This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Safety and Tolerability of Vortioxetine (LuAA21004) - Open Label Extension Study (NCT01152996), a na phase 3 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01152996 |
| Phase | Phase 3 |
| Condition | Depressive Disorder, Major |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 1075 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Takeda |
| Results posted | Yes |
2. Clinical Question
Population
Participants with major depressive disorder entered a phase 3, long-term extension study. The registry lists an enrollment of 1075 and identifies the safety set for the primary outcome.
Intervention
Participants received vortioxetine once daily. The described regimen began with 10 mg for the first week, followed by an increase to 15 mg or 20 mg for up to 51 weeks.
Comparator
No concurrent comparator is reported. The study is described as open-label and single-group, and allocation is recorded as NA.
Primary question
The primary endpoint asks how many participants in the safety set had treatment-emergent adverse events meeting a frequency threshold of at least 5% over the 52 week period.
This is principally a question about safety and tolerability during extended exposure, rather than a randomized estimate of treatment effect. The endpoint definition includes events that begin after study drug is received and within 30 days after the last dose. It also includes some events present before dosing if they increase in severity after dosing starts.
The registry also lists changes from baseline in depression symptoms, anxiety symptoms, illness severity, and functioning as secondary outcomes. These outcomes include the MADRS, HAM-A, CGI-S, and SDS measures. Their presence does not establish that a change occurred or that any observed change was caused by treatment. Results for these secondary measures are not reported in the registry record.
3. Trial Design
The registry describes a phase 3, long-term, open-label, flexible-dose extension study of vortioxetine (Lu AA21004) in participants with major depressive disorder. It is a single-group study, with allocation recorded as NA and masking recorded as none. These features mean that the posted design does not include random assignment to different treatment groups or a blinded control group.
The treatment description starts with vortioxetine 10 mg, taken orally once daily for the first week. The dose was then increased to 15 mg or 20 mg once daily, for up to 51 weeks. The primary endpoint timeframe is described as the 52 week period. The registry gives no further details about how the dose was selected for individual participants or how dose changes were managed; those details are not reported in the registry record.
The registry lists an enrollment of 1075. For the primary endpoint, the population is identified as the safety set; the adverse-event summary lists 1073 participants at risk. The registry does not explain the relationship between enrollment and the safety-set count, so reasons for the difference are not reported in the registry record.
The study is marked completed, with a start date of 2010-09 and primary completion date of 2013-05. These registry dates describe the study record and do not, by themselves, establish when individual participants began or finished treatment.
Secondary outcomes cover changes from baseline in depression, anxiety, global illness severity, and disability or functioning. The registry lists 10 outcome measures and 0 analyses. It does not report a randomized comparison, and the single-group design cannot separate treatment-associated changes from changes that might occur over time or for other reasons.
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: Patients who completed Studies LuAA21004\_315 (NCT01153009), LuAA21004\_316 (NCT01163266), and LuAA21004\_317 (NCT01179516) and were willing to continue, and judged by the investigator to benefit from a 52-week continuation treatment with Lu AA21004, were enrolled and received flexible doses of study drug, based on patient response and tolerability.
Overall Study
| Stage | Vortioxetine |
|---|---|
| STARTED | 1075 |
| Treated | 1073 |
| COMPLETED | 538 |
| NOT COMPLETED | 537 |
Reasons for not completing this period:
| Reason | Vortioxetine |
|---|---|
| Withdrawal by Subject | 142 |
| Adverse Event | 115 |
| Lost to Follow-up | 112 |
| Lack of Efficacy | 68 |
| Noncompliance | 41 |
| Other | 36 |
| Protocol Violation | 22 |
| Elevated liver enzymes | 1 |
Analysis population for the primary outcome, as defined in the registry: Safety 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.
