Efficacy and Safety of Vortioxetine (Lu AA21004) for Treatment of Generalized Anxiety Disorder in Adults.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Vortioxetine (Lu AA21004) for Treatment of Generalized Anxiety Disorder in Adults. (NCT00744627), a randomized phase 3 study. The primary outcome is Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8.

2. Clinical Question

The primary outcome was a continuous score change, analyzed as a least-squares mean. Because lower HAM-A scores indicate fewer or less severe symptoms, a more negative change represents a larger reduction from baseline. The posted least-squares mean difference was defined for vortioxetine relative to placebo, and was negative.

This question concerns the average difference between the randomized treatment groups under the trial’s analysis, not the experience of every participant. The record also describes secondary outcomes covering anxiety, global improvement, disability, response, and health-related functioning. Those outcomes add context to the primary comparison, but they do not replace the prespecified primary endpoint.

The registry record identifies the study as completed and lists 301 enrolled participants. The primary analysis population is defined by treatment exposure and availability of a post-baseline assessment; it is not simply described as every enrolled participant.

3. Trial Design

This was a randomized, parallel-group, placebo-controlled phase 3 study with quadruple masking. The official title describes it as a fixed-dose comparison, and the treatment arms listed in the record are placebo and vortioxetine 5 mg. Vortioxetine was taken orally once daily for up to 8 weeks; the placebo capsules were designed to match it and were also taken once daily for up to 8 weeks.

The study’s stated purpose was to evaluate the efficacy and safety of once-daily vortioxetine in adults with generalized anxiety disorder. The registry record lists Takeda as the sponsor, a start date of 2008-09, primary completion in 2009-07, and completed status. The record does not report the sites, geographic locations, participant demographic profile, or details of the randomization procedure.

For the primary outcome, the registry reports least-squares means and standard errors for the two groups. The primary analysis used a mixed model for repeated measurements (MMRM) based on observed cases. The Full Analysis Set included randomized patients who received at least 1 dose and had at least 1 post-baseline primary efficacy assessment. Thus, the analysis was not described as an intention-to-treat analysis that included every randomized participant regardless of post-baseline data.

The primary outcome was change from baseline in HAM-A total score at Week 8. The registry lists 25 outcome measures and 7 analyses. It does not report the original sample-size justification or the full statistical analysis plan, so the rationale for the planned enrollment and the prespecified handling of every outcome cannot be established from 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: Participants with a diagnosis of generalized anxiety disorder were enrolled equally in one of two treatment groups, once a day placebo or 5 mg vortioxetine.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set included all patients who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline value for assessment of primary efficacy. A mixed model for repeated measurements (MMRM) based on observed cases was used.

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 Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8, measured over Baseline to Week 8.

The primary endpoint was change from baseline to Week 8 in total score on the Hamilton Anxiety Scale (HAM-A). The HAM-A is a 14-item rating scale covering anxious mood, tension, fear, insomnia, cognitive symptoms, depressed mood, behavior at interview, and several bodily symptom domains. Each item is rated from 0 (absent) to 4 (maximum severity), and total scores range from 0 to 56.

The registry describes scores below 17 as mild severity, 18-24 as mild to moderate, and 25-30 as moderate to severe; scores above 30 are described as rare and indicative of very severe anxiety. This gives the scale a way to represent symptom severity across multiple aspects of anxiety rather than relying on a single symptom or question.

Change from baseline focuses the comparison on how scores moved during the treatment period. In this trial, more negative change indicates a larger reduction in total score. The Week 8 least-squares means were estimated with an MMRM that included baseline-by-week, center, week, and week-by-treatment factors. Least-squares means are model-based group estimates; they are not necessarily identical to unadjusted arithmetic averages.

The endpoint is useful for comparing average symptom-score changes between randomized groups. It does not, by itself, establish how each participant felt, whether changes were noticeable to participants, or whether all aspects of generalized anxiety changed to the same extent.

