not answer the pharmacodynamic question.

In general, a Phase 1 study can characterize early pharmacodynamic, pharmacokinetic and safety questions under the conditions studied. This record identifies those aims, but its available numerical results are insufficient to assess the primary endpoint. The enrollment of 17 and the specified healthy male population also delimit the scope of what could be learned from this study. Findings, if available elsewhere, would need to be interpreted in light of the actual analysis, its uncertainty and the population studied; those details are not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable for a distinction between a detailed measurement schedule and the absence of posted endpoint results. The registry specifies plasma serotonin AUEC over a 24-hour interval and lists sampling from predose through 24 hours after dosing. It identifies three assessment occasions: baseline, Day 1 and Day 14. That level of measurement detail makes the intended endpoint understandable, but it is not enough to evaluate the treatment contrast without the numerical summaries and analysis.

The randomized, parallel-group, placebo-controlled design frames a comparison between assigned groups. In general, randomization is valuable because it can reduce systematic baseline differences, while a placebo comparator provides a reference under the study conditions. A design description does not establish how well those aims were implemented or what the results were. The registry record does not provide allocation procedures, the identity of those masked or the statistical analysis plan.

The primary outcome’s several time points also illustrate why the target comparison needs to be clear. A result at Day 1 may address a different stage of dosing from one at Day 14, and the relationship among those results matters. The registry record does not report a multiplicity approach or analyses connecting the assessments. The record’s statement that the outcome was not reduced to one comparison underscores that no single treatment-effect summary is available in the registry record.

Finally, the record distinguishes an endpoint population rule from a complete analysis report. It defines the pharmacodynamic set and excludes parameter results when profiles have three or fewer data points, yet does not give endpoint-specific sample counts. That makes the handling of available measurements partly visible while leaving the actual analyzed population and the consequences of missing data unknown. These gaps are important for readers assessing precision and reproducibility.

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 main limitation for statistical interpretation is that the registry record does not report the primary endpoint values or analyses. There is no posted group mean, standard deviation, treatment contrast, confidence interval or p-value for plasma serotonin AUEC. The direction, size and precision of any difference therefore cannot be assessed. The record also does not give the analysis method or statistical plan, so assumptions and adjustment choices cannot be reviewed.

The study enrolled 17 participants and was restricted to healthy male adults. The posted safety counts list 12 participants at risk in the vortioxetine group and 5 in the placebo group. Those details describe the study but do not establish how many participants contributed to each primary endpoint assessment. The number analyzed at each time point is not reported in the registry record.

Although the pharmacodynamic-set definition includes a threshold based on the number of concentration-profile data points, the record does not describe other missing-data handling, reasons for missing measurements or sensitivity analyses. It also does not report how multiple outcomes and the primary endpoint’s several time points were addressed statistically. These omissions limit assessment of bias, uncertainty and the robustness of any potential findings.

The record identifies the design as single-blind but does not state who was masked or how masking was maintained. It names the study as single-center, but provides no further detail about study conduct in the registry record by the registry record. Death counts are not reported. Serious and other adverse-event counts are posted, but event-level details and comparative analyses are not. These limitations require a cautious, descriptive reading rather than conclusions beyond the recorded information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effects of Vortioxetine (Lu AA21004) on the Concentrations of Selected Neurotransmitters in Healthy Male Adults — NCT01299805.
• Registry record last updated 2013-12-13; status last verified 2013-10.
• Results first posted 2013-12-13.
• 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

The registry describes NCT01299805 as a completed Phase 1, randomized, single-blind, single-center, placebo-controlled, parallel-group study sponsored by Takeda. Enrollment was 17. The recorded study start was 2011-03 and primary completion was 2011-06. Participants received vortioxetine 20 mg or matching placebo orally once daily for up to 14 days.

The primary endpoint was plasma 5-hydroxytryptamine AUEC from time zero to 24 hours after dosing, measured at baseline, Day 1 and Day 14. Blood sampling was scheduled predose and at 1, 2, 4, 8, 12, 16 and 24 hours post-dose. The registry lists 12 outcome measures and zero analyses. Numerical primary endpoint results and the statistical analysis plan are not reported in the registry record.

Serious adverse events affected zero participants in each posted group. Other adverse events affected 11 participants in the vortioxetine group and 4 in the placebo group. Death counts are not reported in the registry record.