| Characteristic | Unit | Vortioxetine |
|---|---|---|
| Participants analysed | 1075 | |
| Age, Continuous | years | 44.5 (SD 12.05) |
| Sex: Female, Male: Female | Participants | 790 |
| Sex: Female, Male: Male | Participants | 285 |
| Race/Ethnicity, Customized: Caucasian (or White, including Hispanic) | participants | 813 |
| Race/Ethnicity, Customized: Black/African American | participants | 249 |
| Race/Ethnicity, Customized: Asian | participants | 7 |
| Race/Ethnicity, Customized: American Indian/Alaska Native | participants | 5 |
| Race/Ethnicity, Customized: Native Hawaiian/Other Pacific Islander | participants | 1 |
| Race/Ethnicity, Customized: Hispanic or Latino | participants | 104 |
| Race/Ethnicity, Customized: Non-Hispanic and Non-Latino | participants | 971 |
| Weight | kg) | 88.77 (SD 24.160) |
| Body Mass Index (BMI) | kg/m^2 | 31.60 (SD 8.061) |
| Height | cm | 167.44 (SD 9.456) |
| Montgomery Åsberg Depression Rating Scale (MADRS) total score | scores on a scale | 20.0 (SD 10.70) |
| Hamilton Anxiety Scale (HAM-A) total score | scores on a scale | 11.6 (SD 6.65) |
| Clinical Global Impression - Severity scale (CGI-S) score | scores on a scale | 3.3 (SD 1.21) |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%, measured over Over the 52 week period.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the number of participants with treatment-emergent adverse events at a frequency threshold of at least 5%, over the 52 week period. It is a count-based safety measure: it describes how many participants experienced qualifying events, rather than the severity or duration of every event or a change in a clinical scale.
The registry defines a treatment-emergent adverse event as an event that begins after study drug is received and within 30 days after the last dose. An event that was present before the first dose can also qualify if it becomes more severe after dosing starts. This definition makes the endpoint about events arising or worsening during the specified treatment-emergent window, not necessarily events caused by the drug.
A frequency threshold can help focus attention on events that occur often enough to meet the stated criterion. It does not replace review of less frequent events, serious events, timing, severity, or clinical context. The registry record identifies the endpoint but does not report the qualifying primary-endpoint result by event term. That result is not reported in the registry record.
Counts are useful for describing the observed experience in the study population. In a single-group, open-label study, however, they do not provide a controlled estimate of how much risk is attributable to treatment. A comparator group and a prespecified comparative analysis would be needed for that kind of estimate.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted adverse-event summary lists 29 participants with serious adverse events and 854 participants with other adverse events, with 1073 at risk in each summary. These are descriptive counts from the vortioxetine group. They do not establish whether the events were caused by treatment, and they do not provide a comparison with an untreated or differently treated group.
The serious adverse-event term summaries include suicide attempt at 0.3%, acute cholecystitis at 0.2%, female breast cancer at 0.2%, atrial fibrillation at 0.1%, abdominal pain at 0.1%, and esophageal rupture at 0.1%. These are the percentages recorded for the listed terms. The registry record does not provide term-specific counts or the denominator details behind these percentages. The terms should therefore be read as reported frequency descriptions, not as comparative risks.
The primary endpoint asks for participants with treatment-emergent adverse events meeting a threshold of at least 5%. The adverse-event summary counts do not supply the event-by-event result for that threshold. The number meeting the primary endpoint, and the corresponding list of qualifying events, are not reported in the registry record.
The registry names several secondary outcomes based on changes from baseline, including symptom ratings and functioning measures. Their results, estimates of change, uncertainty intervals, and analyses are not reported in the registry record. Without those results, the listed outcomes cannot support a conclusion about the magnitude or precision of change.
In general, a count describes what was observed among participants included in the relevant analysis population. Its interpretation depends on who was followed, how events were elicited and classified, and whether participants contributed the same amount of observation time. The registry record does not report enough detail to assess these factors fully. In particular, it does not report event-specific observation time or a statistical comparison with another group.
The study's open-label, single-group design is suited to describing outcomes during the study's treatment period, but it does not control for time trends, expectations, changes in clinical care, or other influences. No causal conclusion should be drawn from the counts alone. The posted data describe events recorded during the study; they do not show what would have happened to the same participants under a different treatment or without treatment.