7. Results Posted in the Registry

• Vortioxetine 5 mg: mean -14.30 versus -10.49 on control; difference -3.81 (95% CI -5.74 to -1.88), standardized effect d = -0.49; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Week 8

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Vortioxetine 5 mg: mean -6.49 versus -4.20 on control; difference -2.29 (95% CI -3.38 to -1.20), standardized effect d = -0.51; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Vortioxetine 5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Clinical Global Impression Scale-Global Improvement at Week 8

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Vortioxetine 5 mg: mean 2.19 versus 2.66 on control; difference -0.47 (95% CI -0.74 to -0.20), standardized effect d = -0.43; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Vortioxetine 5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Vortioxetine 5 mg: mean -8.10 versus -6.14 on control; difference -1.96 (95% CI -3.74 to -0.18), standardized effect d = -0.30; z-test p = 0.031.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Vortioxetine 5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry record lists secondary outcomes spanning anxiety symptoms, global improvement, disability, response, and health-related functioning. It reports 24 secondary outcomes. Among the secondary endpoints with arm estimates and comparisons described in detail, the treatment contrasts are negative and the reported p-values are < 0.001, < 0.001, and 0.031. This direction is broadly consistent with the negative primary contrast, but each endpoint measures a different aspect of outcome and should not be treated as an interchangeable replication of HAM-A.

The record identifies secondary measures including the HAD anxiety subscale, Clinical Global Impression Scale-Global Improvement, and Sheehan Disability Scale total score at Week 8, alongside other measures. Their results can add context to the primary symptom-scale comparison. However, a consistent direction across different measures does not establish that every outcome improved to the same degree, nor does it establish a shared clinical meaning for the numerical contrasts.

In general, testing many outcomes creates more opportunities for small p-values to occur by chance. A multiplicity procedure can control the overall false-positive risk across a defined family of tests, but the registry record does not report whether such an adjustment was planned or applied. The reported secondary p-values should therefore be read as unadjusted unless the registry documents otherwise. They carry less confirmatory weight than the primary result, which is the principal endpoint identified for the trial.

The registry record does not provide detailed statistical estimates for every listed secondary outcome in the material summarized in the outcome results. Consequently, a complete comparison of all secondary measures, their missingness, and any prespecified ordering cannot be established. The secondary results are best treated as supportive context, not as a substitute for the primary analysis or as proof of a broad effect across all measured domains.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Week 8
• Clinical Global Impression Scale-Global Improvement at Week 8
• Change From Baseline in Sheehan Disability Scale (SDS) Total Score at Week 8
• Percentage of Responders in HAM-A Total Score at Week 8
• Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score at Week 8 in Participants With Baseline HAM-A ≥25
• Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Social Functioning Subscore at Week 8
• Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score at Other Weeks Assessed
• Change From Baseline in the Hospital Anxiety and Depression (HAD) Anxiety Subscale at Other Weeks Assessed

9. Statistical Interpretation

10. Statistical Methods Explained

The primary analysis compared model-based changes in HAM-A total score from baseline to Week 8. The registry reports least-squares means, standard errors, a least-squares mean difference, a 95% confidence interval, and a p-value. The stated method was a mixed model for repeated measurements (MMRM), based on observed cases.

What does a least-squares mean represent?

In general, a least-squares mean is a model-based estimate of a group mean after accounting for factors included in the model. It can differ from a simple average of participant scores because the model uses the structure and covariates specified for the analysis. The registry states that the primary MMRM included baseline-by-week, center, week, and week-by-treatment as factors. The least-squares means therefore summarize the fitted model’s estimated group changes, rather than raw averages alone.

The treatment contrast compares those estimated means. For the primary endpoint, the reported difference was -3.81. A negative contrast means the estimated change was more negative in the vortioxetine 5 mg group than in the placebo group, given the reported comparison orientation. Since the endpoint is change from baseline, that direction corresponds to a larger average reduction in score.

Why use repeated-measures modeling?

In general, repeated-measures models can use observations collected at multiple assessment times while accounting for the fact that measurements from the same participant are related. They can estimate treatment differences over time and use the observed outcome data without requiring every participant to have a measurement at every time. The registry identifies MMRM as the method, but does not report the model’s covariance structure, estimation details, or all assumptions used in fitting it.

The primary analysis population was the Full Analysis Set, defined as randomized patients who received at least 1 dose and had at least 1 post-baseline primary efficacy assessment. The description says the MMRM was based on observed cases. In general, use of observed data does not make missingness irrelevant: the validity of a model-based estimate can depend on how missing assessments arose and on the model’s assumptions about the relationship between observed and missing outcomes. Those assumptions and sensitivity analyses for missing data are not reported in the registry record.

What do standard errors and p-values convey?

In general, a standard error describes the sampling uncertainty of an estimate. Smaller standard errors indicate greater precision under the model and data structure used. The reported primary standard errors were 0.697 for placebo and 0.695 for vortioxetine 5 mg. These are uncertainties around the estimated group means, not measures of the spread of individual participant scores.