9. Statistical Methods Explained
The registry identifies the primary outcome as a count of participants with qualifying treatment-emergent adverse events. This is a binary outcome at the participant level: for a given event or endpoint definition, a participant either meets the criterion or does not. The resulting summary is a count, not a mean score. The registry record does not report a confidence interval, hypothesis test, or adjusted estimate for this primary endpoint.
What does a participant count describe?
In general, a participant count records whether a person met a defined event criterion during the observation window. It differs from an event count, which may count repeated occurrences in the same person. A participant-level count avoids treating repeated events in one participant as though they came from different people. But its interpretation still depends on the event definition, the time window, and how completely participants were observed.
Here, the endpoint definition is based on treatment emergence and includes a post-treatment window extending to 30 days after the last dose. It also includes certain pre-existing conditions that worsen after dosing begins. This definition establishes which events can qualify; it does not establish that the study drug caused them. The primary endpoint's stated frequency threshold is at least 5%, but the qualifying primary result is not reported in the registry record.
Why does the single-group design matter?
In general, a concurrent control group helps distinguish outcomes associated with one treatment from outcomes that might occur under another condition. Random allocation can make comparison groups more alike on average at the start of a study, while blinding can reduce some influences on reporting and assessment. These design features are not reported for this study: it is recorded as single-group, open-label, with allocation NA and masking none.
Without a concurrent comparator, the adverse-event counts are descriptive. They cannot estimate a treatment-versus-control difference. Nor can they determine whether an event would have occurred in the absence of treatment. The registry record does not report a comparative model or inferential analysis for these outcomes.
What does a confidence interval usually add?
In general, a confidence interval communicates uncertainty around an estimate under a statistical model. A narrower interval indicates greater precision under that model; a wider interval indicates more uncertainty. An interval does not correct for bias from a nonrandomized design, incomplete follow-up, or differences in event ascertainment. No confidence interval for the primary safety endpoint is reported in the registry record.
How should sample-size illustrations be read?
In general, a sample-size calculation is a planning exercise that asks how many participants a future study might need under stated assumptions. It is not a measure of the power actually achieved in a completed study. The registry's stated illustration assumptions refer to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of an observed effect. Those are illustration assumptions, not the design of this single-group trial. The registry record does not report the trial's own sample-size justification or a statistical plan supporting those assumptions.
For count outcomes, the distinction between participants and events matters. In general, repeated events in one person can create dependence among observations, so methods that treat every event as independent may understate uncertainty. The posted summary is expressed as participants with events, but the registry record does not report a model for recurrent events or a method for adjusting for differing observation time.
The registry lists 10 outcome measures and 0 analyses. This does not reveal whether analyses were performed outside the registry record; it means that no analysis results are listed in that record. Statistical methods, model specifications, and any adjustment strategy are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists a primary safety outcome and multiple secondary outcomes, including changes in depression symptoms, anxiety symptoms, illness severity, and functioning. When several outcomes are examined, the chance of at least one apparently notable result can increase if each is tested separately without a prespecified approach to multiplicity. In general, multiplicity methods can control that risk or organize which outcomes are confirmatory and which are exploratory. The registry record does not report a multiplicity strategy or a statistical analysis plan.
The listed secondary outcomes are not accompanied by results or analysis details in the registry record. It is therefore not possible to assess their estimates, uncertainty, or how any set of tests was handled. The registry lists 10 outcome measures and 0 analyses; this should not be interpreted as evidence that no analyses were conducted outside the record.
Missing-data methods are also not reported in the registry record. The record does not describe how participants who stopped treatment, missed assessments, or had incomplete follow-up were handled in outcome analyses. It also does not report sensitivity analyses for missing observations. These details matter because participants with less follow-up may have had less opportunity for an event to be recorded.