A p-value measures how incompatible the observed data are with a specified null hypothesis, under the analysis assumptions. The primary p-value was < 0.001. It is evidence against a zero treatment difference under the reported model, but it does not measure treatment magnitude, probability of benefit, or clinical importance. It also does not address all possible sources of bias or model misspecification.

How does the independent recalculation differ?

The unadjusted recalculation uses the posted group summary statistics to obtain an approximate contrast and confidence interval. It is not a replacement for the sponsor’s MMRM analysis: the trial’s reported estimate comes from the stated repeated-measures model, while the recalculation uses summary statistics and an approximate standard deviation. The two approaches answer closely related but not identical statistical questions. The sponsor’s reported analysis is the trial analysis to prioritize when describing the registry result.

More generally, a recalculation from group summaries cannot reproduce every feature of a participant-level longitudinal model. It cannot inspect individual trajectories, verify model assumptions, account independently for the timing of missing observations, or reproduce the original model specification in full. It is best read as a transparent check on the scale and direction of the posted contrast, not as a second analysis with the same evidentiary status.

What is not documented?

The registry record does not report the full statistical analysis plan, the planned hierarchy among outcomes, whether any interim analyses were conducted, the randomization sequence or concealment procedure, or detailed missing-data sensitivity analyses. It also does not report the original sample-size justification. These omissions limit independent assessment of which analyses were planned in advance and how the study handled all possible deviations from complete follow-up.

General statistical interpretation should keep the design, analysis, and uncertainty together: randomization supports a group comparison, the MMRM estimates the primary contrast using observed repeated measurements, and the confidence interval describes uncertainty conditional on the model. None of these elements removes the need to consider missing data, multiplicity, the treatment period, or the limits of the population represented by the trial.

11. Confidence Intervals and Precision

The sponsor-reported primary 95% confidence interval for the least-squares mean difference was -5.74 to -1.88. The recalculated unadjusted interval was -5.739 to -1.881. Both intervals are below zero and describe a range of negative between-group differences compatible with the respective analyses and their assumptions. The sponsor-reported estimate was -3.81; the recalculated estimate was also -3.81.

In general, a confidence interval communicates both the direction and precision of an estimate. A narrower interval indicates more precision than a wider interval, all else being equal. The interval does not mean there is a 95% probability that the true difference lies inside these particular limits. Rather, the confidence level describes the long-run performance of the interval procedure under its assumptions.

The primary interval excludes zero, which is consistent with the reported p-value of < 0.001. The interval also helps convey the range of effect sizes compatible with the analysis; it is more informative about magnitude than a p-value alone. Its limits remain conditional on the model, the analyzed population, and the observed data used in the MMRM.

The standard errors describe uncertainty around the separate least-squares means, while the confidence interval describes uncertainty around their contrast. They should not be confused with the variability of scores among individuals. The registry record does not provide participant-level distributions or additional intervals for all outcome measures, so the precision of individual responses and the consistency of effects across subgroups cannot be assessed from these summaries.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are expressed as participants per arm, not as total events. They are illustrations based on the observed primary effect, not the trial’s original design calculations. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect.

For planning around 100% of the observed effect, the illustration gives 67 participants per arm for 80% power and 90 participants per arm for 90% power. For planning around 75% of the observed effect, it gives 119 participants per arm for 80% power and 159 participants per arm for 90% power. For planning around 50% of the observed effect, it gives 267 participants per arm for 80% power and 357 participants per arm for 90% power.

In plain terms, 80% power is the probability of detecting an effect of the assumed size at the stated significance level if that effect is present and the planning assumptions hold. The 90% column uses a higher target probability of detection. A smaller effect is harder to distinguish from random variation, so planning for a smaller fraction of the observed effect requires more participants per arm. These figures are not observed power.

The original trial’s sample-size assumptions and justification are not reported in the registry record. The planning figures should therefore be read as hypothetical design guidance based on the posted effect estimate, not as evidence about what the investigators planned or whether the completed trial was adequately powered for every endpoint.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -3.810; pooled standard deviation σ = 7.844.
2. n = 2 × (1.96 + 0.842)² × 7.844² / -3.810² = 66.5, rounded up to 67 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -3.81                      # observed difference in means
sigma <- 7.84359665789528                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(744627)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 67 (80% power), 90 (90% power)
 75% of observed effect: n per arm = 119 (80% power), 159 (90% power)
 50% of observed effect: n per arm = 267 (80% power), 357 (90% power)
power.t.test: 67.5 
Simulated power at n = 67 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor-reported primary MMRM analysis gave a least-squares mean difference of -3.81, with a 95% confidence interval of -5.74 to -1.88 and p < 0.001. The unadjusted recalculation from the posted summary statistics gave a difference of -3.81, with an approximate 95% interval of -5.739 to -1.881 and p < 0.001. The point estimates agree, and the interval limits are close, with small differences in rounding and method.

The registry’s sponsor analysis is the primary result to use when describing the trial. It uses the stated mixed model for repeated measurements, whereas the recalculation is a simple unadjusted check based on summary statistics and an approximate standard deviation. It cannot reproduce the full longitudinal model or independently evaluate its assumptions.

The record does not flag a discrepancy between the posted analysis and recalculation. Their agreement supports the direction and approximate size of the primary contrast, but it does not make the recalculation equivalent to the trial’s original analysis or provide a separate confirmation based on participant-level data.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and lists 25 outcome measures, including 24 secondary outcomes. It reports 7 analyses. Multiple outcomes and analyses raise a multiplicity question: when many hypotheses are tested, the chance of at least one apparently unusual result can increase even if none of the underlying effects is real. In general, prespecifying a primary outcome and controlling the testing family can help limit this concern.

Whether the sponsor used a formal multiplicity adjustment for secondary outcomes is not reported in the registry record. The record also does not report a testing hierarchy or a detailed statistical analysis plan. The primary p-value should be distinguished from the secondary p-values, for which no adjustment is documented. Interim analyses are not reported in the registry record.

The primary population was the Full Analysis Set, defined as randomized patients who received at least 1 dose and had at least 1 post-baseline primary efficacy assessment. The primary MMRM was based on observed cases. This definition excludes randomized participants without a qualifying post-baseline assessment from the stated primary analysis population. The registry does not report how many participants lacked such assessments or the reasons for missing data.

In general, repeated-measures models can use the available observations, but their interpretation depends on assumptions about the data-generating and missingness processes. The registry record does not report a missing-data sensitivity analysis, the specific assumptions used for missing outcomes, or whether another imputation approach was applied. It also does not give a complete accounting of withdrawals or endpoint-specific missingness. These gaps make it difficult to assess how robust the primary result is to alternative missing-data assumptions.

The record’s definition of the analysis population and its statement that observed cases were used are useful, but they do not fully describe how missingness affected precision or potential bias. The record also does not report whether all randomized participants were included in any additional efficacy analysis. These are limitations of the documentation available in the registry record, not evidence that a particular analysis was or was not conducted.

16. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: intervertebral disc protrusion (0.7%).

The registry lists serious adverse events among 150 participants at risk in the placebo group and 150 at risk in the vortioxetine 5 mg group. There was 1 serious adverse event in the placebo group and 0 in the vortioxetine group. These are the serious-event counts reported for the groups; they do not, by themselves, establish whether an event was caused by treatment.

Other adverse events were reported for 36 participants in the placebo group and 48 in the vortioxetine 5 mg group, with 150 at risk in each group. The registry lists intervertebral disc protrusion at 0.7% among the top serious adverse event terms. Death counts are not reported in the registry record.

In general, safety counts need to be read in light of the observation period, definitions, and how events were collected. Treatment was described as once daily for up to 8 weeks, so these figures do not characterize longer-term safety. The registry summary does not provide event severity, timing, recurrence, exposure-adjusted rates, or enough clinical detail to attribute individual events to study treatment. Small counts also make comparisons imprecise. These data describe reported events during the study, not a definitive comparative safety profile.

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

The primary result shows a statistically significant difference in mean change from baseline to Week 8 in HAM-A total score between the randomized groups under the reported MMRM. The vortioxetine 5 mg group had a more negative estimated change than the placebo group, with a least-squares mean difference of -3.81 and a sponsor-reported 95% confidence interval of -5.74 to -1.88. This is evidence about an average score contrast in the trial’s stated analysis population.

It does not mean that every participant had a larger reduction, that all participants improved, or that a given individual would experience the group-average difference. The registry record does not report the distribution of individual changes, responder counts for the primary outcome, or a clinical threshold that would establish the practical importance of the observed contrast. A statistically significant result and a clinically meaningful result are related but distinct questions.

The result also does not establish persistence beyond the assessment period. The intervention was taken once daily for up to 8 weeks, and the primary endpoint was measured at Week 8. Longer-term outcomes are not reported in the primary result. Nor does the primary endpoint answer every question about functioning, quality of life, or safety.

Randomization and masking strengthen the intended comparison by reducing some sources of systematic difference between groups, but the registry record does not provide every detail needed to evaluate implementation. Interpretation also depends on the observed-case MMRM and its assumptions. Missing-data sensitivity analyses and detailed multiplicity procedures are not reported in the registry record.