The primary outcome population is identified as the safety set, but the criteria defining that set are not reported in the registry record. The adverse-event summary lists 1073 at risk, while enrollment is 1075; the record does not explain the difference. No conclusion about exclusions or missing follow-up should be inferred from those counts alone.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Vortioxetine | 29 | 1073 | 2.7% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Vortioxetine | 854 of 1073 |
Most frequent serious adverse event terms
| Event term | Organ system | Vortioxetine |
|---|---|---|
| Suicide attempt | Psychiatric disorders | 3 of 1073 |
| Cholecystitis acute | Hepatobiliary disorders | 2 of 1073 |
| Breast cancer female | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 2 of 1073 |
| Atrial fibrillation | Cardiac disorders | 1 of 1073 |
| Abdominal pain | Gastrointestinal disorders | 1 of 1073 |
| Esophageal rupture | Gastrointestinal disorders | 1 of 1073 |
| Cholecystitis | Hepatobiliary disorders | 1 of 1073 |
| Cholelithiasis | Hepatobiliary disorders | 1 of 1073 |
| Anal abscess | Infections and infestations | 1 of 1073 |
| Latent syphilis | Infections and infestations | 1 of 1073 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Vortioxetine |
|---|---|---|
| Nausea | Gastrointestinal disorders | 258 of 1073 |
| Headache | Nervous system disorders | 136 of 1073 |
| Diarrhea | Gastrointestinal disorders | 80 of 1073 |
| Vomiting | Gastrointestinal disorders | 68 of 1073 |
| Nasopharyngitis | Infections and infestations | 68 of 1073 |
| Viral upper respiratory tract infection | Infections and infestations | 66 of 1073 |
| Constipation | Gastrointestinal disorders | 65 of 1073 |
| Weight increased | Investigations | 65 of 1073 |
| Upper respiratory tract infection | Infections and infestations | 60 of 1073 |
| Insomnia | Nervous system disorders | 56 of 1073 |
Serious events with the highest arm-level rate: suicide attempt (0.3%), cholecystitis acute (0.2%), breast cancer female (0.2%), atrial fibrillation (0.1%), abdominal pain (0.1%).
The serious adverse-event summary reports 29 participants affected, with 1073 at risk. The other adverse-event summary reports 854 participants affected, also with 1073 at risk. These are participant counts in the registry's vortioxetine group. They are not comparative estimates and do not indicate how many events each participant experienced.
The record lists serious-event terms with percentages: suicide attempt at 0.3%, acute cholecystitis at 0.2%, female breast cancer at 0.2%, atrial fibrillation at 0.1%, abdominal pain at 0.1%, and esophageal rupture at 0.1%. The registry does not report term-specific counts or the denominator details for these percentages. The percentages should not be used to infer a treatment-attributable risk or compared with an external population without compatible definitions and observation periods.
Seriousness and frequency are different aspects of safety. A serious event can be uncommon, and a frequently reported event need not be serious. In general, safety interpretation also considers event timing, clinical course, exposure duration, and whether an event led to treatment changes. Those details are not reported in the registry record. The listed summaries describe what was recorded, not whether vortioxetine caused each event.
12. What the Result Does, and Does Not, Mean
The registry describes extended, open-label exposure to vortioxetine among participants with major depressive disorder and reports adverse-event counts for the study group. It also specifies a primary safety endpoint based on treatment-emergent events meeting a frequency threshold. The primary endpoint's qualifying result is not reported in the registry record, so the endpoint cannot be fully evaluated from the posted results.
The serious and other adverse-event counts provide descriptive information about participants recorded as affected during the study. The listed serious-event percentages add detail about selected event terms. Neither the counts nor the percentages establish causality. Because there is no concurrent comparator, they also cannot show whether the observed experience differs from what would have occurred under another treatment or without treatment.
The registry lists secondary changes in symptom ratings and functioning, but does not report their results. The presence of these outcomes in the record does not establish improvement, worsening, or any particular size of change. Estimates and their precision are not reported in the registry record.