The evidence should therefore be described narrowly: the posted analysis estimates a greater average Week 8 HAM-A reduction in the vortioxetine 5 mg group than in the placebo group, with the reported interval excluding zero. It should not be expanded into a claim about universal response, long-term outcomes, effects in populations not represented by the trial, or individual treatment decisions.

18. Why This Trial Matters Statistically

This trial illustrates why a treatment comparison needs more than a statement that one group’s score fell. The placebo group also had a negative mean change, so the central statistical question is the difference between randomized groups, not whether either group improved from baseline in isolation. The primary MMRM contrast addresses that comparative question.

It also shows the role of uncertainty alongside an estimate. The sponsor reported a difference of -3.81 with a 95% confidence interval from -5.74 to -1.88. The interval communicates a range of values compatible with the model and observed data, while the p-value summarizes evidence against a zero-difference hypothesis. Neither statistic alone establishes clinical importance or predicts an individual outcome.

The repeated-measures approach is relevant because the primary analysis used observations over time and a model with stated factors. At the same time, the record’s observed-case description makes missing-data assumptions important. Without reported sensitivity analyses, readers cannot fully assess how alternative assumptions about missing outcomes might change the estimate.

The registry also makes the distinction between a primary result and a set of secondary findings important. Several secondary comparisons point in the same numerical direction, but the multiplicity adjustment and outcome hierarchy are not reported. That limits the strength of conclusions drawn from secondary p-values.

Finally, sample-size planning based on an observed effect is not evidence of the trial’s original design rationale or of observed power. Planning illustrations can show how assumptions about a smaller target effect translate into larger required group sizes, but the record does not report the original sample-size justification. Together, these points demonstrate how effect estimates, uncertainty, analysis choices, and documentation gaps all shape a responsible reading of a clinical trial.

19. 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 trial evaluated one listed vortioxetine dose, 5 mg once daily, against placebo. The record does not provide a dose-ranging comparison, so this result cannot describe how other doses compare. Treatment was given for up to 8 weeks, and the primary outcome was assessed at Week 8; longer-term efficacy and safety are not reported in the primary results.

The primary analysis used a Full Analysis Set requiring at least 1 post-baseline primary efficacy assessment and an observed-case MMRM. The registry does not report the number or reasons for missing assessments, detailed withdrawal information, or sensitivity analyses under alternative missing-data assumptions. These omissions constrain assessment of potential bias from incomplete follow-up.

The registry does not report the original sample-size justification, full analysis plan, interim analyses, or a multiplicity procedure for secondary outcomes. This makes it difficult to establish how the analyses were prioritized and whether the secondary testing family was controlled. The registry lists many outcomes, but detailed results are not available for every measure in the described results.

Information about participant demographics, study locations, and representation of clinically relevant subgroups is not reported in the registry record. That limits assessment of how well the trial population represents other adult populations with generalized anxiety disorder. The record also does not provide the distributions of individual HAM-A changes or a threshold for clinically meaningful change, so the range of individual experiences and practical importance cannot be determined from the group means alone.

Safety reporting is summarized by counts, with limited detail on event timing, severity, exposure, and attribution. The registry record does not report deaths. These reporting limitations mean the safety counts should not be treated as a complete account of comparative risk.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety of Vortioxetine (Lu AA21004) for Treatment of Generalized Anxiety Disorder in Adults. — NCT00744627.
• Registry record last updated 2014-03-03; status last verified 2014-01.
• Results first posted 2014-03-03.
• 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.

23. Record Summary

The registry record describes a completed, randomized, quadruple-masked, parallel-group phase 3 study of vortioxetine 5 mg versus matching placebo in adults with generalized anxiety disorder. Both treatments were taken orally once daily for up to 8 weeks. The record lists Takeda as sponsor and 301 enrolled participants.

The primary outcome was change from baseline to Week 8 in HAM-A total score. The analysis used a mixed model for repeated measurements in a Full Analysis Set defined by randomization, receipt of at least 1 dose, and at least 1 post-baseline primary efficacy assessment. The sponsor-reported least-squares mean difference was -3.81, with a 95% confidence interval of -5.74 to -1.88 and p < 0.001.

The registry lists 24 secondary outcomes, but multiplicity procedures, the original sample-size justification, detailed missing-data sensitivity analyses, and longer-term outcomes are not reported in the registry record. The result is an estimate of the average Week 8 treatment-group contrast under the stated analysis, not an individual prediction or a complete account of clinical importance and safety.