In general, an open-label extension can describe events and clinical measurements during continued follow-up, but interpretation depends on the population entering the extension, the completeness of follow-up, and the way outcomes were assessed. The registry record does not report enough information to evaluate all of those features. The listed enrollment and safety-set count also differ, and the reason is not reported in the registry record.
Accordingly, the posted data support a descriptive account of the recorded safety experience, not a comparative or causal conclusion. They do not establish the likelihood of an event for an individual, and they do not establish how the results would compare with another treatment or a different population.
13. Why This Trial Matters Statistically
This study is statistically informative as an example of the distinction between describing events and estimating comparative effects. The registry's single-group, open-label design produces observations about participants receiving vortioxetine, but it does not provide a randomized control group against which to estimate a treatment contrast. That distinction is central when interpreting adverse-event counts.
The primary outcome is framed as a participant count using a treatment-emergent definition and a frequency threshold. Such an endpoint requires clear event definitions and a specified observation window. The record supplies those features, including the window extending to 30 days after the last dose, but does not report the qualifying primary-endpoint result. This leaves the stated primary question unanswered by the posted result summary.
The record also illustrates why outcome listings and outcome results are not interchangeable. It names several symptom and functioning measures, yet does not provide their findings or statistical uncertainty. A list of planned or registered outcomes cannot establish the direction, magnitude, or precision of an effect.
Finally, the difference between enrollment and the number at risk in the adverse-event summaries highlights the importance of defining analysis populations and reporting participant flow. The reason for that difference is not reported in the registry record. Transparent reporting of who contributed to each endpoint, how missing follow-up was handled, and what analyses were used would help readers assess the completeness and precision of the evidence.
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 interpretation is the absence of a concurrent comparator. Because the study is single-group and open-label, the posted adverse-event summaries cannot estimate a treatment-versus-control difference or separate treatment-associated events from events that might occur for other reasons. The record does not report randomized allocation or masking.
The primary endpoint is specified, but its result by the stated frequency threshold is not reported in the registry record. The adverse-event summary gives overall counts for serious and other events, plus selected serious-event percentages, but does not provide a complete event-by-event account for the primary endpoint. Term-specific counts and denominator details for the listed percentages are not reported in the registry record.
The record lists enrollment of 1075 and 1073 at risk in the adverse-event summaries. It does not explain the difference or provide the safety-set criteria. Participant flow, the extent of follow-up, and reasons for missing observations are not reported in the registry record.
Methods for handling missing data, repeated events, and differences in observation time are not reported in the registry record. Nor are confidence intervals, hypothesis tests, adjusted analyses, or a multiplicity approach reported. The registry lists secondary outcomes but does not report their results.
The treatment is described as flexible-dose, with a starting dose and subsequent dose options. The record does not report how participants were assigned to the dose options, how often doses changed, or whether outcomes differed by dose. It also does not report the study's sample-size justification or detailed statistical plan. These omissions limit assessment of precision, completeness, and the scope of conclusions that can be drawn from the posted data.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Safety and Tolerability of Vortioxetine (LuAA21004) - Open Label Extension Study — NCT01152996.
- Registry record last updated 2014-05-28; status last verified 2014-04.
- Results first posted 2014-05-28.
- 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.
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18. Record Summary
The registry record describes NCT01152996, a completed phase 3, long-term, open-label, flexible-dose, single-group extension study of vortioxetine in participants with major depressive disorder. Enrollment is listed as 1075. Treatment began with 10 mg once daily for the first week, followed by 15 mg or 20 mg once daily for up to 51 weeks.
The primary endpoint is the number of participants with treatment-emergent adverse events meeting a frequency threshold of at least 5% over the 52 week period. Its qualifying result is not reported in the registry record. The adverse-event summary lists 29 participants with serious events and 854 with other events, with 1073 at risk in each summary. Selected serious-event terms are reported with percentages.
The record lists secondary symptom and functioning outcomes but does not report their results. A comparator, analysis details, missing-data methods, and the reason for the difference between enrollment and the safety-set count are not reported in the registry record.